RSSDI Textbook of Diabetes Mellitus Shashank R Joshi
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Abacavir 436
Abatacept 183
Abdomen 129
Abetalipoproteinemia 516
Abortion 711
spontaneous 216, 713, 720
Abscess
perinephric 424, 433, 490
periodontal 490
Acamprosate 831
Acanthosis nigricans 528, 529, 547
Acarbose 131, 657, 658, 735, 739
Acetate, active 69
Acetylcholine 343
Acetyl-coenzyme A 65-67, 69
Acidosis 209
hyperchloremic 304
metabolic 773
Acinar cells, pancreatic 778
Acinar parenchyma, loss of 55f
Acromegaly 44, 126, 127, 285
etiology of 127, 127b
treatment of 128, 128b
Acute coronary syndrome 165, 236, 385
Acute respiratory distress syndrome 309
Acute stroke 402
management of 402
Acylglycerol formation 66
Adaptor protein 170
Addison's disease 86, 94
Adeno-associated viral-delivery methods 113
Adenocarcinoma 194, 248
Adenomas
familial isolated pituitary 127
pituitary 127
Adenosine
diphosphate 68, 69, 632
monophosphate 69
triphosphate 65f, 68f, 632, 633
sensitive potassium 105
Adipocyte 73, 78
derived bioactive metabolites 138
hypertrophy 100
triglyceride, breakdown of 77
Adipocytokines, proinflammatory 138
Adipokine
dysregulation of 484
receptors 135
Adiponectin 248, 513
Adipose
derived stem cells 821
tissue 62, 72, 73, 97, 133, 290, 778, 818, 837
macrophages 819
Adiposity, visceral 256
Adjuvant aluminum hydroxide 801
Adrenal cortex, glucocorticoids secreting tumor of 126
Adrenal disease 276
Adrenal insufficiency 343
Adrenal medulla 129
function 129
Adrenaline 48, 126
Adrenergic symptoms 229
Adrenocorticotropic hormone
secreting tumors 127
serum 127
stimulation testing 276
Adrenocorticotropin 126
Advanced glycation end products 109, 112, 131, 143, 490
production of 142
Aerobic dancing 580
Aerobic exercise 574
intensity of 574
Aerobic fitness 574
Agenesis
congenital pancreatic 194
pancreatic 171
renal 209
Agranulocytosis 637
Alanine 121
transaminase 426
Albiglutide 684, 685
Albumin-to-creatinine ratio 383, 699
Albuminuria 360
evaluation of 359
Alcohol 558, 566, 751, 752
abuse 195
consumption 232, 385, 516, 546, 752
effects of 751, 752
moderate 320
dependence, neurobiology of 752
intake
high 624
moderation in 385
use disorders identification test 830
Alcoholism 42, 753
Aldosteronoma 44
Alendronate 486
Aliskiren 360
Alkali therapy 305
Alkalinization reduces oxygen delivery, rapid 308
Allergic reaction 455, 661
Allogeneic sources 818
Allograft rejection 772
Alloxan 90
Alogliptin 642
coadministration of 658
Alopecia areata 276
Alpha-1-antitrypsin 801
Alpha-cell function, dysregulation of 103
Alpha-glucosidase inhibitors 10, 233, 234, 655, 657, 754, 809
mechanism of action of 655
molecular structure of 655, 655f
pharmacokinetics 656
Alpha-interferon 44
Alpha-lipoic acid 349
Alprazolam 829
Alteplase 402
Alveolar epithelium, thickening of 429
Alveolar osteitis, prevention of 499
Alzheimer's disease, risk of 553
Ambulatory autonomous care 767
American Association of Clinical Endocrinology 370, 371
American College of Cardiology 270, 370, 418
American College of Gastroenterology 516
American College of Obstetricians and Gynecologists 43
American Diabetes Association 41, 161, 179, 194, 212, 213, 228, 231t, 339, 358, 371, 452, 455, 470, 637, 639, 715, 773, 785
guidelines 358, 601, 722
procedure 213
Scientific Sessions 769
American Diabetic Retinopathy Study 11
American Gastroenterological Association 516
American Heart Association 370, 418
guidelines 270
American Psychiatric Association 830, 832
Amino acid 60f, 65, 66, 73, 78, 206, 744
delivery of 120
metabolism 67, 116fc
Aminoketone antidepressant combination 258, 259
Amiodarone 516
Amitriptyline 828, 830
Amputation 464f, 473, 484
lower
extremity 464
limb 464
minor 473
risk of 478, 479
Amylase 301
Amylin 54, 103
analog 233, 687, 761
mimetics 105
role of 762
Amyotrophy, diabetic 230
Anaerobic exercise 574
Anemia 343, 389
aplastic 637
autonomic dysfunction 345
normochromic normocytic 348
pernicious 86, 94
Anencephaly 209
Anesthesia
effects of 743
types of 743
Anesthetic agents, types of 743
Aneurysm
abdominal aortic 410
bleeds 399
Angina
stable 236
unstable 236
Angiogenesis 818
Angiography, coronary 386
Angioplasty 417
percutaneous transluminal 417
Angiopoietin-1 819
Angiotensin receptor
blocker 236, 349, 356, 391, 392, 403
neprilysin inhibitor 392
role of 391
Angiotensin-converting enzyme 164, 354, 392, 403
inhibitor 236, 321, 349, 391
use of 109
Angular cheilitis 489
Anion gap metabolic acidosis 300
Anionic trypsinogen 196
Ankle
brachial
index, measuring 415
pressure index 471
edema 391
nocturia 391
reflex 470, 479
Anomaly, types of 209
Anorexia 431
Anoxia accelerates 70
AntagomiRNA 113
technology 113
Antagonize 113
Antibody
autoimmune 179, 228
presence of 94
response, poor 451
Anti-CD3 monoclonal antibodies 183, 800
Anti-CD5 immunotoxin 800
Anticonvulsants 258
Antidepressants, atypical 828
Antidiabetic
agents 431, 704, 706, 761t
drugs 760
therapies, choice of 393
Antifibrinolytic agents 499
Antifibrotics 524
Antigens
immune recognition of 86
stimulated T-cells 141
viral 89
Anti-hepatitis C virus antibody 515
Anti-hyperglycemic
action 656
medications, safety of 739t
therapy 257
Anti-insulin receptor antibodies 44
Antiobesity agents 763
effects of 764t
Antioxidant 513
capacity 111
supplementation 200
Antiplatelet therapy 413
Antipsychotics
atypical 44
depot formulation of 831
first generation 831
second generation 831
Antiretroviral
agent 278, 516
regimen 434
therapy 434
Antiseptic application 675
Antithymocyte globulin, low dose 801
Antithyroid peroxidase, presence of 264
Antitubercular treatment 448
Antituberculosis drugs, pharmacokinetics of 432
Antivascular endothelial growth factor 327, 329, 331
Anxiety 147, 554
minimal 829
moderate 829
severe 829
short-term control of 829
ApoB antisense oligonucleotide 376
Apolipoprotein 368, 369, 371
Apoplexy 399
Apoptosis 110
Arcuate nucleus 133
Ardha matsyendrasana 581
Ardhakati chakrasana 581
Aripiprazole 828, 831
Arm circumference 549
Armanni-Ebstein lesion 80
Arterial blood gas 692
Arterial revascularization therapy study 386
Arteriosclerosis 230
Artery
lower extremity 405
superior pancreaticoduodenal 820
Arthropathy
diabetic neuropathic 487
neuropathic 483
Artificial pancreas 766, 775
systems, development of 610, 701
Asberg depression rating scale 828
Ascites, pancreatic 200
Aspartic acid 673
Aspiration pneumonitis, risk of 744
Aspirin 109, 236
administration of 403
role of 384
Assessing cardiovascular
adrenergic function 346
autonomic function 345
parasympathetic function 346
Asthma 451
bronchial 552
Atherogenesis 145
Atherosclerosis
accelerated 401
multi-ethnic study of 256
screening for asymptomatic 410
Atherosclerotic cardiovascular disease 236, 366, 371, 384, 386, 413
major 385b
management of clinical 386fc
Atherothrombosis 112
Atorvastatin 370, 372
collaborative 374
pilot studies 518
Atreya's quadruple 825, 825f
Atrophy 467
tubular 358
Attack
autoimmune 90
transient ischemic 236, 399, 626
Attractive theory 249
Australian Technical Advisory Group on Immunization 455
Autoantibody 45, 92t, 179, 228
multiple 274
Autoimmune diabetes, adult-onset 179
Autoimmune disease 94, 553
organ-specific 86, 262
Autoimmune disorders 275, 276
Autoimmune endocrine diseases, organ-specific 94
Autoimmune thyroid
disease 94, 262, 275
disorders, development of 264
Autoimmunity 90, 273, 274
celiac associated 275
evidence of 85, 91
Automate glycemic management 767
Autonomic function 338
clinical testing of 345
Autonomic nerve fibers 465
Autonomic nervous system 148, 343f
activation of 103
Autonomic neuropathy 315, 336, 338, 484, 537
diagnosis of 347
leads 467
presence of 439
symptoms of 338b
Autonomic reflexes, quantitative measures of 348
Autophagosome formation, step of 120
Autophosphorylation, rapid 61
Autoreactive T-cells 90
against islet antigens 86
Autosomal dominant 94
inheritance 169
Axillo-bifemoral bypass 418
Azathioprine 496, 772
B
Bacillus calmette-guérin 800
vaccination 89
Baclofen 831
Bacterial infections, recurrent 282
Bariatric surgery 255, 524
goal of 524
medical management of 257
role, mechanism of 525
Basal bolus 745
insulin therapy 677
regimen 677, 695
Basal human growth hormone 187
Basal insulin 672, 673, 676, 680, 694
analogs 696
long-acting 673
delivery 767
Basal lamina, pulmonary 429
Basal only insulin regimen 676
Beat-to-beat heart rate variation 346
Beck's anxiety inventory 829
Beck's depression inventory 828
Behavioral activation 829
Behavioral modification 584
Benzene ring, position of 632
Benzodiazepines 829, 831
Beta-adrenergic agonist 44
Beta-blocker
combination therapy 366
evidence of 391
Beta-cell 74f, 89, 90
adenomas, diagnosis of 292
autoimmunity, evidence of 94
biology 175
damage 90
autoimmune 426, 427
defect 47
destruction 44, 90
differentiation 172
dysfunction 148, 171
precedes 817
exhaustion 280
function 95, 101, 159, 660, 802, 836
genetic defects of 44
loss of 101
maintenance of mature 172
gene defects 47
hyperplasia 205
loss of 101, 817
mass and function 817
presentation of 89
replacement, sources of 817
transdifferentiation of 101
tumors 294
Betamethasone 736
Bethanechol, use of 507
Bevacizumab 329
Bhujangasana 581
Bicarbonate therapy 305, 305b
Biguanide 233, 519, 704, 760, 761
Bihormonal bionic pancreas 767
Bile acid
binding resins 664
sequestrants 372, 375
Bile duct
common 200
strictures, irregular 201
Biliary disease 518
autoimmune 509
Bimodal distribution 273
Biobreeding rat 800
BioChaperone Lispro 700
Bionic pancreas 766
Biopsychosocial model 824
demands 825
triptych 825f
Birth weight, high 88
Bisoprolol 349
Bisphosphonates 486
Bladder 248
cancer 627
control, loss of 338
Bleeding, intraperitoneal 776
Blood
amino acid concentration, product of 120
brain barrier 134, 348
flow, peripheral 135
glucose 436, 697t, 717, 728, 733
acute fluctuations of 596
application, self-monitoring of 606
changes, management of 438
cost benefits, self-monitoring of 597
current compliance levels, self-monitoring of 597
elevated 267
levels 596, 698, 718
limits 606f
maternal 171
monitoring of 235, 595, 736, 796
rapid lowering of 308
records, self-monitoring of 595
regimen, self-monitoring of 597t, 598t
self-monitoring of 216, 596, 597, 600-602, 602fc, 603, 607, 609, 615t
target for 220, 728, 731t
pressure 232, 256, 345, 358, 549t
control of 324, 383
diastolic 346, 365
elevated 131
higher 256
management 232t, 358
monitoring 359
nonpharmacological interventions on 385t
response 345
targets 550b
very low diastolic 232
samples drawn, number of 213
sugar levels 746
transfusion set 729
urea nitrogen 410
B-lymphocytes 55
Body insulin-mediated glucose 62
Body mass index 129, 138, 141, 149, 161, 189, 267, 281, 321, 381, 483, 706, 807, 808
category 259t
Body weight, low 284
Body's glucose reserves 768
Bolus insulins 676
Bone 501
density 483, 484
deposition 467
disease 483
epidemiology of 483
pathophysiology of 484
risk factors of 484
formation 468
fractures 627
fragmentation of 469f
loss, mechanism of 484
marrow 778
autologous 476, 821
derived stem cells 818
transplant 742
pentosidine levels 485
resorption 467
markers C telopeptide 485
structural alterations 485
turnover markers 486
Bony deformity 469
Bony prominences 468
Bowman's afferent 357
Bowman's layer 339
Bradycardia 345
Bradykinin B2 receptor 354
Brain 62, 73
derived neurotrophic factor 752
injury 401
ischemia 401
Branched chain amino acids 121
Breast cancer 249
Breastfeeding 89
Brexpiprazole 828
Brief psychiatric rating scale 831
Bromocriptine 233, 663
clinical efficacy of 664
mechanism of action 664
safety 664
Bronchial reactivity, reduced 429
Bronchus carcinoma, history of 127
B-type natriuretic peptide 383, 390
Bull, diabetic 528, 529
Bullous pemphigoid 528, 534
Buprenorphine 831
Bupropion 258, 259, 828, 831
Burning mouth syndrome 489, 494
management of 495
prevention of 495
Bypass angioplasty revascularization investigation 386
C
Calcineurin inhibitors 772
minimization strategy 772
Calcitriol 840
Calcium 218
channel blockers 366
formulations of 840
salts, composed of 196
sensing receptor 196
Calculi, pancreatic 196, 197, 198f
Callus 468, 469f, 472
debridement of 472
presence of 479
Calorie 557, 717
diet, high 431
Canadian National Advisory Committee on Immunization 455
Canagliflozin 13, 649t, 763
cardiovascular assessment study 396
Cancer 246, 247, 249, 553
hepatopancreatic 246
pancreatic 247, 249, 644
Candesartan 321
Candida 779
albicans species 493
infections 505, 547
risk factors for 493
Candidiasis 424, 440, 528, 532
oral 489, 493, 493f
Cannabis 831
Capillary blood glucose 728
monitor 729
Capillary nonperfusion 324
Captopril 438
Carbimazole 264
Carbohydrate 65, 134, 558, 560, 744
foods and daily intakes 718
meals 104
metabolism 65, 76
smooth regulation of 509
nonglucose 134
sources 232
Carboxyl ester lipase 170
Carboxymethyl 143
Carbuncle 531
Carcinoid
excision of 127
tumor 126, 127
Carcinoma, hepatocellular 509, 553
Cardiac denervation syndrome 343
Cardiac dysfunction 401
Cardiac regenerative therapy 349
Cardiac resynchronization therapy 392
Cardiomyocyte mass 840
Cardiomyopathy 401
hypertrophic 390
Cardiorenal syndrome 393
Cardiorespiratory endurance 574
Cardiovascular autonomic neuropathy 342
association of 344
clinical manifestations of 343
Cardiovascular disease 140f, 157, 236, 243, 267, 316, 317, 365, 369, 380, 381, 383b, 394, 451, 516, 556, 621, 627, 708, 744, 840, 840fc
clinical manifestations of 389
incidence of 109
kidney pretransplant screening for 773
prevalence of 785
prevention 236
reduce 394fc
risk of 141, 263
treatment of 236, 517
Cardiovascular events
high-risk for 385
major 344
Cardiovascular health study 256
Cardiovascular mortality 109, 353
risk of 389
Cardiovascular reactions 660
Cardiovascular risk
evaluation of 549
factors 231
Cardiovascular safety 636
Cardiovascular symptoms 338
Carnosine 354
Carotid
artery disease 320
circulation obstruction 399
intima-media thickness 428, 622
Carpal tunnel syndrome 230, 483, 486
Casein hydrolysate formula 802
Cassava toxicity 195
Catabolic status 678
Cataract surgery 332
Catatonic behavior 831
Catecholamine 297
excess 278
secreting pheochromocytomas 129
Cathepsin B 196
Cationic trypsinogen 196
Caudal regression 209
Cavity, peritoneal 776
Celiac disease 86, 94, 275, 276
Cell
apoptosis 355
mediated abnormalities 451
replacement therapy 113
Cellular immunity, impaired 448
Cellular mediated autoimmune destruction 45
Central memory T-lymphocytes 801
Central nervous system 133, 660, 743, 778
Cerebral
edema 308
ischemia 401
Cerebrovascular disease 230, 254, 280, 317, 399, 405, 428
association of 344
Cervix 248
Cesarean delivery 49
Cesarean section, planned 744
Charcot deformities, severe 474
Charcot foot 467, 469f
involving ankle joint 469f
presentation of 468
Charcot joint 467
Chemokine 640
receptor 5 promoter 354
Chemotaxis 144, 423
Chennai Urban Population Study 797
Chennai Urban Rural Epidemiology Study 31, 316, 381, 797
Chiropathy, diabetic 230
Chlamydia pneumoniae 145
Chlordiazepoxide 831
Chlorpromazine 831
Chlorpropamide 9, 519, 634
Cholecalciferol 836, 840
Cholecystitis 424, 439, 509, 518
chronic 439
emphysematous 439
Cholecystokinin 74, 133
receptor antagonists 200
Cholelithiasis 509, 518
Cholesterol 66, 558, 565
absorption inhibitor 373, 374
dietary 565
Cholesteryl ester 369
transfer protein 369
transfers cholesterol 376
Cholinesterase inhibitor 349
Chromosomal anomalies, screening for 222
Chromosome 44
Chronic diabetes complications, pathophysiology of 111
Chronic illness
implications of 825
treatment of 824
Chronic obstructive pulmonary disease 552
Chymotrypsinogen C 196
Cirrhosis 290, 428, 509
Citalopram 828, 829
Citric acid cycle 66f
Clinical information delivery systems 824
Clofibrate 636
Clonazepam 829
Clonidine 211
Closed-loop
glucose control system 768
insulin delivery 775
Clot supporting agents 499
Clozapine 831
Cognitive behavioral therapy 829, 830
Cold pressor response 345
Colesevelam 233, 664
Collaborative islet transplant registry 776, 818
Collagen, nonenzymatic glycosylation of 484
Colloid osmotic pressure 309
Coma, hyperglycemic 293t
Combination injectable therapy 677
Compassion fatigue 834
Completely edentulous mandibular arch 500f
Complex therapeutic schedule 826
Congenital malformation 216, 223, 711
risk of 244
Congenital rubella 44
infection leads 89
Congestion, hepatic 290
Constipation 259, 344, 505
Continuous glucose monitoring 595, 614, 615t, 766
clinical utility of 613
demerits of 614
indications for 613
system 217, 609-611, 611t, 612
development of 609
Continuous subcutaneous insulin infusion 696
pumps 9, 200
Contraceptive and intrauterine death, use of 212
Contraction stress test 222
Conus arteriosus defects 209
Cori's cycle 73
Corneal epitheliopathy 319
Corneal microscopy, confocal 338
Coronary artery bypass graft 386, 387, 743
surgery 727
Coronary artery disease 230, 284, 380-382, 382fc, 383, 383f, 389, 390, 405, 428, 435, 545, 550, 744
diagnosis 382
lower risk of 365
pathophysiology of 382
primary prevention of 382, 384fc
screening 382
Corticosteroids 126
Corticotroph adenomas, frontline treatment of 127
Cortisol 48, 73, 205, 297, 576
Counter-regulatory hormone 126
responses 229
Couple coping enhancement training 755
Cow's milk 88, 802
formula 802
protein 95
Coxsackie
A virus 89
B virus 88, 89, 273, 275
C-peptide 694, 801
concentration 45
levels 94
Cramps, abdominal 348
C-reactive protein 137, 140, 142, 383, 434
levels of 623
Cuboidal cells, small pale 53f
Cushing's syndrome 44, 126, 127, 149, 278, 285
diagnosis procedure of 127, 127b
etiology of 126b
remission of 127
treatment of 127
