Clinical Approach to Renal Diseases in Diabetes T Dhinakaran
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Diabetes Mellitus— A Worldwide Health Challenge CHAPTER 1

T Dhinakaran,
Suganya Sivakumar
 
INTRODUCTION
The prevalence of diabetes is rapidly rising all over the globe at an alarming rate. The 21st century has the most diabetogenic environment in human history. Over the past 25 years or so, the prevalence of type 2 diabetes in the United States has almost doubled, with threefold to fivefold increases in India, Indonesia, China, Korea and Thailand. In 2007, there were 246 million people with diabetes in the world, but that number is estimated to reach 380 million by 2025. People with impaired glucose tolerance (IGT), 1 a prediabetic state, numbered 308 million in 2007 and will increase to 418 million by 2025. The increase in prevalence of diabetics will be greater in developing countries. For example, 18% of Mexico’s adult population will have type 2 diabetes by 2025. According to the World Health Organization (WHO), China and India will have about 130 million people with diabetes by 2025, who will consume about 40% of their country’s healthcare budget, reducing productivity and hindering economic growth.
 
THE INDIAN SCENARIO
Nowhere is the diabetes epidemic more pronounced than in India as the WHO reports show that 32 million people had diabetes in the year 2000. 2 2
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Fig. 1.1: Estimated number of diabetic subjects in India
The International Diabetes Federation (IDF) estimates the total number of diabetic subjects to be around 40.9 million in India in 2006 and this is further set to rise to 69.9 million by the year 2025 (Fig. 1.1). 3
A national survey of diabetes conducted in six major cities in India in the year 2000 has shown that the prevalence of diabetes in urban Indian adults was 12.1%. The onset of diabetes among Indians is about a decade earlier than their western counterparts and this has been noted in Asian Indians in several studies. 4 In the national survey 54.1% of diabetics developed it in the most productive years of their lives i.e. before the age of 50 years and they also had a higher risk of developing chronic complications of diabetes.
 
REASONS BEHIND THE RISING TREND IN INDIANS
 
Genetic Reasons
 
Asian Indian Phenotype
Genetic predisposition: Several studies on migrant Indians across the globe have shown that Asian Indians have an increased risk for developing type 2 diabetes and related metabolic abnormalities compared to other ethnic groups. 3,5 Although, the exact reasons are still not clear, certain unique clinical and biochemical characteristics of this ethnic group collectively called as the “Asian Indian phenotype” is considered to be one of the major factors contributing to the increased predilection toward diabetes. Despite having lower prevalence of obesity as defined by body mass index (BMI), Asian Indians tend to have greater waist circumference and waist-to-hip ratios (WHR) thus having a greater degree of central obesity. Again, Asian Indians have more total abdominal and visceral fat for any given BMI 6 and for any given body fat they have increased insulin resistance. 7 Moreover, they have lower levels of the protective adipokine adiponectin and have increased levels of adipose tissue metabolites.
3
 
Thin Fat Phenotype
Studies on neonates suggested that Indian babies are born smaller but relatively fatter compared to Caucasian babies and are referred to as “the thin fat Indian baby.” 8 A recent study confirmed this finding and suggested that the “thin fat phenotype” in neonates persisted in childhood and could be a forerunner of the diabetogenic adult phenotype. 9 These findings suggest that Asian Indians are more prone to diabetes and related metabolic abnormalities. Genetic factors that determine body fat distribution and glucose metabolism have to be fully elucidated for the better understanding of the biochemical and molecular mechanisms behind the etiopathogenesis of diabetes. Studies have shown that, while some genes seem to confer increased susceptibility to diabetes in Indians, 10 some protective genes in Europeans do not appear to protect Indians. 11
 
Thrifty Phenotype
Another way to explain the diabetes epidemic in Asian Indians is through Neel’s “thrifty genotype” hypothesis. 12 This hypothesis proposes that some genes are selected over previous millennia to allow survival in times of famine by efficiently storing all available energy during times of feast. However, these very genes lead to obesity and type 2 diabetes when exposed to a constant high energy diet. In virtually all populations, higher fat diets and decreased physical activity and sedentary occupational habits have accompanied the process of modernization which has resulted in the doubling of the prevalence of obesity and type 2 diabetes in less than a generation.
 
The Epidemiological Factors
The dramatic rise in the prevalence of type 2 diabetes and related disorders like obesity, hypertension and the metabolic syndrome could be related to the rapid changes in life style that has occurred during the last 50 years. Although this “epidemiological transition,” which includes improved nutrition, better hygiene, control of many communicable diseases and improved access to quality healthcare have resulted in increased longevity, it has also led to the rapid rise of the new age diseases like obesity, diabetes and heart disease.
 
Rural versus Urban Living
Increase in the prevalence of type 2 diabetes may also be due to migration (a move from one environment to another, either external or internal), which brings with it marked social and cultural changes. 4 Many epidemiological studies on diabetes in migrant populations, mostly in people originating from developing countries, have reported a higher prevalence of diabetes than the host populations of those countries.
 
Socioeconomic Status
The influence of economic status on the prevalence of diabetes in India was studied in the Chennai Urban Population Study (CUPS). The CUPS was a study involving two residential areas comprising the lower and middle income groups in Chennai, in South India. A total of 1,262 individuals aged above 20 years, underwent a glucose tolerance test (GTT) and were differentiated into persons with normal GTT, impaired glucose tolerance test (IGTT) and diabetes.
The overall prevalence of diabetes was 12% in the population above the age of 20 years. The age-standardized prevalence rate of diabetes was significantly higher in the middle income group compared to the lower income group (12.4 vs 6.5%, respectively). The prevalence of obesity and other cardiovascular risk factors were also markedly higher in the middle income group than the low income group. Moreover, the “fast food culture” which has overwhelmed our cities and towns is also a major driver of the diabetes epidemic.
 
Sedentary Lifestyle
Another factor driving the epidemic is what has been referred to as “sedentarism” or the adoption of sedentary behavior. Over the past few decades, a huge number of the working population has shifted from manual labor associated with the agriculture sector to physically less demanding office jobs. With the advent of highly addictive computer and video games, sedentarism is