Cyclic adenosine monophosphate 68, 355, 539
Cyclosporine 183, 258, 278, 800
Cystic changes 430
Cystic fibrosis 44, 57, 194, 545
transmembrane conductance regulator 57, 196
Cystopathy 344
Cystoscopic-guided transduodenal pancreatic biopsy 775
Cysts, renal 46, 173
Cytokine 430
activation of 355, 356
chemotactic 640
synthesis 357
of acute-phase proinflammatory 139
tumor necrosis factor 207
Cytomegalovirus 44, 775
Cytoplasm 60
Cytoplasmic islet cell 92
Cytotoxic T-lymphocyte-associated protein 4 93
D
Daclizumab 818
Dapagliflozin 763
dosing of 649t
De novo mutations 173
De novo synthesis 322, 411
Deep breathing 345
Deep plantar compartments 470
Defective postreceptor insulin signaling 62
Degludec 696
Dehydration 229, 343
Delta cell 74f
Delusions 831
Dementia 236, 553
increased risk of 553
Denosumab 486
Dense lymphoplasmacytic infiltrate 55f
Dental caries 489, 492, 492f
pathogenesis of 493
prevention of 493
Dental implant 501
indications of 499
Dental pulp 818
Denture stomatitis 489, 493
Deoxyribonucleic acid methylation, modulation of 112
Depressed mood 828
Depression 147, 259, 554, 585
mild 828
minimal 828
moderate 828
presence of 554
severe 828
spreading 401
Depressive disorder, major 826, 828, 828t
Dermal matrix 476
Dermatitis herpetiformis 528, 534
Dermatophytosis 528, 531
Dermatoses 528, 533
Dermopathy, diabetic 528, 531
Desipramine 828, 830
Desquamative gingivitis 489, 491, 491f
Desvenlafaxine 828
Detemir 696
Dexamethasone 736, 737
Dextrocardia 209
Dextrose normal saline 222
Dhanurasana 581
Diabesity, medical management of 759
Diabetes 25f, 41, 70f, 126b, 157, 365, 399, 410, 431, 400, 444, 490fc, 504, 509, 552, 570t, 756, 757
adult-onset 179t
after transplant, new onset 642, 745
age of onset of 320
and heart failure 389
and immune-compromised state 552
and infections 142
and malignancy 246
and menopause 242
and polymorphonuclear leukocytes 143
and pregnancy 205, 241
and stress-related depression and anxiety 150
and stroke 400
and vascular smooth muscle cell 411
Association of Nigeria 639
autoimmune 180
type of 54
awareness, education and creation of 806
burden of 25, 25fc, 27, 797
causative factor for 31
cell therapy for 817
cerebrospinal fluid of 80
chemical induced 545
chronic complications of 229
classification of 43, 43fc, 545b
clinical features of 228
community lifestyle improvement program 810
complications of 145, 313, 587, 821
comprehensive management of 547
consequences of 210
control 538
optimal 471
development of 87, 94, 137, 147, 198, 243, 428
diagnosis 41, 157, 228, 817
complications of 317t
drug induced 48, 278
duration of 708
during pregnancy, screening for 243f
Electronic Medical Record 797
endemic proportions of 817
exercise therapy in 578
family history of 281, 435, 808
fracture risk assessment in 485
French Study Group 800
global
burden of 17, 17t
prevalence of 18
hepatogenous 521
heterogeneous nature of 27
high-risk for development of 94
history of 3
hotspots of world 824
immune mediated 44
immunization in 451, 455t
inflammation 410
insipidus 276
interventions and complications trial, epidemiology of 109
juvenile-onset 45, 169
ketoacidosis 275
kidney disease 551
lifestyle intervention reduced risk of 164
lipoatrophic 44
macrovascular complication of 109
management of 216, 244, 522, 676, 703, 789
medication 234t, 484
mitochondrial 46
muscle infarction 487
nephropathy, management of 358t
new onset 49, 374
nurse practitioner 787, 788
onset of 546
pathogenesis of 187, 188fc, 426
pathophysiology of 227
prediction 89
pregestational 205, 211
prevalence of 19b, 20, 21, 22b, 23b, 30, 32, 33f, 246, 742
prevention of 164, 805
primary prevention of 806
principles of management of 200
problems in India 797
psychosociology of 824
quality of life scale 755
registers, development of 795
registry 458
related mortality 35, 256
renaissance of 5
risk scoring system 808
screening camp 283
severe 80
spectrum of 197f
statin intervention trials in 374t
subtype 179
syndrome 46, 173
Technology Society 604
therapy 8t
armamentarium of 246
transient neonatal 44
treatment, skin reactions to 528, 532
type 1.5 180
type 2 547b
types of 253, 280, 437
undiagnosed 24f
with waist-to-hip, type 2 283f
Diabetes care 824
organization of 795
psychosocial aspects of 824
team 785
composition of 787
implementation of 787
Diabetes complications 10
cutaneous manifestations of 528
Diabetes control and complication trial 12, 41, 108, 313, 403, 766, 785
results of 339
Diabetes distress 149, 826, 827, 827t
risk factors for 826b
screening scale 827
Diabetes in pregnancy 211t, 241, 710, 712f, 716t
Study Group in India 715
Diabetes management
and surgery 742
biopsychosocial model of 584
during travel 749
evidence-base of 588
in multifactorial manner 825
integral part of 548
intrapartum 222
strategies for 796
Diabetes mellitus 27, 65, 73, 78, 108, 123, 126, 149, 175t, 262, 276, 285, 341, 353, 371, 381, 383, 384, 384fc, 391fc, 407, 423, 433, 436, 437, 451, 492, 574, 773, 779, 790, 836
advanced type 2 105
and inflammation 137
and tuberculosis 429
treatment of 432
antituberculosis regimen for 448
approximate frequency of 48fc
bone of 483
causes of 186, 194, 382fc, 437
classification of 41, 157
complications of 229
diagnosis of 41, 157, 437, 446
type 1 55, 693, 694f
effects of 428, 447
epidemiology of 445
type 2 27
etiologic classification of 44b, 54
etiology of 148
exercise and lifestyle modulation in 574
foods in 568
global trend of 380f
hallmark of 78, 609
histopathology of type 1 691 55
historical developments in type 1 691
hypertension in 365
incidence of 242f, 425f, 431t, 595
type 2 242f
malnutrition-modulated 186, 187, 189, 189b, 189t, 190, 191, 191t, 192
management
of type 1 691, 694, 703, 759
pharmacist-led module for 789
monitoring of 437
musculoskeletal manifestations of 483
neonatal 47, 277
noninsulin dependent 430
nutrition management of 556
obesity and type 2 253, 256
ongoing medications for 486
onset of type 2 41, 169
oral complications of 489
oral manifestations of 489t
pathogenesis of 426b
pathophysiology and genetics 85
post-transplantation 49
pre-gestational 216, 218
presence of 423
prevalence of 528, 785
risk factors 241, 281b
screening in 359t, 446
slowly progressive
insulin-dependent 180
type 1 94
specific considerations in type 2 579
stages of type 1 45, 90, 274t, 693t
stress-induced 430
transplantation in 771, 773
treatment of type 2 259, 522
type 1 9, 18, 34, 43, 46t, 85, 88t, 92t, 93t, 95, 121, 169, 186, 208, 217f, 246, 274t, 280, 281t, 323, 353, 399, 451, 545, 559fc, 576b, 597t, 605f, 653, 692fc, 692t, 699t, 750, 777, 786, 800
clinical presentation 274
differential diagnosis 277
epidemiology 273
genetic disorders 276
in special populations 275
risk factors 273
clinical features 282
complications of 283
differential diagnosis 284
epidemiology 280
management of 256
types of 247
varieties of 57
Diabetes prevention 89, 165
program 157, 256, 581, 810
scenarios of 446
study 165
trial 93, 802
Diabetic autonomic neuropathy 341, 344, 349, 429, 550, 552
clinical presentation 342
course of disease 342
epidemiology of 341
imaging techniques 347
pathogenesis 341
perioperative management 349
therapeutic approaches 348
Diabetic complications 144, 428
formation of 110
Diabetic dyslipidemia 368, 369
management 370
pathophysiology of 368, 369f
saroglitazar in 661
Diabetic foot 424, 440, 463, 478
care 340t
infection 478, 480
classification of 472
severe 470f
syndrome 463
classification 465
diagnosis 470
epidemiology 464
management 471
pathogenesis 465
prevention 474
socioeconomics 464
ulcer 464, 478, 480
ischemic 475
management 479
pathways of 468fc
prevention 479
Diabetic ketoacidosis 6, 10, 35, 46, 48, 211, 229, 298, 302, 305b, 306, 308, 424, 692, 746, 817
diagnostic criteria for 302t
euglycemic 650, 651f
management of 303, 303fc
pathogenesis of 297, 298fc
risk of 46, 297
Diabetic kidney disease 353, 354, 357
management of 358, 360
pathogenesis of 354
pathophysiology of 355
prevention of 359
screening for 359
Diabetic macular edema 318, 327, 627
intravitreal injections in management of 326
management of 328
steroid in 326
surgery for 329
treatment of 325, 329
Diabetic microvascular complications, risk of 108
Diabetic nephropathy 145, 230, 314, 355, 771, 779
prevention of 230
recurrent 772
risk of worsening 211
treatment of 230
Diabetic neuropathy 230, 315, 335, 338b, 551
classification of 336
complications of 339
diagnosis 338
diagnostic tests for 324, 338b
epidemiological aspects 335
pathogenesis of 335, 336fc
prevention of 339
preventive measures 339
progression of 339
risk factors 335
screening methods 315
symptoms of 337
treatment of 339
types of 336b
Diabetic pregnancy, effects of 208
Diabetic retinopathy 145, 211, 230, 313, 314, 318, 325, 331, 551
candesartan trials 321
combination of therapies 329
epidemiology 318
grading of 319
management of 324
pathogenesis of 321
progression of 321
risk factors of 320
screening protocols for 323
treatment for 314, 330
Diabetic therapy 249, 519
Diabetogenic drugs 285
Diacylglycerol 355
activation of 336, 401
causing over-activation 322
Diarrhea 344
diabetic 505
Diazepam 831
Diazoxide 44
Didanosine 434-436
Diet
high protein 431
management 232
modification 131
trackers 572
Dietary
amino acids, storage of 115
calcium, low 836
factors 33, 89
fat, sources of 563
management 548
measures 199
potassium 385
enhanced intake of 385
protein intake 359
sodium 385
reduced intake of 385
toxins 195
vitamin D, absorption of 836, 838
Digestive enzyme 76
Digital subtraction angiography 471
Dilantin 44
Diltiazem 211
Dimerization 141
Dipeptidyl peptidase-4 12, 105, 233, 394, 640, 735
gene family 640
inhibitors 105, 234, 260, 395, 524, 640, 644, 645t, 754, 762, 817
prevents 438
Disk, neovascularization of 319
Disulfiram 831
Dizygotic twin 274
Dizziness 644
Dobutamine 393
Docosahexaenoic acid 371
Domperidone, use of 506
Dopamine
agonists 128
antagonists 831
Dorsal motor nucleus 133
Down syndrome 44, 276
Doxepin 828, 830
Drug
eluting stents 387
therapy 233
Dry socket-alveolar osteitis 497
management 498
onset and duration 498
pathogenesis 498
sign 498
symptoms 498
treatment 499
Dual hormone 767
Dual-chamber infusion pump 767
Dulaglutide 684, 685, 762
Duloxetine 828
Duodenum 200
Dupuytren's contracture 230, 483, 487
Dysfunctional alpha cells 103
Dysglycemia 274
test 90
Dyslipidemia 42, 138, 236, 256, 269, 270, 401, 407, 413, 438
control of 383
management of 386fc
treatment of 553
Dysmetabolic syndrome 267
Dyspareunia 338
Dysphagia 338
Dysplasia, pancreatic 173
Dyspnea 391
Dysrhythmias 209
E
Early treatment diabetic retinopathy study 318
Echoviruses 88, 89
Economical test 214
Edema
macular 319, 323
peripheral 391
Edentulism
complete 499
partial 499
Edmonton obesity staging system 257, 257f
Edmonton protocol 818
Education Treatment Program, component of 602fc
Effector T cells natural killer 100
E-health technologies 571
Eicosapentaenoic acid 371
Ejection fraction 392
mid-range 390, 391
reduced 392, 392fc
Electrocardiogram 390
Electrolytes 746
Electrophysiology 338
Embden-Meyerhof pathway 69
Embryonic stem cells
based therapies 777
form of 818
Emergency life-saving procedures 734
Emotion 586
focused strategies 585
Emotional disorders 554
Empagliflozin 649, 649t, 652, 763
effects of 396
Emphysema 231
Employment decisions 756
End diastolic velocity 538
Endocrine
abnormalities 48b
cell
pancreatic 53
subsets 54
diseases 285
disorder 126, 126b, 131
affecting glucose regulation 278
disturbances 241
function 199
neoplasia type 1, multiple 127
symptoms 338
Endocrinopathies 44, 48
Endometrium 246
Endomysial antibody 275
Endoneuronal ischemia 342
Endophthalmitis 440
Endoplasmic reticulum 100
Endothelial cell 141, 322
dysfunction 410
exposure of 111
proliferation 323
vascular pole of 117f
Endothelial dysfunction 111, 118, 401
Endothelial function 423
Endothelium 122
capillary 324
dysfunction 401
Endotoxemia, metabolic 255
Energy, loss of 828
Enfuvirtide 436
Enteral feeding 735
Enteral nutrition 746
Enteropathy 505
diabetic 507
Enterovirus 88, 273
Enzyme
action 70
defects 290
hexokinase 70
tyrosine phosphatase 92
Epalrestat 349
Epidermal growth factor 475
Epidermophyton 531
Epigenetic therapy 113
Epinephrine 75, 126
inhibits β-cell insulin secretion 129
Erectile dysfunction 284, 338, 345, 537, 755
diabetic 345
pathogenesis of 537
Ergocalciferol 836, 840
Eruptive xanthomas 80, 528, 533
Erythematous crusting lesion 493
Erythrasma 424
Erythromycin, use of 506
Erythropoietin 348
Escherichia coli 9
Escitalopram 828, 829
Esophageal enteropathy 344
Esophagus, adenocarcinoma of 248
Estimated glomerular filtration rate 383, 624, 643, 699, 760, 772
Ethambutol 432
Etizolam 829
Etravirine 436
Euglycemia
importance of 402
maintenance of 401
Euglycemic clamp 120
Eukaryotic elongation factor 2 119
European Nicotinamide Diabetes Intervention Trial 94, 802
European Society of Cardiology 400
guidelines 394
Evogliptin 643
Excessive fluids, use of 309
Exenatide 684, 762
Exendin-based therapies 684
Exercise 232, 371, 574
effects of 578
intolerance 343
management of 349
maximum benefit of 580
role of 122, 580
types of 574
Exocrine
function 199
pancreas, disease of 44, 47, 278, 545
Extra mitochondrial isocitric acid dehydrogenase system 72
Extracellular fluid 510
volume 297
Extracellular matrix
dynamics 355
synthesis 355
Extrahepatic tissues, oxidation in 72f
Extravascular fluid depletion 297
Eye
disease 323
examination 547
comprehensive 324
Ezetimibe 113, 236
F
Fagerström test 830
Fasciitis
necrotizing 424
polymicrobial necrotizing 228
Fasting blood
glucose 205, 268, 695
sugar 717
Fasting glucose
impaired 42, 160, 280
isolated impaired 807
Fasting hyperglycemia
causes of 290t
impaired 274
mild 171
Fasting plasma glucose 41, 157, 189, 267, 274, 446, 734, 738
Fat 65, 558, 563
cells 62
in nutrition therapy 564
intake during pregnancy 718
Fatal cardiovascular disease 34
Fatigue 391
Fatty acid 65, 72, 139f, 564t
abundance of 75
biosynthesis of 72
dissemination of 100
metabolism 437
disorder of 342
non-esterified 70, 128, 130
oxidation 103
polyunsaturated 269
synthesis 65
Fatty liver 138
Fecal incontinence 344, 505
Fecal urgency 258
Fed state hypoglycemia 289
Femorofemoral bypass 418
Fenofibrate intervention 321, 375
Ferritin 515
Fetal
activity, maternal assessment of 222
beta-cells, hypertrophic 217
biophysical profile 222
cord 818
development, effects of maternal fuels on 212
evaluation 221
growth retardation 211
heart rate monitoring, antepartum 221
hyperinsulinemia 208f
implications 712
loss 711
macrosomia 216
nutrient transport, maternal 208f
Fever, mild-to-moderate 821
Fiber 558, 562, 718
Fibric acid derivatives 372
Fibroblast 141
activation protein 640
growth factor 475
Fibrocalculous pancreatic diabetes 48, 57, 187, 190, 194, 195, 195t, 197f, 198, 198f, 199b
clinical features 197
complications 200
diagnosis 198
epidemiology 194
etiological hypotheses of 195
etiopathogenesis 195
familial aggregation of 196
management 199
pathology 196
Fibroma, diabetic irritational 496f
Fibrosis 55f, 515
tubulointerstitial 358
Fidarestat 349
Finnish Diabetes Prevention Study 810
Finnish Dietary Intervention Trial for Prevention of Type 1 Diabetes 802
Fistula, pancreatic 200
Flank pain 228
Flash glucose monitoring 615t
Flavin adenine dinucleotide 356
Flexor tenosynovitis 483, 486
Fludrocortisone acetate 348
Fluid therapy 303
Fluorescein angiography 324
Fluorodeoxyglucose-positron emission tomography 248
Fluoroquinolones 44
Fluoxetine 828, 829
Flupenthixol 831
Flutamide 131
Fluvastatin 370
Fluvoxamine 828, 829
Follicle-stimulating hormone 191
Food and Drug Administration 433
Approved Agent 348
Foods
consumption patterns 269
groups 568
high fiber 718
ingredients, measured 568t
Foodstuffs, oxidation of 67
Foot
and ankle, joints of 467
care 339
advice 481
team, treatment of 475
deformity 468, 479
infection 470
recurrent 480
pulse 479
ulcers 464, 468t, 484
majority of 465
primary healing of 464f
Forxiga 763
Fractures 484
risk of 483
Framingham
heart study 348
offspring study 256
Frank diabetes mellitus, prevalence of 434
FRAX scoring 488
Free fatty acids 140, 190, 298, 369, 438
high blood level of 437
higher intraportal 254
importation of 512
increased delivery of 368
Free oxygen radicals, generation of 209
Freinkel hypothesis 212f
Frozen shoulder 487
Fructosamine, serum 213
Fructose
1,6-diphosphatase 73
6-phosphate 70
concentrations of 70
Fuel metabolism, physiology of 575
Fulminant hepatic failure 509, 521
Functional mutations, heterozygous loss of 173
Fungal infections 424, 440
Furunculosis 531
G
Gadolinium enhancement 127
Galectin attenuate insulin signaling 100
Galega officinalis 9
Gallbladder
dysfunction 173
function of 439
motility, impaired 439
stones 254
Gangliocytoma, hypothalamic 127
Gangrene 11
Gaseous exchange 475
Gastric
failure patients 507
inhibitory polypeptide 103
Gastritis, atrophic 94
Gastrointestinal
autonomic neuropathy 344
complications, clinical symptoms of 505
glucose absorption 263
hormones, role of 134f, 135f
involvement 552
peptide hormones, number of 74
reactions 660
surgeries 746
symptoms 338, 657
pathophysiology of 504
system 133-135
therapeutic system 634
tract 504
Gastroparesis 344, 349, 505
diabeticorum 344
management of 506
treatment of 349
Gastropathy, diabetic 211
Gemigliptin 643
Generalized anxiety disorder 827
rating scale 829
Genes, proinflammatory 112
Genetic
defects 46
disorders 276
factors 322
importance of 207
loci 86
predisposition 273, 354
risk markers 93
Genitourinary
autonomic neuropathy 344
infections, chronic 439
involvement 552
symptoms 338
Genotype, association of 480
Geriatric
depression scale 236
population 227
syndromes 227
Germline mutations 127
Gestational diabetes mellitus 42, 44, 48, 49, 54, 56, 171, 205, 211, 215, 219t, 222, 223, 241, 280, 323, 545, 578, 600, 657, 710, 712, 712f, 713t, 715-717, 717fc, 718, 722
diagnosis of 42, 43t, 715, 716t
etiology of 212b
management of 218, 244, 710, 717
epidemiology 711
risk factors 711
maternal 208f
mild 716
pathogenesis of 212b
pathophysiology of 207
postpartum management of 43
prevalence rates 711
rates of 240
screening of 42, 715, 716fc
Gestational glucose
intolerance 215, 716
tolerance 716
Ghrelin 54, 752
Gingival biopsy specimens, microscopic examination of 492
Gingival disease 433
Gingivitis 489
chronic desquamative 491
Glargine 696
insulin 674
Glaucoma 230, 319
neovascular 319
Glibenclamide 9, 632, 634, 719
Gliclazide 9, 172, 632, 634, 635, 739
dose of 737
extended release 632
Glimepiride 9, 632, 635
Glinides 10
Glipizide 9, 632, 634, 635
Gliptins 640, 708
Glitazars, chemical structures of 662f
Glitazones 439, 553, 817
Glomerular filtration rate 356, 358, 650, 738
impaired 109
Glomerulosclerosis, nodular 357
Glossitis, benign migratory 497f
Glucagon 48, 75, 105, 126, 297, 354
antagonist 106
blocks glycolysis 75
functions 103
secreting tumors 278
secretion
advanced type 2 diabetes mellitus 104f
and alpha-cell function 103
excessive 103
failure of 104
stimulation test 800
suppression, establishing failure of 104
Glucagonemia 640
Glucagon-like peptide 12, 74, 103, 105, 133, 134, 640, 677, 700, 735, 754, 817
Glucagonoma 44, 126, 130, 194
Glucagon-stimulated C-peptide 821
Glucocorticoids 44, 76, 229, 278, 285, 516, 736, 772
cause centripetal redistribution 149
effects of 127f
excess 126
pathological role of 126
hormone, endogenous 126
synthetic 126
Glucokinase 175
Glucolipotoxicity 255
Glucometers 604
accuracy of 604
use of 600
Gluconeogenesis 66f, 77, 103, 510fc
enzyme system 63
hepatic 263
vital enzymes in 73
Gluconeogenic substrate 76
Glucose 65, 67, 75
6-phosphate 65, 69, 70
dehydrogenase 322
absorption 76
and lipid metabolism, regulation of 59, 62
concentrations 219
control 764t
entry of 69
optimize 486
counter-regulation 290
dependent insulinotropic
peptide 134, 135
polypeptide 74
entry 62
fasting 157
fatty acid cycle 70f
homeostasis 129, 135f, 194, 509, 520
abnormalities of 521
classification of 41
diagnosis of 41
hypothesis 108
in isolated β-cell 74f
intolerance 126b, 127, 160, 205
developing during pregnancy, pathogenesis of 207, 714
diagnosis of 263
levels
fluctuation 263
high 103
lowering medications 703
effects of 760
management, intrapartum 737
membrane transport of 72
metabolism 126, 127fc, 510, 753
abnormal 131, 434
optimizing 837
monitoring system, real-time continuous 610, 611
phosphorylation 171
processes of 70
rate of 70
production 510fc
serum 299
stimulated insulin secretion 212
synthesis 133
target for 231t
tolerance 127, 129
clinical implications of impaired 160
development of impaired 161
etiology of impaired 159
impaired 25f, 27, 42, 126, 128, 140, 141, 157, 160, 209, 215, 274, 381, 436, 437, 622, 627, 716, 805
instability of impaired 158
isolated impaired 807
normal 149, 158, 207, 807
pathogenesis of impaired 159
regulation of abnormal 809
stage of impaired 280
test 446
toxicity 148
transporter 2 61, 72, 119, 198, 208, 354
translocation of 818
utilization, peripheral 262
Glucosuria 42
Glucotoxicity 101
Glutamic acid
carboxylase 92
decarboxylase 45, 92, 93, 175t, 179, 801
antibodies 180, 182, 187
development of 87
Glutamine 78, 121
Glutathione, reduced 110
Gluten rich food 95
Glyburide 221, 244, 634, 719
Glycated hemoglobin 190t, 429, 621, 692, 695, 727, 734, 738, 746, 821
in pregnancy 716
test measures 595
Glycemia 320, 743
regulation of 395
short-term measures of 149
Glycemic control 294, 320, 324, 354, 358, 393, 412, 545, 699, 732, 763, 772
for surgery, importance of 742
level of 607
monitoring 220
optimizing 348
stabilization of 339
stable 734
targets for 695t
Glycemic index 561, 561t
low 270
Glycemic load 562
Glycemic management 734, 737, 738
Glycemic memory 108, 324
Glycemic monitoring, consensus guidelines for 603
Glycemic optimization, treatment for 821
Glycemic status 708
Glycemic targets 717
Glyceraldehyde-3-phosphate dehydrogenase, activity of 322
Glycogen
breakdown 70
deposition 509, 511
deposits, excess 80
storage disease 509, 522
synthesis 69, 72, 73, 510
processes of 69
stimulates 75
synthetase 68, 70
D, activation of 70
Glycogenesis 510
Glycogenolysis 62, 63, 67, 68, 74, 510, 510f
stimulates hepatic 103
Glycolysis 65, 67, 68, 70, 72
regulation of 68f
Glyconeogenesis, regulation of 68f
Glycoprotein 2 196
Glycosuria 78
indications for 282
recurring 710
Glycosylated hemoglobin 12, 190, 213, 445, 509, 703
Glycoxidation products 143
Goiters, multinodular 264
Golgi apparatus 669
Gonadal failure 94
Graft
pancreatitis 773
thrombosis 773
Granulocyte
colony stimulating factor 801, 820
macrophage colony-stimulating factor 322, 447
Graves’ disease 86, 94, 264
Great toe, phalanges first metatarsal head of 471f
Group B streptococcal bacteremia 440
Growth
factor
alpha, transforming 322
beta, transforming 354
platelet-derived 475, 819
serum insulin like 127
hormone 48, 73, 76, 126, 128, 191, 278
insulin-like growth factor 128
stimulation 818
Guanosine
5’-triphosphate 68
diphosphate 68
Guardian link transmitter 769
Gut microbiota 255, 506
Gut-brain-adipose tissue 255
H
Halitosis 489, 496
treatment of 496
Hallucinations 831
Haloperidol 831
Hamilton
anxiety rating scale 829
depression rating scale 828
Hand abnormalities 483, 486
Hartmann's solution 304
Hashimoto's thyroiditis 86, 94, 262
Headache 259, 761, 764
Healing 464f
Heart 625
disease 264, 283
atherosclerotic 283
coronary 240, 268, 406, 772
failure 380, 389-391, 391fc, 392-394
causes of 389, 390t
congestive 230, 626
diagnosis of 389, 390fc
hospitalization for 165
management of 391
mechanism of 389
symptomatic 392fc
types of 389, 390t
outcomes prevention evaluation 165
rate 343, 345, 392
response 346
variation 345
transplant 49
Helicobacter pylori 145
Hematologic reactions 660
Hematopoietic stem cells 778
role of 819
Hemochromatosis 44, 194, 509, 521
Hemodynamic mechanisms 354
Hemoglobin 316
A1C 41, 42, 175
Hemoglobinopathies 42
Hemoptysis, greater tendency of 431
Hemorrhage
intracerebral 399
intraretinal 319
recurrent vitreous 331
subarachnoid 399
symptomatic intracranial 401
vitreous 319, 331
Hepatic cell plasma membrane 75
Hepatic disease, severe 624
Hepatic fibrosis, pathogenesis of 518
Hepatic glucose
mechanisms of 133
output 77
Hepatic lipase 369
Hepatic steatosis 434
alternative causes of 516
Hepatic transplant 425f
Hepatitis 509
A vaccinations 517
autoimmune 522
B
and diabetes 457
surface antigen 515
vaccination 457, 517
virus 424, 425, 457
C 434, 440, 516
virus 49, 425-428, 520
severe 290
viral 520
Hepatobiliary reactions 660
Hepatocyte
ballooning 515
glucose transporter 2 protein 129
Hepatotoxicity, minimal evidence of 519
Herpes zoster 456
infection 456
live-attenuated vaccine 456
vaccination 457
Heterozygous mutations 171
Hexokinase, inhibition of 70
Hexosamine pathway 357
Hexose monophosphate shunt pathway 67
Hexosediphosphatase 73
High blood pressure education program 786
High triglycerides 375
plus low high-density lipoprotein cholesterol 267
High-intensity statin therapy 370t
Highly active antiretroviral therapy 44, 433
Hip
fractures, risk of 553
measure 557
Histocompatibility complex, major 181
Homeostasis 133
Hormone 575
anticatabolic 205
deficiencies 290
secretion 127
secretion of 48
Hospital anxiety and depression scale 828, 829
Human
body regulates energy 133
brain, sole fuel for 73
chorionic gonadotropin 206, 222
diet, integral part of 562
growth hormone 188
immunodeficiency virus 302, 437, 516
infection 424, 433, 434b, 436t
leukocyte antigen 45, 86, 87fc, 186
placental lactogen 205
T-lymphotropic virus type 1 273
Huntington chorea 44
Hybrid closed-loop system 769
Hydramnios 49
Hydrocephalus 209
Hydrocortisone 736
injections, multiple 737
Hydroxychloroquine 659
adverse drug reactions 660
approval status 660
novel mechanism of action 660
reduction in inflammation 660
Hygiene hypothesis 89
Hyperactivity 401
Hyperaldosteronism, primary 126, 130
Hyperbaric oxygen 475
therapy 475, 819
role of 349
Hyperbilirubinemia 210, 710
Hypercholesterolemia 80
Hyperglucagonemia 103
Hyperglycemia 103, 108, 111, 213, 244, 275, 307, 318, 322, 401, 727, 746, 757, 773
acute 743
burden of 727
chronic 41, 321, 465
classification of 711, 727
complications of 595
context of 104
control 703
of maternal 210
correction of severe 694
degree of 144
development of 115
during pregnancy 25f
hyperinsulinemia hypothesis 212
in acromegaly 128fc
in hospital management of 727
induced tissue damage 109
management of 703, 737
maternal 712fc
measure of 446
mechanisms of 130fc
amelioration of 818
mild 172, 821
monitoring of 595
new onset 434
persistent 501
postprandial 115, 269
prevalence of 742
primary cause of 41
reversing 778
severe 173, 743
stable fasting 171
symptoms of 280, 291t
treatment of 553, 742
Hyperglycemic crises, association of 297
Hyperglycemic emergencies 297
diagnostic criteria 302
management 308
Hyperglycemic hyperosmolar nonketotic
coma 297
state 297
Hyperinsulinemia 104, 141, 145, 205, 244, 247, 248, 269, 281, 401
Hyperkalemia 209
Hyperlipidemia 321
control of 340
postprandial 112
Hyperosmolar hyperglycemic
nonketotic syndrome 229, 307
state 10, 297, 302, 307
syndrome 229, 302t, 308
management of 303fc
pathogenesis of 307fc
Hyperosmolar nonketotic
coma 297
state 10
syndrome 285
Hyperosmotic nonketotic coma 306
Hyperostosis, diffuse idiopathic skeletal 483
Hyperparathyroidism, primary 126, 131
Hypersomnia 828
Hypertension 42, 138, 165, 230, 270, 320, 360, 365, 389, 407, 412, 547, 549, 761
diagnosis of 550
management of 384fc
optimal treatment study 365
supine 348
Hyperthyroidism 44, 126, 128, 129, 262, 343
transient 263
Hypertriglyceridemia 269, 752
Hypertrophy 357
left ventricular 391
myocardial 840
renal 357
Hypocalcemia 210
Hypochlorhydria 130
Hypoglycemia 35, 209, 211, 229, 237, 289, 290, 290t, 294, 308, 484, 635, 637, 657, 746, 750, 757
autoimmune 294
causes of 750
classification of 291, 292f
clinical features 291
complications 292
concern 708
course and prognosis 292
differential diagnosis 292
episode of 294, 295, 757
etiology 289
fear of 554, 754
increased risk of 112
insulin induced 752
ketotic 290
lesser chances of 696
life-threatening 766
management 293
neonatal 294
one hand 553
postprandial 291
prevent 294
risk of 112
severe 209, 752
signs of 291t
symptoms of 752
treatment of 216
unawareness 293
Hypoglycemic
coma, differential diagnosis of 293t
episodes, history of 546
Hypogonadism 553
Hypokalemia 308
Hypoplasia 194, 209
Hyposalivation 494
Hypothalamic disorders 262
Hypothalamic-pituitary
adrenal axis 127
adrenocortical, perturbation of 148
Hypothesis 144
Hypothetical islet secretion 6
Hypothyroidism 126, 129, 262
subclinical 264
Hypoxia 342
I
Icodextrin 604
Imipramine 828, 830
Immune
cells, infiltrating 89
function 143, 644
intervention trials 93
response 86, 90
stress 151
tolerance network 801
Immunity
cell mediated 779
cellular 144
humoral 144
innate 143
Immunization 273, 458, 552
Immunofluorescence 92
Immunogenetics 186
Immunoglobulin 423
Immunohistochemical staining 338
Immunomodulation 818
Immunosuppression 773, 776
Immunosuppressive drugs 772, 773
Implant placement 500f
Incretin 75, 524
based therapies 234, 250, 644, 705
hormones 760
physiology of 640
Indian Council of Medical Research Guidance 838
Indian Council of Medical Research-India Diabetes 30, 158
Indian Diabetes Prevention Program 807, 808, 810
Indian Diabetes Prevention Study 797
Indian Pregestational Diabetes Mellitus 721
Indian Scenario of Immunization 457
Indian Standards Organization 604
Indinavir 435, 436
Infection 44, 88, 505, 773
bacterial 424
chronic 423, 424, 439, 440
cutaneous 528, 531
periapical 489
periodontal 424, 492
pneumococcal 451
prevention of 440
treatment of 414
Inflammation 111, 112, 144, 322, 357, 430, 660
chronic 247
low-grade 112
signs of 472
Inflammatory cells, recruitment of 323
Inflammatory cytokines 228, 248
levels of 368
Inflammatory pathways, activation of 100
Inflammatory processes 111, 137
Influenza
infection 453
vaccination 455
guidelines 455
vaccines 454
Injury, hepatocellular 513
Insomnia 828
Insulin 54, 73, 88, 103, 115, 120, 170, 228, 235, 250, 285, 395, 532, 697t, 738, 739, 754
absorption 675
accelerates glucose uptake 72
action
genetic defects in 44
integrative physiology of 116
mechanisms of 117f
molecular mechanism of 59
administration, routes of 671
amounts of 695
analog 220, 250, 672
first long-acting 8
antibodies, development of 86
autoantibodies 92, 93
binding 61, 61f
choice of 695, 730
correctional 732
crystallization techniques 8
deficiency 41, 44, 103, 426, 427
consequences of severe 79f
degree of 115, 123
presence of 62
severe 70f
degludec 674
degradation 212
delivery of 767
dependency 180, 281
dependent diabetes mellitus 85, 186, 430
treatment for 11
detemir 722
discovery of 7, 8
dosage, adjustment of 750
effects of 120
endogenous 92
era 6
first clinical use of 8
formulations of 671, 672t
gene mutation 173
glargine 112, 722
human 218, 672
hypoglycemia, adjust 680
indications of 678
infusion
preparation for 728t
protocol 728
rate 729, 729t, 730t
systemic 120
inhaled 671
initiation 696, 697, 826
in hospital 732
injection sites 698
titration and correction doses 697
injections 601, 755
sites 675f
insensitive tissues 212
intermediate-acting 696
intra-islet 104f
intravenous fluid 222t
like growth factor 59, 61, 247, 322, 354, 475, 819
lispro 721
lower concentrations of 255
metabolism effects of 74fc
molecule, structure 62
action relationship of 59
multiple-dose 601
nutritional 732
omission 755
pen, set of 749
producing cells 818
pump 696
therapy 601
receptor 59, 61, 61f, 63
mutations 285
substrate 100, 119, 139, 207, 818
regimens 676
regular 673, 695
release 74f
requirement 179, 216, 693
resistance 56, 140, 207, 241, 247, 248, 254, 267, 400, 401, 426, 512, 545, 821
background of 817
causes of 434b
development of 119, 254
intervention after stroke 627
parameters 149
pathways 837
prevalence of 381
stages of 281
syndrome 267, 556
type A 44
underlying 162
response
adequate 215
first phase 207f
responsiveness 60
role of 112
secretagogues 631, 632t
classification of 631, 631fc
secretion 76, 171, 212, 212b, 228, 281, 703, 837b
inhibition of 126
poor 426
secretory defect, progressive 545
sensitivity 46, 131, 207, 256, 281, 660, 836, 837
during gestation 207f
maternal 205
sensitizers 621
sensitizing peroxisome proliferator 250
signaling 115, 139f
cascade 207
sources of 221
specific cell surface receptors 63
stimulated protein synthesis 119
stimulates glucose 69
structure 670f
and synthesis 669
synthesis, modulator of 174
therapy 8, 219t, 304, 519, 669, 678-680, 720, 721, 737, 738
complications of 681
initiating 219, 679
total daily dose of 733t
transport 117
treatment 218, 523
types of 672t
Insulinoma 292
associated antigen-2 179
Intensity, moderate 370t
Intensive care unit 746
Interferon-gamma interferon gamma, inhibition of 89
Interleukin 140, 141, 383, 743
International Association of Diabetes in Pregnancy Study Groups 213, 242, 715, 716
International Diabetes Federation 17, 27, 28t, 29f, 158, 232, 240, 241, 267, 268, 451, 595, 639, 703, 710, 785, 794, 795, 805
Guidelines 601
International Expert Committee 42
International Federation of Gynecology and Obstetrics 711
Interpersonal psychotherapy 829
Interphalangeal joints 468
Interstitial fluid 74, 609
Intestinal microbes 513
Intestinal mucosal barrier function 255
Intra-arterial mechanical thrombolysis 402
Intra-arterial thrombolysis 402
Intracellular bactericidal activity 779
Intracellular calcium
content 840
levels 837
Intracellular insulin signalling, impaired 212
Intracellular metabolic pathway 66f
Intracellular myoinositol, diffusion of 209
Intracellular protein, breakdown of 304
Intracellular signaling pathways 118
Intraepidermal bullae 228
Intraocular pressure 327
Intrapancreatic cells 778
Intrapenile injections 540
Intraretinal microvascular
abnormalities 319
anomalies 330
Intrauterine death 217
Intravenous glucose 74f
tolerance test 159, 430
Intravenous insulin infusion 728
variable rate 746
Intravenous radio contrast material, use of 624
Intravenous tissue plasminogen activator 402
Intravitreal elimination half-life 327
Intravitreal injection treatment paradigms 328
Intrinsic minus foot 467
Ipragliflozin 524
Iron 218, 513
deficiency 42
overload, hepatic 521
stores 426, 428
Irritation fibromas 496
Ischemia 329
high-risk of 386
signs of 418
Ischemic foot, treatment of 413
Ischemic heart disease
history of 391
risk of 165
Ischemic stroke 399, 626
history of 385
onset of 402
Islet amyloid
nature of 56
polypeptide 101
Islet antibodies 90, 92
development of 88
Islet antigens 91, 92t
numerous 91
Islet autoantibodies, measurement of 93
Islet autoimmunity 92, 95
Islet beta-cells
protection of existing 819
regeneration of 818
Islet cell 771
antibodies 93, 175, 228, 800
autoantibodies 45, 181, 277
presence of 180
prevalence of 187t
secrete glucagon 54
transplantation 8, 775
adverse effects 776
developments and research in field 776
limitations 776
Islet donors 776
Islet function 821
Islet of Langerhans 55, 74f
alpha cell in 74f
normal 53
Islet transplantation 775, 777
Isocarboxazid 828
Isoleucine 121
Isometric resistance 385
Isoniazid 431
hyperglycemic effects of 430
Isophane 696
J
Jaundice, neonatal 274
Jejunostomy feeds 739
Joint
dislocation of 468, 469f
disorders 254
Joint National Committee 353
Jugular venous pressure 391
K
Kapalbhati 581
Kaposi's sarcoma 528, 534
Karnal glucocoper 833f
Kerala Diabetes Prevention Program 810
Ketoacidosis 275, 285
alcoholic 299
Ketoacids 300
Ketoanion metabolism 305
Ketogenesis 103
consequent 77
Ketone 190, 190t, 746
bodies 70f, 71, 73, 79
transport of 72f
production by liver 510f
serum 299
Ketosis 510f
Ketotic smell 275
Kexin type 9 inhibitors 374
Kidney 62, 626, 645
disease 358
chronic 138, 293, 353, 389, 706, 739, 739t, 790
end-stage 771
outcomes quality initiative 772
pathology of 357
injury, acute 746
living-donor 771
pancreas transplantation 773
post-transplantation care 772
pre-transplant evaluation 772
standard-criteria donor 771
transplantation 771
benefits of 771
living donor 771
Kimmelstiel Wilson nodules 357
Klebsiella infections 440
Klinefelter syndrome 44, 276
Knee 483
Krebs cycle 66f, 67
Kupffer cells 139, 524
Kussmaul breathing 298
L
Labor, inductions of 221, 738
Lactate dehydrogenase, action of 511
Lactic acidosis 623
Lacunar infarcts 399
Lamivudine 436
Lansoprazole 183
Laparotomy 776
Larva therapy 476
Laser
panretinal photocoagulation 330
role of 326
therapy 326
L-asparaginase 278
Latent autoimmune diabetes 45, 57, 92, 179-181, 285, 285t
Laurence-Moon-Bardet-Biedl syndrome 44
Lecithin sphingomyelin 210
Left atrial volume index 390
Left ventricular
ejection fraction 390, 391
mass index 390, 396
Leprechaunism 44
Leptin 100, 133, 248, 513, 752
receptors 135
Lethal malformations, occurrence of 216
Leucine 121
nonoxidative utilization of 121
Leukocyte
endothelial adhesion molecule-1 354
function, impaired 451
Leukocytosis 301
Levamisole 496
Levomilnacipran 828
Levosimendan 393
Levothyroxine 264
Libido, loss of 338
Lichen planus 489, 528, 533
reactions, treatment of 495
oral 495, 495f
Lichenoid reaction 495
treatment of 495
Limb amputation 464t
Linagliptin 641-643, 739, 762
Lipase 301
inhibitor 258, 764
Lipemia 80
Lipid 301
lowering agents 109
pharmacology of 372t
lowering
drugs 113
therapy 324
management 359, 550
metabolism 66, 76
modifying drugs 374
peroxides, levels of 110
profile
abnormal 131
atherogenic 256
target for 231t
Lipodystrophy 285, 434, 436, 516
Lipogenesis 73
Lipolysis, excessive 77
Lipopolysaccharide
bacterial 139
form of 433
level of 100, 255
Lipoprotein
abnormalities 80
cholesterol
elevated low-density 368
high-density 175, 190, 268, 371
low high-density 162, 368
low-density 138, 190, 263, 358, 370, 371, 384, 386, 761, 776
very low-density 190
high-density 131, 140, 157, 369, 373, 381, 622, 627
lipase 369
low high-density 281, 368
low-density 131, 140, 175, 369, 373, 375, 381, 381f, 547, 622, 627, 375, 753
very low-density 138, 368, 510
Lipotoxicity, molecular mechanism of 140
Liraglutide 13, 131, 258, 259, 270, 518, 684, 739, 762
Live attenuated influenza vaccine 454t, 456
Liver 62, 68f, 72, 127fc, 173, 510, 645
abscess 440
biopsy, role of 515
cirrhosis 744
cytosol 510
damage 439
disease 509, 511, 521
acquired 290
alcoholic 516
association of 509
chronic 425f, 428
complications of 520
frequency of 519
progression of viral 428
treatment of 522
during fasting conditions 510fc
failure 258
function tests, elevated 776
oxidation in 69f
phosphorylase 290
role of 509
secretory proteins, synthesis rate of 121
transplant 49
Lixisenatide 684, 685
Loci 88
Long-chain fatty acids 66
Lorazepam 831
Lorcaserin 259, 764
Losartan 165, 349
angiotensin 518
Lovastatin 370
Low calorie diet, consumption of 760
Lower extremity, pulses of 418
Lung
carcinoid tumor of 127
diseases, chronic 552
maturity, amniocentesis for 221
small cell carcinoma 126
transplant 49
Luteinizing hormone 191
Lymphocyte 55
blastogenesis, reduced 451
dominate 55
function 423
Lysine 143
M
Macroalbuminuria 354
Macroangiopathy, peripheral 428
Macroglial cells, major class of 135
Macrophage 55
colony-stimulating factor 322
Macrosomia 49, 210
history of 711
occurrence of 215
Macrovascular complications 108, 316, 463, 703
screening for 316
Macrovascular disease 34, 112, 230, 401, 621
risk of 621
Macular degeneration, age-related 323
Macular optical coherence tomography 324
Madras Diabetes Research Foundation 174
Magnesium 218
Malate dehydrogenase 72
Malformations
arteriovenous 399
types of 209t
Malic enzyme 72
Malnutrition-related diabetes mellitus 186
clinical features 188
complications 191
diagnostic criteria 188
etiopathogenesis 187
investigation 189
management 190
Malonyl-CoA stimulates, level of 79
Mammalian cells 65
Mammary artery, internal 387
Mandibular arch, implants in 500f
Mania, precipitation of 259
Mannitol 567
Mantoux test 433
Marrow adiposity 484
Matrix metalloproteinases 100
Matsyasana 581
Maturity onset diabetes of young 43, 46, 169, 170, 172-174, 175fc, 277, 284, 285, 285t, 694
diagnostic criteria of 46
genetics of 170
pathophysiology of 170
prevalence of 169
studies on 174
subtypes of 47t, 171t
Meal-priming insulin bolus 768
Mean plasma glucose, maintenance of 220
Medical nutrition therapy 218, 219, 371, 548, 556, 717
goals of 558
Meditation 581
Mediterranean diet 270
Meglitinides 233, 234, 638, 735, 754
chemical structure of 638f
Memory
hyperglycemic 108
T cell subsets 447
Menorrhagia 283
Mental
disorders 744
health professionals 790
Mesangial cell
apoptosis 355
number 357
Mesenchymal stem cells 778, 818
sources of 818
Metabolic cum vascular disorder 179
Metabolic disease, chronic 483
Metabolic memory 108-113, 112fc
concept of 112
molecular basis of 108, 109
phenomenon of 110
Metabolic pathways 65, 73
major 65
Metabolic recovery, stage of 693
Metabolic surgery 260
role of 259
Metabolic syndrome 131t, 240, 254, 267, 268t, 269, 434, 570t, 839
component of 270
control of 269
development of 268
prevalence of 240, 268
prevention of 269
treatment effect in 623
Metabolism, integration of 67, 71f
Metabolize pyruvate 65
Meta-iodobenzylguanidine 347
Metastatic cancer, uncontrolled 231
Metatarsophalangeal joints 467
Metformin 112, 131, 172, 200, 233, 244, 250, 393, 439, 517, 621, 624b, 624t, 694, 700, 704, 706, 719, 733, 735, 754, 760, 761
actions of 622f
adverse effects 623
continuation of 221
indications and dosage 624
mechanism of action 622
metabolic effects of 622t
pharmacokinetics 623
precautions 624b
and contraindications 623
therapy 623
use of 623
Methadone 831
Methicillin-resistant Staphylococcus aureus 476
Methotrexate 516
Methyldopa 211, 604
Methylhistidine excretion 122
Methylprednisolone 736
pulse therapy 737
Metoclopramide 349
use of 506
Metoprolol 349
MICA gene, sequence determination of 187
Michaelis constant 70
Microalbuminuria 283, 354
Microaneurysms, presence of 319
Microangiopathy 428
Microbiota-driven inflammation, state of 255
Microdrip set 729
Micronized 221
Micronutrients 566
Microribonucleic acid 111, 819
Microsporum 531
Microvascular and macrovascular disruption 415
Microvascular complications 162, 313, 463
Microvascular disease 227
risk of 47
Midodrine 348
Migration 269
inhibition factor 100
Milk exchange 568
Mindful meditation 830
Mineral 558
metabolism disturbances, role of 840
Mineralocorticoid receptor antagonists 391
Mini-mental state exam 236
Mipomersen 376
Mirtazapine 828
Mitochondria, myocardial 634
Mitochondrial
deoxyribonucleic acid 44
damage 109
mutations 285
dysfunction 110
electron transport chain 356
malate transporting system 72
overproduction 109
proteins, glycation of 109-111
Mitogen-activated protein kinase pathway 61, 118
Mixed meal tolerance test 800
Mobile diabetes apps 599, 600
Monoamine oxidase inhibitors 828
Monocytes
chemoattractant protein 100, 248
macrophages 141, 144, 357
Monogenic diabetes 170t, 277
syndromes 43, 545
Monogenic disorder 170
Monogenic gene panel 175
Monounsaturated fatty acids 269
Monozygotic twin 274
Montgomery 828
Motor nerve functions 821
Motor neuropathy leads 467
Moxifloxacin 432
mTORC1 signaling 120, 122
Mucocutaneous disorders 489, 495
Mucormycosis 779
Mucous membrane pemphigoid 491
Multidrug-resistant tuberculosis 430, 448
Multi-vessel disease 387
Muscle 62, 73, 78
abnormalities 483
cramps 284
infarction, diabetic 483
lipid accumulation 434
mass, loss of 121
tension 829
wasting of 338
Muscular atrophy, evidence of 486
Muscular contraction 70
Muscular fitness 574
Mycobacteria 431
Mycobacterium
bovis 800
tuberculosis 444
Mycophenolate 772
mofetil 774
sodium 773
Myelocele 209
Myocardial infarction 228, 236, 390, 401, 621, 622, 625
onset of 381
rate of acute 437
Myofibrillar protein breakdown, index of 122
Myoinositol, metabolism of 80
Myonecrosis, diabetic 487
Myosin 423
Myotonic dystrophy 44
N
Nail deformities 470
Naltrexone 131, 258, 259, 831
Nateglinide 632, 739
National Cholesterol Education Program 267, 381, 786
National Diabetes Data Group 212, 280
National Diabetes Surveillance System 253
National Glycohemoglobin Standardization Program 12
National Health and Nutrition Examination 785
Survey 269, 425, 839
National Health Department of Seriousness of Diabetic Foot Problem 463
National Institute for Health 639, 811
National Institute of Clinical Excellence 323
National Institute of Diabetes and Digestive and Kidney Diseases 776
National Kidney Foundation 358
National Pancreas Allocation System 773
National Urban Diabetes Survey 254
Natural killer cell 141
function 451
Necrobiosis lipoidica diabeticorum 528
Necrosis factor-kappa-B 112
Nefazodone 828
Negative pressure wound therapy 475
Neoplasia 44
Nephropathy 162, 211, 317
cyclosporine induced 800
Nerve
damage, common symptoms of 338b
sorbitol 349
Neural crest-derived chromaffin cells 129
Neural stem cells, intravitreal injection of 821
Neuralgia, postherpetic 456
Neuroendocrine cells, embryological origin of 53
Neuroendocrinological pathways, abnormalities of 149
Neuroischemic foot 414, 469, 471
management of 473
Neurological disorders 277
Neurological examination like neuropathy symptoms score 338
Neuronal nitric oxide formation, reduced 537
Neurons 62, 634
Neuro-osteoarthropathic joint 468
Neuropathic cachexia 228
Neuropathic foot 467, 470, 472
ulcer 479t, 528
clinical symptoms of 479
Neuropathic plantar ulcer 465f
Neuropathic ulcer 479
treatment of 472
Neuropathy 162, 317, 424
classical triad of 463
clinical manifestations of 337f
diabetic peripheral 315, 551, 790
symptoms of 790
Neuropeptides 640
Neurosensory disorders 497
Neutral protamine Hagedorn 250, 673, 695-697, 730, 736
Neutropenia 776
Neutrophil
chemotaxis adherence 779
dysfunction 429
Nevirapine 436
New York Heart Association 395
Niacin 113, 373, 375
Nicotinamide
adenine dinucleotide 68, 69
hydride 356
phosphate 65, 322, 356
diabetes intervention study 802
Nicotine
dependence-smokeless tobacco, Fagerström test for 830
patches 751
replacement therapy 751, 831
Nicotinic acid 44, 373
Nitric oxide 90, 401
concentrations of 90
synthase, inducible 354
Nitroprusside testing
false-negative 299
false-positive 299
Nocturia 484
Nonalcoholic fatty liver disease 160, 426, 428, 511, 512, 553, 623, 663
activity score 516
and steatohepatitis 511
associations 512
clinical features 514
diagnosis 514
differential diagnosis 516
laboratory findings 514
management 516
mortality 516
pathogenesis 512
prevalence 511
etiology of 623
Non-clostridial gas gangrene 424
Noncommunicable diseases 381, 381f, 805
major burden of 246
Nondihydropyridine calcium channel blocker 359
Nonenzymatic glycation reactions 497
Non-exercise activity thermogenesis 581
Noninsulin injectable therapies 683
Nonnucleoside reverse transcriptase inhibitors 436
Nonoxidative leucine disposal 121
Nonproliferative diabetic retinopathy 314, 314t
mild 330
moderate 330
severe 319
treatment for severe 330
Nonstress test 222
Nonsulfonylurea secretagogues 10
Nonsurgical periodontal therapy 490
Nonulcer pathologies 470
Noonan syndrome 277
Norepinephrine 75, 343
Normoglycemia 274
Nortriptyline 828, 830
Novorapid 220
N-terminal pro-brain natriuretic peptides, elevated 643
Nuclear factor-kappa beta ligand 467
Nucleic acid, locked 113
Nucleoside reverse transcriptase inhibitors 434, 435
Nucleotide
oligomerization domain 100
reverse transcriptase inhibitors 436
Nurses’ health study 621, 839
Nutrition
and health awareness 806
in surgery 746
intervention 556
parenteral 516
proximate principles of 65
recommendations 557
therapy, goals of 549b
Nystatin 494
O
Obesity 241, 244, 248, 254, 255f, 259t, 268, 270, 273, 389, 407, 710
abdominal 131, 267, 268
criteria for 557t
development of 269
dyslipidemia syndrome 267
early stages of 141
evaluation of 548
incidence 253
insulin resistance-diabetes 759
major causes of 133
management of 257
new onset of 698
paradox 256, 257, 260
persistence visceral 127
points 255
prevention of 570t, 806
visceral 149
Obeticholic acid 518
Obstetric surgery 744
Obstruction, mechanical 200
Obstructive sleep apnea 254, 553
prevalence of 553
Octreotide 348
low doses of 348
Ocular muscle palsies 319
Olanzapine 831
Omega-3 fatty acids 88, 376, 565, 567
Ominous octet 640, 683
Onychomycosis 470
Opioid antagonist 258, 259
Optic
atrophy 276
disk swelling 319
neuropathy 319
Optimal chronic care model 794b
Oral anticoagulants, newer 403
Oral antidiabetic
agents 738
development of 9
transition to 732
drugs 112, 221, 532, 678, 732, 772 745
treatment 718
Oral glucose
load 75, 207
tolerance test 18, 41, 93, 157, 175, 215t, 430, 716
Oral hypoglycemic agents 169, 221, 229, 438, 439, 519, 677
Oral ulcers, higher prevalence for 496
Orlistat 131, 164, 270, 518, 763, 764
Orthostatic hypotension 343, 346, 348, 484, 550
treatment of 348
Osseointegration 501, 501f
Osteoarthritis 483, 487
Osteoarthropathy, diabetic 487
Osteocalcin 485
Osteomyelitis 471, 471f
Osteoporosis 483
specific therapy for 486
Osteoprotegerin 490f
Otelixizumab 800
Otitis externa, malignant 424
Ovarian failure, primary 94
Oxalate nephropathy 258
Oxazepam 831
Oxidative stress 110-112, 143, 355, 356, 423, 497
Oximetry, transcutaneous 415
Oxygen 65
transcutaneous pressure of 409, 471
P
Padhastasana 581
Pain, abdominal 199, 258, 821
Paliperidone 831
Palpitations 229
Pancreas 194, 248, 644, 771
after kidney transplantation 774
beta-cell of 73, 95
carcinoid tumor of 127
carcinoma of 249
development of 53, 172
duodenum homeobox-1 777
endocrine 103
pancreatic beta cell of 85
pathology of 53
transplantation 773, 774, 777
Pancreatic acini
chromogranin 54f
normal 54f
Pancreatic beta-cell 45, 632, 634, 836
autoimmune destruction of 212
glucose sensor of 171
Pancreatic carcinoma 48
development of 200
Pancreatic diabetes, causes of 194b
Pancreatic disease 194, 285
types of 48fc
Pancreatic ducts 778
Pancreatic enzyme supplementation 200
Pancreatic function tests 190t, 199
Pancreatic infection 426, 427
Pancreatic inflammation, role for 101
Pancreatic islet 778
beta-cells, destruction of 273
cell antibodies 186
hormone 687
Pancreatic polypeptide 54
Pancreatic structure, tests of 198, 199
Pancreatitis 44
acute 194, 301, 644
alcoholic chronic 194, 195, 195t
chronic 55f, 194, 198, 200b, 285
calcific 194
tropical
calcific 194, 197f
chronic 197f
Pancreatopathy 196
fibrocalculous 44
Pancreatozymin 190t
Papaverine 540
Paracrine 105
Paraesthesias 259
Paragangliomas 126, 129
diagnosis of 129
treatment of 129
Parasitic infestations 100
Parasympathetic system, assessment of 345
Parathyroid hormone 484, 840, 840fc
concentration of 837
Parathyroidectomy 131
Paresthesias 348
Parivrtta trikonasana 581
Paroxetine 828, 829
Peak plasma insulin 212, 223
Pedersen hypothesis 212f
Pegvisomant 128
Pelvis 129
Pen injectors 220
Penile
arterial insufficiency 537
prosthesis 540
Pentamidine 44, 285
Pentosidine 485
Pentoxifylline inhibits 518
Peptide YY 133, 640
Percutaneous coronary intervention 386, 391, 743
Periodontal disease 433, 489, 490fc, 554
nonsurgical management of 490
pathophysiology of 490
severity of 489
surgical management of 490
Periodontitis 433, 489, 492
aggressive 433
chronic 433
severe 490f
Peripheral artery disease 317, 405, 479
lower-extremity 418
symptomatic 385
Peripheral fat, loss of 436
Peripheral neuropathy 138, 230, 464, 467, 484
presence of 479
prevalence of 284
risk of 432
Peripheral vascular disease 230, 405, 424, 465
clinical
evaluation 408
presentation 408
diagnosis 408
etiopathogenesis 406
evaluation of 772
imaging studies 415
investigations 415
laboratory studies 410
management 416
medical management 411
mortality risk 406
noninvasive evaluation for 409
pathophysiology 406
prevalence and incidence 405
prognosis 418
risk factors 407
structured exercise therapy 411
treatment of symptomatic 413
Peritoneal dialysis solution 604
Permissive hypertension, concept of 402
Peroxisome proliferator activator receptor 523, 760, 837
Petrosal sinus sampling, bilateral inferior 127
Phagocytes, activated mononuclear 141
Phagocytosis 144, 423, 779
Phenelzine 828
Phentermine
extended release 258, 259, 763
safety of 764
Phentolamine 540
Pheochromocytomas 44, 126, 129, 130fc, 278
diagnosis of 129
treatment of 129
Phosphate
replacement 306
serum 301
Phosphatidylinositol-3-kinase 61
Phosphodiesterase-5 inhibitors 539
mechanism of action of 539
Phosphoenolpyruvate carboxykinase 73
Phosphofructokinase 70
activation of 70
inhibition of 70
Phosphoglycerokinase 73
Phosphoinositide
3-kinase signaling 255
activation of 118
dependent kinase 1 119
Phosphorylase 68, 70
Phosphorylation, oxidative 66f, 67
Physical activity 164, 269, 385, 548, 574, 718
intensity levels 575
Piloerection 348
Pinprick sensation 470
Pioglitazone 112, 325, 439, 484, 625, 626, 739, 754
antiatherosclerotic action of 625
association of 250
risk-benefit analysis of 627t, 628
Pitavastatin 370
Placenta 818
delivery of 745
during pregnancy 48
Placental chorionic somatomammotropin 205
Plantar
assessment, sites of 315f
callus, growth of 467
metatarsal pads 472
pressure 466, 467
quantitative measurement of 466
ulcers 467
xerosis 467
Plasma 190
C-peptide levels 281
glucagon secretion 105
glucose 43, 215, 222t, 274
fasting, measure of 43
postprandial 734, 738
insulin, basal level of 77
iron 515
ketones 190
after epinephrine 190
osmolality 300
triglycerides 70f
Plasminogen activator
inhibitor 122, 248, 268, 622
production of 634
Plastazote 474
Platelet
activated 145
aggregation 401
Pluripotent stem cell 777, 821
Pneumococcal vaccines 452
Pneumonia
community-acquired 451
related hospitalizations, risk of 451
Pneumovax 23 452
Polioviruses 89
Polyclonal anti-T-cell antibodies thymoglobulin 774
Polycystic ovarian
disease 221
syndrome 42, 131, 131t, 243, 623, 711
Polycythemia 210
Polydipsia 274, 280, 435
Polyendocrine syndrome, autoimmune 94
Polyethylene foam 474
Polyhydramnios 211
Polymorphisms 142, 276, 354
Polymorphonuclear leukocytes, action of 143
Polyneuropathy 283, 465
Polyol pathway 143, 341, 357
activation of 401
Polypeptide, pancreatic 76
Polyphagia 280, 435
Polyunsaturated fats 558, 564
Polyuria 274, 280, 435
Porphyria 44
Portal vein 200
Postpartum, vicious cycle of 241
Postprandial blood glucose 220, 695, 717
monitoring of 220
Post-translational histone modifications 111
Potassium 304, 761
channel 170
sensitive 632
serum 301
therapy 305b
Potent phagocytic stimulus 100
Potent protein anabolic hormone 115
Prader-Willi syndrome 44
Pramlintide 688, 694, 698, 761, 762
Pranayama 151, 581
Prandial glucose regulators 638
Pravastatin 370
Prazosin 211
Preadipocytes, insulin stimulates differentiation of 255
Prediabetes 157, 162
complication 162
prevalence of 158
Prednisolone 736, 773
single dose 736
Prednisone 774
Pre-eclampsia, increased risk of 49
Pregnancy
acute fatty liver of 516
insulin requirement of 217
prediabetes in 710
second trimester of 221
third trimester of 221
Premixed insulins 672, 677
analog 672
conventional 672
Primary care physician 785, 787, 788
Probucol 518
Professional continuous glucose monitoring system 610, 611
Proinflammatory cytokines 447, 759
release of 138
serum levels of 139
synthesis of 139f
Prolactin 149, 205
Proliferative diabetic retinopathy 211, 283, 330
management of 331
treatment for 330
Prolyl endopeptidase 640
Propranolol 290
Proprotein convertase subtilisin 374, 386
Prostaglandin 354, 540
Prosthesis, implant supported partial 500f
Prostoglandin analogs 349
Protease inhibitor 278, 433-436
therapy 435, 436t
Protective pain sensation, loss of 467
Protective sensation, loss of 315, 315f, 467
Protein 65, 558, 563, 718
degradation 743
energy malnutrition 186
homeostasis 123
kinase 119b
activation of 109, 140, 355
C 322, 336, 341, 382
loss, rapid 115
metabolism 41, 115, 116, 117f, 118, 121-123
normal metabolism of 115
synthesis 73, 120, 840
role in 67
tyrosine phosphatase 88
Proteinuria 11, 354
Protriptyline 828, 830
Pruritus 348, 528
Pseudocyst 200
Pseudohyperchloremia 301
Pseudohypoglycemia 290, 301
Pseudomonas aeruginosa 228
Psoriasis 528, 534
Psychiatric comorbidity and diabetes 826
Psychiatric disorders 277, 826
Psychological disorders, prevalence of 554
Psychomotor agitation 828
Psychosocial disorders 554
Puberty 273
Pump failure 749
Pyelonephritis 424
Pyoderma 528
Pyogenic infections 547
Pyrazinamide 432
Pyridostigmine bromide 349
Pyridoxine 432
Pyruvate 65
carboxylase 73, 290
dehydrogenase 68, 72
transamination of 73
Q
Qsymia 259, 763
Quadrivalent vaccines 455
Quantitative plantar pressure measurements 463
Quantitative sensory testing 338, 339
R
Rabbit thymoglobulin 773
Rabson-Mendenhall syndrome 44
Radiobinding assay 92
Radioimmunoassay 92
Raloxifene 486
Raltegravir 436
Ramipril 349
Randomized controlled trials 809
Ranibizumab 329
Rapamycin complex 2, mammalian target of 119
Rapid acting insulin analogs 220, 221, 673, 695
Rectal sensations, impaired 344
Reflex sympathetic dystrophy 483, 487
Regular macrodrip set 729
Relaxation technique 581, 830
Renal damage 357, 753
Renal disease 320, 321
end-stage 353
Renal failure 229, 552, 744
chronic 424
Renal function tests 746
Renal impairment 624, 649
Renal parenchymal cells 821
Renal transplant 49
Renin–angiotensin–aldosterone system 356, 840
Repaglinide 632, 739
Research Society for Study of Diabetes 631, 637, 678, 703
Resilience 465
exercise, intensity of 575
Respiratory distress syndrome 210
Respiratory system 53
Restore oxygen delivery 323
Retardation, growth of 121
Retinal capillaries, leak out of 324
Retinal detachment 319
rhegmatogenous 331
tractional 331
Retinal vein occlusion 319
Retinopathy 128, 163, 317, 750
Revascularization procedures, indications of 415
Reye syndrome 516
Rhabdomyolysis 309
Rheumatoid arthritis 126, 276
Rhinocerebral mucormycosis 424, 439
Rhizopus oryzae 439
Rhomboid glossitis 493
Ribose-5-phosphate 65
Rifampicin 431, 432
Rifampin 430
Ringer's lactate 304
Risedronate 486
Risperidone 831
Ritonavir 436
Rituximab 183
Root canal treatment 493
Rosiglitazone 325, 395
Rosuvastatin 370
Rubella 88
Rubeosis iridis 319
Rubeotic glaucoma 331
Ryle's tube 739
S
Saint Vincent declaration 795
Salicylate 290, 604, 636
poisoning 299
Salivary dysfunction 489
Salivary gland functions, impaired 489, 494
Salivation test 347
Salmonella enteritidis 440
Saquinavir 436
Sarcopenia 483, 487
Saroglitazar 373, 524, 662, 663
chemical structure of 661f
clinical placement of 662
use of 663
Sarvangasana 581
Saturated fat 558, 564
Saxagliptin 393, 642, 762
Schizophrenia 826, 827, 831, 831t
features of 827
Scleredema diabeticorum 529
Sclerodactyly, diabetic 483, 487
Scleroderma-like syndrome 528, 529
Seizure disorders 259
Selected proinflammatory cytokine gene polymorphisms 141t
Selective estrogen receptor modulator 486
Selective recurrent beta-cell destruction 92
Selective serotonin 258, 259
reuptake inhibitors 828, 829
Sensation 479
Sensor
augmented insulin pumps 701
glucose levels, target 766
integrated pumps 766
Sensorimotor neuropathy 338, 424
symptoms of 338, 338b
Sensory nerve functions 821
Sensory neuropathy 474
development of 467
presence of 467
Sensory peripheral neuropathy 779
Serine-threonine kinases, activation of 255
Serotonin-dopamine
activity modulators 828
antagonists 831
Serotonin-norepinephrine reuptake inhibitors 828
Sertraline 828, 829
Serum alpha-fetoprotein, maternal 222
Serum beta-hydroxybutyrate, direct measurement of 299
Serum cholesterol 190
levels, low 428
Serum lipid 190t
levels 320
Serum protease inhibitor Kazal type-1 196
Sex hormone-binding globulin 247
production, suppression of 62
Sexual dysfunction 537, 790
Shock, cardiogenic 393
Shoulder
joint
adhesive capsulitis of 483
calcific periarthritis of 483
pain 483, 487
Sialoadenosis 494
Sialoglycoprotein 92
Sight-threatening disease 318
Signal transducer, activation of 248
Sildenafil 539
Silent myocardial
infarction 344
ischemia 343
Simvastatin 370
Single donor islets, use of 775
Sirolimus 818
Sitagliptin 642, 762
Skeletal muscle 127f
cells 634
mass
decrease of 483
loss of 115
protein
anabolism 118
synthesis 118
tissue including 120
Skin 644
and mucosal colonization 779
diseases associated with diabetes 528
disorders 283
in diabetes 528
punch biopsy 338
Sleep
apnea 243
disturbance 283, 829
Slit-lamp laser 330
Smartguard technology 766
Smooth muscle cells 634
Sodium 558, 567
carbonate 305
chloride 303
glucose 763
cotransporter-2, use of 439
linked transporter 2 inhibition, role of 763
myo-inositol co-transporter 402
potassium adenosine triphosphatase 402
serum 300
Sodium-glucose cotransporter 13, 299, 302, 393, 394, 484, 647, 648, 650, 678, 739
inhibitors 233, 235, 260, 396, 524, 563, 647, 651f, 700, 705, 734
contraindications 651
efficacy 648
mechanism of action 647
pleiotropic benefits 649
posology 648
precautions 651
side effects 650
Solar ultraviolet B radiation 836
Solid organ transplantations 642
Somatostatin 54, 76, 103
analog 348
drugs 128
secreting adenomas 126, 129
Somatostatinoma 44, 126, 129
Somogyi effect 293
Sorbitol 567
myo-inositol osmolarity changes 497
pathway 80
Specific cell membrane insulin receptors 510
Speech, disorganized 831
Sphingomyelin 210
Spina bifida 209
Spironolactone 131, 349
Spleen 778
Splenectomy 42
Splenic vein 200
Split-mix regimen 696
Sputum
acid fast bacilli 432
positive disease 431
smear samples 448
Stain-Masson's trichrome stain 54f
Standard height and weight chart 557t
Staphylococcal infections 424
Starch, nature of 561
Starvation 77, 516
ketosis 298
Statin 113, 131, 373, 374
intolerance 373
therapy 232, 373
Stavudine 435, 436
Steatohepatitis, nonalcoholic 425, 509, 511, 524, 623, 663
Steatorrhea 200
Steatosis 515
Stem cells 771, 817, 818
major characteristics of 818
properties of 818
reaching lungs, major bulk of 821
therapy 817, 819
types of 818
undifferentiated 53
Steroids 329
anti-inflammatory agents 499
discontinuation of 737
dose equivalents 736t
induced diabetes, management of 736
sparing regimen 818
tapering of 737
use of 736
Stiff-man syndrome 44, 92
Stomach 248
cancer, prevalence of 246
Stomatitis, aphthous 496, 496f
Streptomyces bacteria 494
Streptozotocin 90
induced diabetic rats 355
Stress 88, 147, 149, 229, 584
and diabetes 147
behavioral 148
chronic 149
diabetogenic 205
endocrine 148
hormone 297
cortisol 149
hyperglycemia 727, 743
clinical implications of 743
pathogenesis of 743
transition in 732
management 151
osmotic 322
presence of 297
psychological 147, 269
response 147, 149, 742
role of 148
test, low-risk 386
Stroke 165, 236, 399, 400, 625
anterior circulation 399
cardioembolic 401, 403
epidemiology of 399
hemorrhagic 399
pathogenesis of 401b
pathophysiology of 400
posterior circulation 399
prevention of 403
volume 343
Stroma, fibrosed 817
Subcutaneous insulin
delivery, devices and techniques 674
infusion pump 8
protocols 306
role of 306
transition to 305
Substance use disorders, diagnosis of 827
Substantial cardiovascular disease 751
Succinyl-CoA 65
Sucrose 562
Sudden cardiac death 381
Sudomotor tests 347
Sukshma vyayama 581
Sulfonamides 636
Sulfonylurea 171, 233, 250, 394, 631-634, 637, 704, 732, 733, 735, 754
adverse effects of 635
compounds, chemical structure of 633f
current positioning of 637
discovery 632
extrapancreatic effects of 634, 634t
high dose of 278
mechanism of action of 633f
second generation 519
structure of 632
Superoxide anion
excess of 110
production, increased 109
Superoxide dismutase 354
activity of 110
Superoxide production 144
Suppresses gluconeogenesis 75
Suprachiasmatic nuclei 134
Surgery
and preoperative management, types of 744
cardiac 745
role of 331
transplant 745
transsphenoidal 127, 128
Surrogate markers 485
Surya Namaskara 581
Sweat glands symptoms 338
Swelling, onset of 469
Swollen foot, unilateral 469
Sympathetic nervous system 575
Sympathetic system, assessment of 345
Sympathomimetic amine anorectic 258, 259
Syntax score 387
Systemic lupus erythematosus 276
T
Tachycardia 345
Tacrolimus 278, 773, 774, 818
Tadalafil 539
Tamoxifen 516
Tarsometatarsal joints 469f
Taste impairment 489, 494
T-cell 90
abnormalities 92
islet reactive 179
lymphocytes, subset of 100
mediated autoimmune disease 92
Technetium diphosphonate bone 469
T-effector cells, activation of 89
Tegaserod, use of 506
Teneligliptin 643
Tenofovir 436
Teplizumab 94, 800, 801
Teriparatide 486
Tetanus diphtheria and pertussis 457
Tetracycline 604
Tetrameric protein 61
Thermal insulation 475
Thermoregulatory sweat test 347
Thiazide 44
diuretics 285
Thiazolidinediones 8, 131, 233, 234, 250, 325, 393, 438, 439, 484, 624, 627, 705, 732, 733, 760
efficacy 625
indications and contraindications 627
mechanism of action of 624, 625f
Thrombocytopenia 428
Thromboembolic events 309
Thrombolysis 402
mechanical 402
Thyroid
abscess 440
diabetes 262
disease 262
disorders 275
prevalence of 262
dysfunction 264
diagnosis of 263
management of 264
underlying 264
hormone 44
effects of 129
replacement 258
peroxidase 275
stimulating hormone 191, 263
Thyroiditis, chronic lymphocytic 94
Thyrotoxicosis 263
Thyrotropin-releasing hormone 191
Thyroxine 126
Tilt table testing 347
Tissue
breakdown 472
damage
chronic 467
hyperglycemia-induced 109
extrapancreatic 778
glycogen storage 205
peripheral 76
plasminogen activator 122
indications for 402
Titrate insulin therapy 680
T-lymphocytes 801
pattern of 801
Toe-
brachial index 409
deformities of 469
Tolazamide 604
Tolbutamide 9, 634
Toll-like receptor 139
signaling 112
Tongue
changes 489, 496
surface of 493
Tooth loss 489, 492
Topiramate 764
extended release 258, 259, 763
Total parenteral nutrition 739, 746
Touch perception, testing of 315
Toxic metabolites 255
Toxic multinodular goiters 262
Trabecular bone score 485
Tractional retinal detachment 331
Tractus solitaries, nucleus of 133, 135
Transcellular exudation 323
Transcription protein signaling pathway, activator of 248
Trans-fatty acid 270, 565
amount of 269
Transplant recipients
scientific registry of 774
types of 49t
Transplant, types of 49
Trauma, external 467
Trazodone 828
Tremors 229
Trialnet nutritional intervention 802
Tricarboxylic acid cycle 67, 70f
Trichophyton 531
Tricyclic antidepressants 828, 830
Trifluoperazine 831
Trigger finger 230, 486
Triglyceride 140, 165, 190, 236, 627, 761
accumulation, causes of 512
content 56
elevated 368
serum 267, 268
Trimipramine 828, 830
Triosephosphate dehydrogenase 73
Tris-hydroxymethyl-aminomethane 305
Trivalent inactivated influenza vaccine 454
Troglitazone 519
Trypsinogen pathway 196
Tuberculosis 424, 430, 431, 431t, 440, 444
and diabetes mellitus 429
causes of 429
diabetes interactions, immunology of 447
peculiarities of 431
severity 448
treatment of 447
Tubular dysfunction 753
Tubules, renal 80
Tumor
necrosis factor 138, 368, 743
alpha 100, 140, 141, 322, 426, 427, 447, 467
gene 87f
suppressor gene 127
encoding 127
Tumorigenicity, soluble suppression of 383
Turner syndrome 44, 276
Tyrosine
phosphatase 45, 92, 694
phosphorylation 140
insulin induced 100
U
Ulcer
characteristics of 479
development of 467
location of 479
traumatic 496
Umbilical cord
blood therapy, autologous 820
derived stem cells 818
United Kingdom Department of Health 455
United Kingdom Prospective Diabetes Study 12, 109, 313, 365, 403
United States Diabetes Prevention Program 810
United States Food and Drug Administration 258, 455, 763
Universal Framework for Glycemic Control Strategy 768
University Group Diabetes Program 12
Upper respiratory tract infection 761, 764
Urea cycle 116f
Uridine diphosphate glucose-glycogen glucosyltransferases 68
Urinary frequency 338
Urinary retention 348
Urinary tract infection 283, 338, 761, 763, 772
chronic 424
risk of post-transplant 772
Urine glucose measurement 42
Urine ketones 699
Urine microalbumin 359
Uronic acid pathway 67
Ursodeoxycholic acid 518
Utero-placental perfusion 221
V
Vaccinations, childhood 88
Vaccine, types of 454
Vacuum
assisted-closure device 475
erection device 540
Vaginal delivery 737
Vaginal dryness 338
Vagus nerve dysfunction 344
Valent conjugate vaccine 452
Valent polysacchari vaccine 452
Valine 121
Valproate 516
Valsalva maneuver 345, 346
Valsalva test 345
Varenicline 831
Varicella-zoster
primary infection syndrome of 456
virus 456
Vascular bypass grafting 417
Vascular diseases 320
Vascular endothelial growth factor 100, 322, 323, 354, 819
Vascular injury, underlying cause for 497
Vascular smooth muscle 634
Vascular thrombosis 775
Vasoactive intestinal polypeptide 131
secreting adenomas 126, 131
Vasodilation, insulin induced 118
Venlafaxine 828
Ventricular septal defects 209
Vertebrobasilar obstruction 399
Vessel disease, large 34
Veterans Affairs Diabetes Trial 109, 316
Viagra 539
Vibration perception threshold testing 470
Victoza 761
Vildagliptin 762
Vipomas 126, 131
Viral infection 48, 273, 275, 424
incidence of 772
Virus 88, 455
Visible fats 564
Visual impairment 280, 484
Visual loss 320
Visual refractive changes 284
Vitamin 558
25-hydroxylase 836
B12 deficiencies 42, 623
B6 218
C 218
absorption 838
and beta-cell function 836
and diabetes 836
and gestational diabetes mellitus 838
and preparations 840
and systemic inflammation 838
and type 1 diabetes mellitus 840
binding protein 836
deficiency 273, 430, 836, 837
effects of 837
emerging role of 836
formulations 840
functions 837
insufficiency 430
intake 838, 838t, 839t
major circulating form of 836
metabolite of 838
optimize 486
physiology of 836, 837fc
preparations, types of 840
receptors, expression of 836
role of 163, 836, 837b
status 836, 838f
supplementation 88, 553
D2 836
metabolite of 838
D3 836
metabolite of 838
E 517
K 11
malabsorption of fat soluble 258
Vitiligo 528, 533
Vulvovaginal pruritis 763
W
Wagner's classification 465, 465fc
Weight gain 636
and edema 626
during pregnancy 717, 717t
gestational 241
rapid 88
Weight
loss 121, 255, 256, 260, 274, 280, 371, 431, 486, 517, 760, 764
reduction and obesity management 359
White's classification 211t
Whole body protein synthesis, indicator of 121
Whole-genome association studies 86
Wilson disease 516
Wolfram syndrome 44
World Health Organization 179, 186, 423, 444, 715
criterion, advantages of 214
procedure 213
Worldwide Prevalence of Diabetes 794
Wound
classification 466fc
debridement 414
dressings of 414
healing 475
delayed 284, 489, 497
prevention of delayed 497
infections, increased risk of 746
X
Xenobiotics 196
Xerostomia 259, 489, 494
management of 494
Xylitol 567
Y
Yoga 151
therapy and diabetes 581
Yogasana 581
Yohimbine 538
Z
Zidovudine 434, 435, 436
Zinc 218
transporter 8 92
antibodies 694
Ziprasidone 831
×
Chapter Notes

Save Clear


1PREAMBLE2

A Brief History of DiabetesCHAPTER 1

V Sri Nagesh,
Shashank R Joshi
 
INTRODUCTION
Any attempt at describing the history of diabetes, is by default, an attempt at describing the history of mankind. Diabetes is a disorder with which mankind has been acquainted since the dawn of recorded history and even a cursory perusal of the history of medicine throws up numerous instances when physicians of yore have given detailed descriptions of the symptoms of diabetes. These descriptions not only give us an insight into the origins of this disorder but are in effect a social commentary on the socioeconomic conditions, religious beliefs, diets, and the scientific practices of the various timelines during which diabetes has been mentioned.
For simplicity and ease of understanding, the history of diabetes can be divided into six distinct timelines:
  1. Antiquity—from the earliest times till the fall of Rome
  2. Middle ages—from the fall of Rome till the fall of Constantinople
  3. Renaissance—from the fall of Constantinople till the Second World War
  4. Modern era—from the 19th century till the discovery of insulin
  5. Insulin era
  6. Postmodern era—from the end of the Second World War till the modern era.
 
ANTIQUITY
The earliest known mention of diabetes appeared in 1552 BC in a 3rd Dynasty Egyptian papyrus authored by Hesy-Ra, one of the world's first documented physicians. This papyrus is well known to all students of medicine as the Ebers Papyrus,1 named after the German Egyptologist George Ebers who first purchased it in Luxor in 1862. It is presently housed in the University of Leipzig, Germany. The papyrus does not give a detailed description of diabetes or for that matter even recognize diabetes as a disease but rather mentions briefly an illness causing the passage of too much urine. Other papyri like the Brugsch Papyrus2 (1350–1250 BC) and the Hearst Papyrus3 (1600–1500 BC) that are less well known, also describe polyuria, but there is no clear differentiation between diabetes and other causes of polyuria.
 
Ancient India
Perhaps the first detailed and by far most accurate description of diabetes was provided circa 6th century BC in India by Sushruta.4 In ancient India, diabetes was known as prameha (pra: excess, meha: urine), a term used to refer to the disease even today in certain Indian languages. It is mentioned in the Chakradatta that Lord Shiva dictated a formulation for the treatment of prameha to his son Lord Ganesha. Another view is that Ganesha himself suffered from prameha in view of his predilection for sweets and sedentary lifestyle.
The Charaka Samhita, describes prameha in great detail. It recognizes 20 types of prameha, which, if not treated, can lead to madhumeha (madhu: honey, meha: urine; literally sweet urine, an unambiguous description of diabetes). It was noted that the disease could be diagnosed by detecting ants congregating around the patient's urine. The hereditary nature of the illness is also described in this ancient text.4
 
Greco-Roman
While it is true that the father of Medicine Hippocrates does not dwell upon diabetes, in one of his works he does mention a disease associated with excess urination and withering away, for which he recommended dietary therapy. A century and a half later, around 230 BC, Apollonius of Memphis5 first called this disease with wasting and polyuria, diabetes, which was the Ionic Greek word for siphon—to signify the siphoning away of fluid from the patient's body.
Three and a half centuries later, the Latin encyclopedist Aulus Cornelius Celsus,5 a contemporary of Augustus and Tiberius, who was responsible for compiling the extensive “De Medicina“ described a painless and invariably fatal polyuria associated with thirst, hunger, and emaciation.
A century later, the Syrian dentist Archigenes, a contemporary of Trajan, recorded diabetes among his list of multiple nervous ailments and recommended narcotics as a treatment. However, noteworthy, none of these physicians of antiquity made any attempt to differentiate diabetes mellitus from insipidus or to differentiate diabetes from other disorders associated with emaciation and polyuria like renal tubular acidosis and referred to all disorders with polyuria as diabetes.
However, the first clear and complete description of diabetes was made by Aretaeus of Cappadocia,6 a famous physician of the late Hellenistic period. Born in Cappadocia, a region of eastern Asia Minor, he studied medicine in Alexandria and practiced in Rome. Aretaeus belonged to the Eclectic School of Medicine. Its members were so called because they selected, from previous medical treatises, those parts which they deemed most rational and discarded irrational concepts. His treatise on diabetes consists of three parts—in the first part, all the common signs and symptoms of the disease are presented. In the second part of Aretaeus’ text, where the patient's symptoms are intricately but eminently clearly analyzed according to the stages of disease progression, valuable new information is presented which is missing from other physicians’ medical texts. In the final part, he hypothesized a correlation of diabetes with other diseases, this leading to the conclusion, probably original in conception, that a series of events occur in the organism that manifest the onset of the disease and also provides differential diagnoses. He also provided a set of dietary modifications to offset this excess thirst that included milk, wine, and cereals in diet.
 
Galen
Perhaps the last great physician of antiquity to write extensively about diabetes was Aelius Galenus or Claudius Galenus (often Anglicized as Galen and better known as Galen of Pergamon, often considered the greatest of the ancient physicians. He was a Greek who lived in the Roman Empire and was a contemporary of Marcus Aurelius, Commodus and Septimius Severus. Starting from the era of Galen, most of the texts of antiquity started ascribing the etiology of diabetes to the kidney.7
 
MIDDLE AGES
The Middle Ages are characterized by a steep decline in arts and sciences that flourished during the antiquity and the same holds true even for diabetes. The beliefs of Galen held sway during the Middle Ages and diabetes continued to be perceived as a disease of the kidney till Paracelsus prompted a relook at the pathology of diabetes as part of his medical renaissance. While progress in the study of diabetes was often limited and dogmatic, the condition was not totally neglected and there are quite a few extant texts that still speak about diabetes, predominantly from Persian and Arabic sources. One of the first mentions of diabetes in the Middle Ages comes from the Byzantine Paul of Aegina's seven-volume Epitome,5 that followed the principles laid down by Galen and attributed diabetes to “weak kidneys”. Treatment included herbal concoctions, knotgrass, hydration, and application of topical creams and poultices to promote cooling and reduce dehydration. Based on his clinical experience, Paul was also critical of the use of diuretics in diabetes.
Later, the 9th century Arab writer Rhazea was one of the first medieval writers to translate parts of Ayurveda in Arabic, including the observations of Sushruta and Charaka about diabetes. The 10th century writer Haly Abbas also mentioned diabetes and attributed it to “excessive heat from the viscus”.
The most significant observations about diabetes in the Middle Ages were undoubtedly from the works of the legendary physician Ibn Sina or Avicenna,8 as he was known to the West. His book, “The Canon of Medicine” was remarkable for its detailed and often accurate descriptions of the complications of diabetes including gangrene, erectile dysfunction, carbuncles, tuberculosis, and blindness, as also the role of hepatic dysfunction in diabetes. He was also perhaps the first person to 5advocate the use of fenugreek in diabetes, an anecdotal and undocumented addendum to the armamentarium of folk remedies for diabetes, that continues to be wildly popular even today, in spite of no concrete evidence whatsoever as to its efficacy. The other major contribution of Avicenna was in his recognition of diabetic neuropathy and in his recognition that diabetic urine was sweet, a fact rediscovered due to his practice of outsourcing the tasting of urine to the water tasters he employed.
The first Western mention of diabetes in the Middle Ages occurs in the work of Gilbert the Englishman, in the book “Compendium Medicinae”9 where he mentioned about diabetes. However, consistent with the set of beliefs prevalent through the Middle Ages, Gilbert considered diabetes as a renal disease and the treatments he suggested for this disorder were based on the theories of humor of Galen and were fanciful at best.
 
THE RENAISSANCE OF DIABETES
The beginning of the renaissance of diabetic medicine can be attributed to the Swiss physician Theophrastus Bombastus von Hohenheim, better known as Paracelsus.10 He was the first person in almost 1500 years to challenge the kidney-centric theories of diabetes and was scathingly critical of water tasting physicians, whom he dismissed as piss prophets. He considered diabetes as a constitutional disease that “irritated the kidneys” and provoked excessive urination. He evaporated the urine of diabetic patients and obtained a whitish residue which he erroneously considered to be a salt, rather than sugar, which the white residue actually was. His importance in diabetes research is due to the fact that he recommended a scientific approach to the diagnosis of diabetes, rather than relying on urine testing and fantastic remedies.
The Milanese magus Gerolamo Cardano,11 who also happened to be a medical astrologer, is best known for his contribution to game theory and the first description of typhoid fever. He was the first person to measure both the input and output of fluids in diabetic patients and concluded that there was a net loss of fluid in people with diabetes.
Andrew Boorde,12 a Carthusian monk who was later discharged from his vows, became a traveling doctor in the 16th century and visited many Universities across Continental Europe. After returning back to England, he published his medical observations in a series of helpful patient information guides accessible to the general public, thus arguably becoming a predecessor of Dr Google and myriad other self-help sites for the patient, that have become the bane of the serious modern medical professional.
In the 17th century, Thomas Willis (better known for first describing the circle of Willis) described that the urine in diabetics, which he evaporated and tasted, was sweet “as if imbued with honey” and it was this observation that prompted further research into the sweet urine in diabetes and ultimately resulted in the differentiation of diabetes mellitus and insipidus. Matthew Dobson,13 a physician at the Liverpool infirmary was the first person to describe the presence of sugar in diabetic urine and hypothesized that the kidneys were perhaps excreting the excess sugar produced by fermentation in stomach. About a century earlier, the Flemish physician Jan Baptista van Helmont, had given the first description of digestion in the body, but even a century later, stomach was still considered a humoral organ. If in the above description of Dobson, fermentation was replaced by digestion, what Dobson actually proposed seemed pretty similar to the actual process of carbohydrate digestion and consequent hyperglycemia induced polyuria.
Subsequently as the concept of sugar in urine became more widespread, John Rollo,14 an army surgeon hypothesized that vegetables were responsible for the generation of sugar in urine and raised the curtains on one of the many fad diets that were to dominate the management of diabetes for the next two centuries and to a great extent still dominate the management of diabetes in the alternate medicine segment. Rollo's diet was a predominantly animal food based and majorly restricted carbohydrates from diet. With minor changes, this remained the most common type of diet prescribed to people with diabetes till the discovery of insulin. The importance of the dietary therapy was that it was one of the first rational attempts to treat diabetes by restricting carbohydrates rather than relying on laxatives, purgatives, and other such medications that were based on Galen's theory of humors.
The British apothecary and astrologer Nicholas Culpeper15 also took a keen interest in diabetes and his brand of folk medicine based on local herbs advised patients with diabetes to use locally available plants such as bistort or snake-weed in any decoction, darnel leaves boiled in wine with pigeons’ dung, and powdered tormentil root in plantain juice to treat their conditions.6
 
MODERN ERA
The modern era started with the application of scientific principles to the study of diabetes and culminated in the discovery of insulin.
In 1815, the French chemist Eugène Chevreul,16 the father of gerontology, was the first person to prove that the sugar in diabetic urine was glucose. Later, Karl August Trommer (1806–79) devised the first test for detecting glucose in urine in 1841. In this test, when urine heated with blue cupric sulfate, in the presence glucose, red cuprous oxide was formed. This was later supplanted by the Fehling test devised by Herrmann von Fehling and though it was quite cumbersome for regular practice, it remained one of the standard methods of detecting blood glucose and is still taught to freshmen in the biochemistry laboratory well into the 21st century, either underscoring its importance or the tendency of a section of the medical community to resist change.
Another dietary modification widely practiced in the 19th century was the starvation diet. The French physician, Apollinaire Bouchardat17 first noticed that starvation as a result food rationing due to the siege of Paris in the Franco-Prussian War of 1870 resulted in a decrease of glucose in urine. This led to his famous advice to diabetics to eat as less as possible and subsequently starvation diets became the mainstay of the management of diabetes till the discovery of insulin.
At around the same time in 1874, Adolf Kussmaul18 gave the first description of diabetic ketoacidosis (DKA). His first description concerned a multiparous obese woman of 35 years who had developed diabetes and gradually lost a lot of weight. She was first referred to Kussmaul by her family physician when she suddenly developed rapid breathing early in the morning, associated with cold extremities, rapid pulse and she eventually became comatose and subsequently died. The deep and rapid breathing was called “diese grosse athmung” (this great breathing) and eventually was labeled with Kussmaul's name. Subsequently the German physician German physician Bernard Naunyn and his pupils discovered that patients with DKA had acidosis and this acid was subsequently identified as beta-hydroxybutyric acid.
Until the 19th century, it was widely believed that diabetes was a renal disease. However, autopsies of diabetes patients failed to show any pathology in the kidneys. The initial steps in piecing together the puzzle were made by the French physiologist Claude Bernard19 in the 1840s. Initially trained as a pharmacist, he later studied medicine and eventually came to be recognized as one of the greatest physiologists in the history of medicine. He invented the term milieu intérieur, and the associated concept of homeostasis. Until Bernard's discovery, it was assumed that only plants could make sugar and that animals did not produce sugar and could only break down sugars made by plants. However, Bernard found that the blood of animals in the fasted state also contained sugar, even if they were not diabetic. He also correctly identified the liver to be the source of glucose in the blood, rather than the lung as was commonly believed and glycogen to be its immediate precursor. He was also one of the principal proponents of vivisection in Europe, a fact that resulted in him being in lifelong conflict with his wife Marie Françoise Bernard, who was a noted anti-vivisection campaigner.
The pancreas first came into the limelight due to the untiring efforts of the Lithuanian scientist Oskar Minkowski20 who discovered that removal of the pancreas in dogs caused diabetes. This focused attention on the pancreas, an organ which had hitherto been considered only as a source of digestive enzymes. Although popular opinion credits the Canadians Frederick Banting and Charles Best with the discovery of the role of pancreas in insulin secretion, it was Oskar Minkowski and his colleague von Mering who demonstrated more than 30 years earlier that the pancreas plays a major role in the cause of diabetes.
The next big step in elucidating the pathophysiology of diabetes was in 1869, when a medical student in Berlin, Paul Langerhans, identified clusters of cells in the pancreas, distinct from the enzyme producing acinar cells.21 These cells were named the “islets of Langerhans” by Gustave Laguesse, who postulated that they might be related to diabetes.
The hypothetical islet secretion was named “insulin” by the Belgian scientist Jean de Meyer in 1909.22
 
INSULIN ERA
The single largest achievement in the history of diabetes is beyond any doubt, and is the discovery of insulin. While Banting and Best did eventually discover insulin, five scientists came tantalisingly close to this great discovery.
In 1905, Eugene Gley, a French scientist, ligated the pancreatic duct of animal and after atrophy of the pancreas, extracted some tissue and he found that the extract decreased glycosuria in depancreatized dogs. However, he did not follow-up on this discovery. 7Similarly, in 1903, two Scottish scientists, John Rennie and Thomas Fraser, attempted to relieve glycosuria in human patients by injecting extracts from fish pancreata. However, the injections produced severe side effects and the experiment was abandoned.
In 1906, the German physician Georg Zuelzer, in association with Minkowski, attempted to alleviate glycosuria in humans by injecting animal pancreas extracts. Again, even though the extracts worked, side effects precluded further research in this area.
Later, in 1919, the Romanian scientist Nicolae Paulescu, in an experiment similar to the one that would be carried out in Canada 2 years later, described a pancreatic extract that cured symptoms of diabetes in depancreatized dogs.23 Unlike the earlier workers, he followed up on his studies and published a series of papers in 1921, culminating in the grant of a patent for “pancreine” in April 1922. However, he did not have the funds necessary to produce his extract in large quantities and his work was ignored when it came to awarding the Nobel Prize for the discovery of insulin.
Therefore, by the end of the second decade of the 20th century, the stage had been set for the orthopedic surgeon and part-time physiology lecturer at the Western University, Toronto, Frederick Grant Banting. When he was asked to lecture to some medical students on the physiology of the pancreas, preparing for his lecture, Banting studied a report by Moses Barron in which he described a patient whose main pancreatic duct had been blocked by a stone, causing atrophy of the exocrine tissue, leaving only the islets behind and in whom diabetes did not develop. The report inspired Banting to set out on the discovery of insulin.
Banting applied to Macleod for financial support. Initially Macleod was unimpressed by Banting's rudimentary knowledge of the pancreas and diabetes. However, Banting's perseverance won through and he was able to persuade Macleod to allow him the use of an old disused laboratory within the facility, along with the services of an assistant. For an assistant, he was offered the choice of two medical students—Charles H Best and Clark Noble. The two tossed a coin to see who should work the first half of the summer and Best won. By the time the second half of the summer came around, Best had become so involved in the work that Noble agreed he should continue for the entire duration.
Banting and Best spent the summer of 1921 in their cramped laboratory, testing out Banting's hypothesis. Banting performed the pancreatectomies and made dogs develop diabetes. Best measured the blood and urinary glucose using the newly developed Benedict-Lewis method. In August 1921, they depancreatized two dogs and treated one with pancreatic extract, leaving the other as control. The control dog died in 4 days while the other survived and did well. However, the process of ligating the pancreatic duct in dogs and waiting for atrophy of the exocrine tissue took close to 7 weeks. This led Banting to look elsewhere for a source of pancreatic extract. He finally found a steady source from fetal calf pancreata, obtained from the local abattoir. Later he found that he could use adult beef pancreas just as effectively. Banting and Best gave the name “isletin” to the active substance in the extract produced by them; the name “insulin” was suggested by Macleod, harking back to de Meyer's work at the beginning of the century.
Around this time, Macleod suggested the addition of Bert Collip, a biochemist, to the team. Collip was able to purify the crude extracts made by Banting and Best and modify it into a form more suitable for use in human patients. The first patient to receive insulin injections was the teenaged Leonard Thompson on January 11, 1922. Thompson, who at 14 years of age weighed only 29.5 kg, received 15 mL of the “thick brown muck”, following which his blood glucose fell from 440 to 320 mg/dL. On January 23, he received a more purified form of the extract prepared by Collip, and this time his glucose levels fell from 520 to 120 mg/dL. This case, along with six others, was reported in the Canadian Medical Association Journal in March 1922.24
So sensational was the discovery of insulin, that scientists concerned were awarded the Nobel Prize in 1923, less than 2 years after the event. The prize actually went to Banting and Macleod. Banting decided to share his prize with Best, whereupon Macleod announced that he would share his with Collip. There remains a considerable debate to this day as to who among the four deserves the most credit for the discovery of insulin. What is certain, though, is that the discovery of insulin ranks as one of the most significant medical achievements of modern times, changing the lives of millions of diabetes patients for the better. It is also of interest that no fewer than three further Nobel Prizes have been awarded in the field of insulin physiology in the succeeding years—to Frederick Sanger in 1958 for the discovery of the amino acid sequence of insulin, to Dorothy Hodgkin in 1964 for deciphering the three-dimensional structure of insulin and to Rosalyn Yalow in 1977 for the discovery of the radioimmunoassay technique to measure insulin levels.8
 
Perfecting the Miracle Drug—Developments in Insulin Therapy
As described earlier, the insulin extracts prepared by Banting and Best were far from the finished product. Even with the best efforts of Collip, the early batches of insulin varied widely in their potency and purity and were as capable of producing allergic reactions as they were of reducing the blood glucose. The product was also susceptible to rapid deterioration. This unsatisfactory state of affairs, fortunately, did not last long.
In January 1923, three of the discoverers of insulin, Macleod, Banting and Best assigned their patent rights to insulin to the Board of Governors of the University of Toronto for the token sum of one dollar each. The University then entered into a contract with Eli Lilly and Company for the commercial production of insulin. This decision was influenced by the fact that in late 1922, George Walden, Lilly's chief chemist, had discovered the technique of isoelectric precipitation, which enabled the manufacture of insulin with stability and purity up to 100 times more than any of the earlier prepared extracts.
In the meantime, August Krogh,25 a renowned Danish scientist and Nobel laureate, happened to visit Toronto during his visit to North America to deliver a lecture at Yale University. He met with Banting and Macleod and left with an authorization from the University of Toronto enabling him to introduce insulin into Scandinavia. By late 1923, Nordisk's insulin production had begun in Denmark.
Further developments occurred in rapid succession (Table 1). In 1926, Abel succeeded in crystallizing insulin for the first time, enabling further improvements in purity. This, however, came at the expense of a reduction in the duration of action, necessitating up to four injections per day in order to ensure stable control of sugars.13 The problem was solved by Hans Christian Hagedorn, who suggested the addition of protamine (an alkaline protein abundant in fish sperm) in isophane (precisely balanced) proportions to insulin.14 The resultant insulin, termed isophane or neutral protamine Hagedorn (NPH) insulin, was the first intermediate-acting insulin preparation. Meanwhile, chemists at Novo (then separate from Nordisk) solved the same problem by adding zinc crystals to insulin; by changing the size of the crystals, one could alter the duration of action of insulin. Thus were born the lente insulins.
In spite of all this progress, there were still several roadblocks to be overcome. A major issue was that allergic reactions were still common, as were disfiguring lipoatrophy and lipohypertrophy. In 1941, the Swedish physician Jorpes26 found that one could prevent these allergic reactions by using highly purified insulin obtained by multiple crystallization. Further work by Steiner demonstrated that these reactions were due to proinsulin and other “contaminants”, which appeared as two additional peaks on insulin electrophoresis. Further efforts by the major insulin manufacturers led to the development of “clean” insulins (monocomponent, highly purified, and single peak) which virtually eliminated the troublesome allergies.
TABLE 1   Landmarks in therapy of diabetes: The modern era
Year
Landmarks
1921
Discovery of insulin
1922
First clinical use of insulin
1926
Insulin crystallization techniques introduced
1946
NPH insulin developed
1955
The first sulfonylurea (carbutamide) introduced
1956
Lente insulin introduced
1957
Introduction of the first biguanide (phenformin)
1963
First premixed insulin introduced
1978
Subcutaneous insulin infusion pump (Pickup, UK)
1982
Recombinant human insulin approved by USFDA
1995
The first alpha-glucosidase inhibitor approved by USFDA
1996
The first rapid-acting insulin analog
1997
The first thiazolidinedione
2000
Edmonton protocol for islet cell transplant
2003
The first long-acting insulin analog approved by USFDA
2005
The first GLP-1 analog
2006
The first DPP-4 inhibitor
USFDA, United States Food and Drug Administration; GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase-4.
The second major issue was a direct consequence of the exploding epidemic of diabetes. By 1976, 1.5 million Americans were taking insulin, with a year-on-year increment of 5%. It was projected that by the year 1992, the world would run out of insulin to supply all these additional patients, even if the entire beef and pork production of the world were diverted to insulin production. This meant that alternative sources of insulin had to be looked for urgently. Fortunately, due to developments in biotechnology, this crisis point was never reached; instead, by 1983, the first “human” insulin 9produced from Escherichia coli bacteria was on the market. Within the space of a single decade, it had displaced both porcine and bovine insulin from the European market. In India, animal insulin held out for somewhat longer but is now virtually unavailable.
The third problem was that subcutaneous insulin therapy using conventional insulin, be it of animal or human origin, could not precisely mimic the body's exquisitely controlled insulin secretion pattern. Regular insulin is not true “prandial” insulin; its slow absorption and delayed clearance cause the blood glucose to rise too high after a meal and fall too low before the next. Similarly, none of the conventional intermediate-acting insulins are true “basal” insulins; their action does not last 24 hours and they have a discrete peak of action, leading to nocturnal hypoglycemia when administered at dinner-time or bed-time. The discovery of the amino acid sequence of insulin by Sanger in 1955 stimulated research into developing new varieties (analogs) of insulin, which while retaining the efficacy of conventional insulin, would have more favorable pharmacokinetic profiles.
The first rapid-acting insulin analog to be introduced was insulin lispro in the mid-1990s, which was soon followed by aspart and glulisine. These molecules have rapid onset of action, enabling injection just before a meal, and rapid decay of action, reducing the risk of postabsorptive hypoglycemia.
The first long-acting (basal) insulin analog was glargine, introduced in 2003. This was followed by insulin detemir in 2006. These analogs have a prolonged and peakless action, enabling once daily administration with reduced risk of hypoglycemia. A very long-acting insulin analog, insulin degludec, is ready to enter the market soon.
Concurrently, with the developments in insulin pharmacology, insulin delivery systems also underwent a sea change. The advent of disposable syringes obviated the need for repeated sterilization and allowed patients more flexibility. The introduction of insulin pens enabled patients to inject themselves more discreetly and with less pain. However, the shortcomings of subcutaneous insulin delivery (even with the newer designer insulins) in mimicking the normal pancreatic secretion of insulin still remained. The first continuous subcutaneous insulin infusion (CSII) pump, introduced by John Pickup in 1978, was an attempt to overcome the limitations of multiple dose insulin injections by providing a constant supply of insulin to the body, supplemented by mealtime boluses of rapid-acting insulin. The first insulin pumps were unwieldy and cumbersome affairs. Advances made over the last three decades have made insulin pumps smaller, smarter and more acceptable to patients than ever before so much that many authorities consider them the insulin delivery mode of choice in individuals with type 1 diabetes mellitus (T1DM), although the cost remains prohibitively high.
 
Development of Oral Antidiabetic Agents
From the mid-19th century onward, there were sporadic attempts to devise some form of oral pharmacological treatment of diabetes. One of the earliest candidate sources of an antidiabetic medication was goat's rue (Galega officinalis), which has been mentioned as a folk remedy for diabetes in different cultures over the years. The active principle of this plant, guanidine, was identified in the early years of the 20th century. The first orally active antidiabetic agent, synthalin, was a derivative of guanidine and was introduced in 1926 by the German scientist Frank.27 Unfortunately, this agent was found to be too toxic for clinical use and was soon withdrawn from the market. Moreover, the discovery of insulin at around the same time cooled enthusiasm toward this line of research for a few years thereafter.
In 1937, Ruiz et al. serendipitously discovered the hypoglycemic action of sulfonamide antibacterials while evaluating a new drug for the treatment of enteric fever. These observations were confirmed in 1942 by Marcel Janbon, who reported hypoglycemia and seizures in patients administered this new sulfonamide agent.28 Based on these observations, Auguste Loubatières was able to establish that this group of drugs caused hypoglycemia through their direct action on pancreatic beta cells.18,19 This marked the beginning of the sulfonylurea era. However, it was not until 1955 that the first agent in this class, carbutamide, was introduced into clinical practice by Franke and Fuchs.29 This was followed in rapid succession by other agents such as tolbutamide, chlorpropamide, glibenclamide, glipizide, gliclazide, and glimepiride.
Meanwhile, the guanidine story just refused to die down. In 1957, the first non-toxic guanidine derivative or biguanide, phenformin, was introduced, followed shortly thereafter by metformin.30 These drugs became widely popular during the next decade, but reports of lactic acidosis led to the removal of phenformin from the US market in the 1960s. Metformin, perhaps unfairly, was tarred with the same brush and did not make it to American shores for nearly four decades. It was, however, 10widely used in the rest of the world. It was only in 1995 that the US market finally opened its doors to metformin, faced with overwhelming evidence on the safety and efficacy of this agent from the rest of the world. Metformin is now the most widely prescribed oral antidiabetic agent worldwide and is the first-line drug for type 2 diabetes mellitus (T2DM) according to most of the global algorithms.
A number of new classes of antidiabetic agents were introduced during the 1990s (Table 1). Two of these classes, namely the nonsulfonylurea secretagogues (glinides) and the alpha-glucosidase inhibitors, are relatively mild agents which have a niche role in the management of T2DM. The third drug class introduced in the 1990s, the thiazolidinediones however had a turbulent history. The introduction of this new class of insulin sensitizers created plenty of excitement, particularly when the initial clinical trial experiences showed encouraging results not only in the treatment but also in the prevention of T2DM. Indeed, the first agent in this class, troglitazone, had the makings of a wonder drug. Unfortunately, its time in the limelight was limited; within 4 years of its launch, it had been banned due to reports of fatal hepatic toxicity. Troglitazone was never marketed in India. The other two drugs in the class, pioglitazone and rosiglitazone, were found to be liver friendly and were widely prescribed over the last two decades. However, in 2007, a meta-analysis showed an increased risk of adverse coronary events in individuals taking rosiglitazone. This led to a number of restrictions in the use of this drug, culminating in the Drugs Controller General of India (DCGI) banning rosiglitazone in 2010. With this, pioglitazone is now the only drug left in the class.
 
A Cure for Diabetes—Still a Mirage?
Type 1 (insulin-dependent) diabetes mellitus is a classical endocrinopathy in which the main and often only pathophysiology is absence of insulin due to destruction of pancreatic beta cells. This disorder therefore lends itself to a cure if only an alternative source of beta cells could be provided to the patient's body. Several approaches have been tried toward this end. The first attempts involved transplantation of the whole pancreas. Unfortunately, the limited availability of donor pancreata, complications involved in major surgery and the problems involved with immunosuppression have precluded this from gaining wider acceptance. Transplantation of pancreatic islet cells was first attempted by Paul Lacy in 1967 and the first clinical trial was done in 1990. The introduction of the Edmonton Protocol by James Shapiro in 2000 improved patient responses to islet transplantation31 but the long-term efficacy of this procedure remains uncertain, with less than 10% of patients remaining free of insulin injections 10 years after the procedure.
Recent efforts have been directed at utilizing stem cells as a source of insulin-producing beta-cells in patients with diabetes. This approach is currently experimental and is limited by ethical concerns about the use of embryonic stem cells.
 
Diabetes Complications
The discovery of insulin and its widespread clinical use in the early 1920s was accompanied by a wave of optimism bordering on euphoria among clinicians dealing with diabetes. In 1930, Frederick Allen confidently stated that diabetes had been conquered and that every diabetic could expect to live out his normal lifespan. However, it soon became clear that the increased life expectancy afforded by insulin was something of a mixed blessing. On the one hand, deaths from the acute complications of diabetes, particularly DKA, dwindled drastically, on the other hand, the very longevity of these patients meant that many of them could now expect to develop one or other of the vascular complications of diabetes, which were considered rarities in the preinsulin era. Insulin therefore had the effect of converting diabetes from a fulminant, frequently fatal illness to a chronic lifelong disorder attended by the involvement of various organ systems of the body.
Diabetic ketoacidosis has been known to physicians from olden days. In 1874, the German physician Adolf Kussmaul described the typical labored respiration of patients with this condition.32 The peculiar fruity odor of the breath in DKA was described by Watson and Foster independently in the 1870s.33,34 In the preinsulin era, most patients with T1DM died due to DKA. However, the starvation regime of Allen (vide supra) was able to bring down the mortality rate from 60 to 40%. The advent of insulin therapy revolutionized the outlook for DKA. Today, in most recognized centers in the world, the mortality rate for DKA is less than 1%.
The other major hyperglycemic emergency, known as hyperosmolar nonketotic (HONK) state was described by Dreschfield in 1886. This entity has recently been renamed hyperosmolar hyperglycemic state (HHS).
Much was known about chronic diabetes complications even in the preinsulin era. Distinctive lesions 11were described in the retinae of patients with diabetes by Jaeger in 1855.35 In 1888, Nettleship described the ophthalmoscopic appearance of new vessel formation in the retina.36 In the preinsulin era, retinopathy occurred only in older diabetic patients and was considered to be due to atherosclerosis. This was disproved by Waite and Beetham,37 who drew clear distinction between the lesions of diabetic microangiopathy and those of atherosclerosis in the retina.37
Until the late 1960s there were no effective treatments for diabetic retinopathy. Various pharmacological agents-like rutin, vitamin K, and vitamin C were tried with disappointing results. In 1953, Jacob Poulsen suggested that hypophysectomy could improve retinopathy by reducing insulin resistance and improving the “metabolic hormonal imbalance”. Although never very popular, this procedure continued to be performed in the 1970s for want of a better alternative; the results were equivocal.
Laser photocoagulation therapy was the brainchild of the German ophthalmologist, Gerd Meyer-Schwickerath, who postulated that he might be able to stop new vessels from bleeding by coagulating them with heat. After various trials during the 1940s, he settled on a xenon arc lamp as the source of light. Although the results were impressive, the procedure was painful and needed up to 1.5 seconds to make the burn. The advent of the ruby laser solved these problems. By the mid-1970s, the American Diabetic Retinopathy Study (DRS) had established laser photocoagulation as the treatment of choice for sight-threatening retinopathy. Meanwhile, in 1972, the German surgeon Robert Machemer pioneered vitrectomy surgery, which offered a ray of hope to individuals who had lost vision due to intraocular bleeding from proliferative retinopathy.
Proteinuria has been described from the days of Rollo and Darwin, who described the presence of coagulable material in the urine of diabetic patients. The first reports on diabetic kidney disease were published in 1936 by Paul Kimmelstiel and Clifford Wilson.38 They described this disease as characterized by proteinuria, edema, and a characteristic microscopic appearance of the kidney, the so-called Kimmelstiel–Wilson lesion (nodular intercapillary glomerulosclerosis). These pathological changes were further delineated by Bell in 1953. The development of the microalbuminuria assay in the 1970s has helped in the early detection and prevention of diabetic kidney disease. Work by Mogensen et al. has identified the risk factors for diabetic nephropathy and elucidated the clinical stages of the disease.
The first description of neuropathy in diabetes is attributed to John Rollo in the 18th century. In 1883, Bouchard described erectile dysfunction in poorly controlled diabetes.39 The first comprehensive description of the cardinal features of diabetic polyneuropathy was given by Pavy in 1885. Trophic ulcers and autonomic neuropathy were described by Auche in 1890.
In 1868, Brigham40 noted that cerebral artery occlusion and sudden death were more common in patients with diabetes than those without. In 1895, Bose reported that angina was more common in diabetes patients compared to the general population.41 By the middle of the 20th century, the relationship between coronary artery disease and diabetes had been proven beyond doubt and many physicians started considering diabetes as a coronary risk equivalent.
Gangrene of the feet was known to be more common in diabetes patients from olden days; however, it was only in the 1920s that this was proven beyond doubt following the work of Bell and colleagues.
Before the discovery of insulin, it was quite unusual for a diabetic woman to conceive. A successful completion of pregnancy was even more uncommon. As late as the 1950s, the outcome of pregnancy in women with diabetes continued to be poor. However, work done by Priscilla White at the Joslin Clinic and Jørgen Pedersen in Copenhagen helped in identifying good diabetes control as the key to a successful outcome. By the 1980s, the fetal mortality rate in diabetic pregnancies had fallen to less than 6% in most of the Western world.
 
THE ERA OF TRIALS AND THE UK PROSPECTIVE DIABETES STUDY SAGA
In the preinsulin era, the treatment options for insulin-dependent diabetes (T1DM and advanced T2DM) were limited. The main aim of treatment was to prolong the life of the patient by avoiding episodes of acute metabolic decompensation such as DKA. The concept of tight control of diabetes was unknown and since patients rarely lived for more than few years after diagnosis, chronic complications were virtually unheard of.
The introduction of insulin therapy meant that diabetes patients were now able to escape the death sentence which the diagnosis would have earlier entailed. However, this development threw up other challenges to physicians as to what the aims of treatment should be, now that the risk of death from acute complications had receded. Should one try to get the glucose levels to 12normal, or should one just be satisfied with keeping the patient alive, avoiding episodes of DKA? Elliott P Joslin of Boston, considered as the Father of Modern Diabetology, was of the former persuasion. In 1935, he wrote that “the aim of diabetes treatment is to keep the blood glucose levels as close to normal as possible”. While the attainment of normoglycemia was indeed a desirable aim, the problem was that any attempts of tight control would invariably be accompanied by an increase in the incidence of hypoglycemia. Also, there was not enough evidence at the time to show that tight control would have any benefits over and above those which could be attained by conventional control. The debate raged on for nearly 70 years. The advocates of tight control were not helped by the results of the University Group Diabetes Program (UGDP) study, which showed increased mortality in patients randomized to receive intensive treatment with sulfonylureas compared to those given conventional treatment.42 The issue was not resolved until the 1990s, when the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) unequivocally established the benefits of tight glycemic control in preventing the development of chronic vascular complications in type 1 and type 2 diabetes patients respectively.43
The conduct of these landmark studies was helped to a great extent by developments in clinical chemistry. The most important among these was the development of a robust indicator for long-term glycemic control. In 1969, Rahbar described the relationship between the blood levels of an “unusual hemoglobin” called glycosylated hemoglobin (HbA1c) and diabetes. In 1972, Bunn et al. showed that the cause of the rise in HbA1c in diabetic subjects is the increased nonenzymatic glycation of the hemoglobin molecule, which was essentially irreversible. Koenig et al. were the first to demonstrate the relationship between HbA1c and fasting blood glucose; they also suggested that HbA1c levels might also correlate with the mean glucose levels.44 By the 1980s, HbA1c was being widely used in clinical practice to assess long-term glycemic control. However, the wide variety of assays available and lack of standardization remained as formidable roadblocks to its wider use. To solve this problem, the National Glycohemoglobin Standardization Program (NGSP) was set up in 1996 to standardize HbA1c assays throughout the US. As a result of this program, more than 99% of the HbA1c assays in the US, UK, and Canada today are standardized, i.e., they are back traceable to the DCCT assay. However, in countries such as India, the problems of standardization remain unsolved to a great extent.
No story of the history of diabetes is complete without a mention of the UKPDS study that permanently and irrevocably changed the paradigms in the management of diabetes.
The UKPDS45 was set up in the late 1970s, by Dr Robert Turner and colleagues in Oxford. Over 5,102 subjects at 23 centers across the UK were included in the study. It was the largest and longest study then undertaken in diabetes; median follow-up was 10 years. As well as attempting to resolve unanswered clinical issues, the study generated a huge epidemiological database, comprising over 20 million data items. The primary aim was to determine the effect of intensive glycemic control on the incidence of complications; the secondary aim was to assess whether there were differences between treatments protocol amendments were made to add topics not originally included. These strengthened the study by broadening its scope, but at the cost of complicating the treatment allocation, conduct and analysis of the study. Numerous substudies were embedded, the most notable being the Hypertension in Diabetes Study. Over 84 papers have been published from the UKPDS database. UKPDS showed conclusively that the complications of T2DM, previously often regarded as inevitable, could be reduced by improving blood glucose and/or blood pressure control. When the intervention trial finished in September 1997, all surviving UKPDS patients were entered into a 10-year, post-trial monitoring program. This was completed in December, 2007. Follow-up data from the trial demonstrate that early intensive glucose control not only continued to reduce microvascular complications, but also reduced risk for MI and all-cause mortality.46 The benefits of earlier metformin therapy were also sustained as well. The importance of the UKPDS trial lies in the fact that it heralded the era of large clinical trials in diabetes like the VADT, VAHIT, etc. that consequently lead to a better understanding of diabetes.
 
POSTMODERN ERA
In the first decade of the 20th century, interest has been focused on a previously neglected aspect of carbohydrate metabolism—the gut-derived hormones or incretins.
The two strategies to improve the availability of glucagon-like peptide-1 (GLP-1) to the cells are: (1) to administer a GLP-1 analog which is resistant to dipeptidyl peptidase-4 (DPP-4) and (2) to inhibit the enzyme DPP-4 13so that the body can make better use of endogenous GLP-1. The incretin mimetics act via the first mechanism whereas the DPP-4 inhibitors (incretin enhancers) utilize the second mechanism.
The first incretin mimetic, exenatide, was developed from a protein derived from the saliva of the Gila Monster,47 a venomous lizard found in the US and Mexico. This agent is given by subcutaneous injection twice daily and is effective in reducing hyperglycemia as well as body weight. The other GLP-1 agonist available in India is liraglutide, which can be given as a once daily injection. Once weekly exenatide is available in the US but has not been introduced in India at the time of writing.
In contrast to incretin mimetics, DPP-4 inhibitors are orally active agents which provide physiological levels of GLP-1 to the cells. The agents currently available in India are sitagliptin, vildagliptin, saxagliptin, and linagliptin. Alogliptin is also available in some countries. These drugs are better tolerated than GLP-1 agonists but are milder and do not produce significant weight loss.
A drug class which has received much interest of late is the sodium-glucose cotransporter-2 (SGLT-2) inhibitors. These agents reduce hyperglycemia by promoting glucose loss through the urine and thereby control diabetes as well as produce weight loss. EMPA-REG, the cardiac safety trial of empagliflozin, an SGLT-2 inhibitor was the first study to demonstrate the superiority of an OAD over placebo and was quickly followed by similar findings for liraglutide (LEADER) and canagliflozin (CANVAS).
The increasing availability and decreasing cost of human genetic analysis makes it likely that precise genome analyses will become routine in clinical medicine and used for diagnosis and therapeutic recommendations in multiple subspecialties beyond the diabetes clinic.
Refinement of algorithms incorporating predictive genetic variation and biomarkers for drug responsiveness and the risk of complications, prospectively validated by clinical trial outcomes data in multiple populations with different ethnic backgrounds, should enhance our ability to transform diabetes care.
It seems certain that the increasing availability and improved accuracy and utility of genomic and clinical biomarkers will further enable precision treatment of diabetes. Simultaneously, information technology will continuously improve our capacity to do global, large-scale, and cost-effective clinical trials. Given the tremendous progress made over the past decade, it is reasonable to predict greater adoption of precision medicine approaches in the T2DM clinic in the years to come.
 
CONCLUSION
The story of diabetes has been a long and eventful one. The path is strewn with glittering achievements and exciting discoveries, but at the same time the journey is nowhere near complete. The prospect of a cure for diabetes remains as elusive today as it was a century ago. Many aspects of the etiopathogenesis of diabetes and its complications await further elucidation. Nevertheless, we have every reason to be grateful to the pioneers in the field of diabetology whose efforts have enabled our patients to lead lives virtually indistinguishable from those of their peers without diabetes.
REFERENCES
  1. Stern, Ludwig Christian (1875). In: Georg E (ed). Papyros Ebers: Das hermetische Buch über die Arzeneimittel der alten Ägypter in hieratischer Schrift, herausgegeben mit Inhaltsangabe und Einleitung versehen von Georg Ebers, mit Hieroglyphisch-Lateinischem Glossar von Ludwig Stern, mit Unterstützung des Königlich Sächsischen Cultusministerium (in German). 2 (1st edition). Leipzig: W. Englemann.  LCCN 25012078.
  1. Benouf P. Note on the Medical Papyrus of Berlin. In: Susanne B, Hans-Werner FE, Antonio L, Sebastian RT (Eds). Zeitschrift für Ägyptische Sprache und Altertumskunde. 2016;11(1-12):123–5.
  1. Wreszinski W. Die Medizin der alter Ägypter: Londoner medizinische Papyrus (Brit. Museum No. 10059) und der Papyrus Hearst, Die Medizin der alter Ägypter, vol. 2. Leipzig: J.C. Hinrichs;  1912.
  1. Parivallal T. Diabetes in ancient India. In: Mohan V, Rao G (Eds). Type 2 Diabetes in South Asians: Epidemiology, Risk Factors and Prevention. Under the Aegis of SASAT. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd;  2006. pp. 97–103.
  1. Medvei VC. The Greco—Roman period. In: Medvei VC (Ed). The History of Clinical Endocrinology: A Comprehensive Account of Endocrinology from Earliest Times to the Present Day. New York: Parthenon Publishing;  1993. p. 34, 37.
  1. Couch JH, Couch HN. The literary illustrations of aretaeus of Cappadocia. Can Med Assoc J. 1935;33(5):556–9.
  1. Eknoyan G. The origins of nephrology—Galen, the father of experimental physiology. Am J Nephrol. 1989;9:66–82.
  1. Zargaran A, Mehdizadeh A, Zarshenas MM, et al. Avicenna (980-1037 AD). J Neurol. 2012;259:389–90.
  1. Getz FM. Healing and Society in Medieval England: A middle English translation of the pharmaceutical writings of gilbertus anglicus. Madison: University of Wisconsin Press;  1991.
  1. Hazard J, Perlemuter L. L'Homme Hormonal. Une Histoire Illustrée. Paris, Hazan;  1995. pp. 291–339.
  1. Anthony G. Cardano's Cosmos: The Worlds and Works of a Renaissance Astrologer. Cambridge, Mass.: Harvard University Press;  1999.
  1. Andrew B. Brevarie of Helth. London: Wylliam Middleton;  1547.
  1. Dobson M. Experiments and observations on the urine in diabetes. In: Medical observations and Inquiries by a Society of Physicians in London Vol. 5. London: Thomas Cadell;  1776. pp. 298–316.
  1. Rollo J. The history, nature and treatment of diabetes mellitus. In: Gillet T, Dilley C (Eds). Cases of the Diabetes Mellitus, Vol. 1. London; 1798.
  1. Nicholas C. Culpeper's School of Physick, or The Experimental Practice of the Whole Art. London: N. Brook;  1659.

  1. 14 Allan FN. “The History of the Treatment of Diabetes by Diet,” in Essays on the History of Nutrition and Dietetics. Chicago: American Dietetics Organization;  1967. p. 235.
  1. Joslin EP. Apollinaire Bouchardat (1806–1886). Diabetes. 1952;1(6):490–1.
  1. Matteson EL, Kluge FJ. Think clearly, be sincere, act calmly: Adolf Kussmaul (February 22, 1822-May 28, 1902) and his relevance to medicine in the 21st century. Curr Opin Rheumatol. 2003;15(1):29–34.
  1. Olmsted JMD, Harris E. Claude Bernard and the Experimental Method in Medicine. New York: Henry Schuman;  1952.
  1. von Mering J, Minkowski O. Diabetes mellitus nach Pankreas extirpation. Zentralbl Klin Med. 1889;10:93–394.
  1. Langerhans P. Beitrage zun mikroscopishen Anatomie der Bauch speicheldruse. Med Diss (Berlin); 1869.
  1. De Meyer J. Action de la secretion interne du pancreas sur differents organs et en particular sur la secretion Renale. Arch Fisiol. 1909;7:96–9.
  1. Paulesco NC. “Recherche sur le rôle du pancréas dans l'assimilation nutritive”. Archives Internationales de Physiologie. 1921;17:85–103.
  1. Banting FG, Best CH, Collip JB, et al. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922;12:141–6.
  1. Larsen EH. [August Krogh and the laboratory of animal physiology situated at Ny Vestergade 11]. Ugeskr Laeger. 2001;163(51):7240–8.
  1. Jorpes JE. Recrystallized insulin for diabetic patients with insulin allergy. Arch Intern Med (Chic). 1949;83:363–71.
  1. Frank E, Nothman M, Wagner A. Uber die experimentelle und Klinische Wirkung des dodekamethy lindiguanids (Syntholin B) Klin Wschr. 1928;7:1996–2000.
  1. Janbon M, Chaptal J, Vedel A, et al. Accidents hypoglycemiques graves par un sulfamidothiazol (le UK 57 on 2254 RP). Montpellier Med. 1942;21-22:441-4.
  1. Franke H, Fuchs J. Ein neues antidiabetisches princip: Ergebnisse Klinische Untersuchungen. Dtsch Med Wochenschr. 1955;80:1449–52.
  1. Tyberguein JM, Williams RH. Metabolic effects of phenethyldiguanide, a new hypoglycemic compound. Proc Soc Exp Biol Med. 1957;96:29–32.
  1. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–8.
  1. Kussmaul A. Concerning a peculiar mode in diabetics. Deutch Arch Klin Med. 1874;14:1–46. Cited in Major RH. Classic Description of Diseases. Springfield, IL: Charles C Thomas; 1932. p. 200.
  1. Watson T. Lectures on the Principles and Practice of Physic, 5th edition. London: Longmans;  1871. p.725.
  1. Foster B. Diabetic Coma: Acetonaemia. Br Med J. 1878;1:78–81.
  1. Jaeger E. Beitrage Zu Pathologie des Auges, siete 33. Eien: KK Hofund and Staatsdruckerei;  1855.
  1. Nettleship EN. Chronic retinitis in diabetes. Trans Ophthal Soc UK. 1888;8:159–162.
  1. Waite JH, Beetham WP. The visual mechanism in diabetes mellitus. N Engl J Med. 1935;212:367–79, 429-43.
  1. Kimmelstiel P, Wilson C. Intercapillary lesions in the glomeruli of the kidney. Am J Pathol. 1936;12:83–98.
  1. Bouchardat A. De la glycosurie ou diabetic sucre. Paris: Librairie Geremer-Balliere;  1875.
  1. Brigham CB. An essay upon diabetes mellitus. Boston: Press of Abner A Kingman;  1868.
  1. Bose KC. Diabetes mellitus and its prevention. Ind Med Gaz. 1895;30:135–44.
  1. University Group of Diabetes Study Program (UGDP). A study of effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19:747–830.
  1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.
  1. Rahbar S. An abnormal hemoglobin in red cells of diabetics. Clin Chim Acta. 1968;22:296–8.
  1. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study Group. Lancet. 1998;352:837–53.
  1. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–13.
  1. Triplitt C, Chiquette E. Exenatide: from the Gila monster to the pharmacy. J Am Pharm Assoc (2003). 2006;46:44–52.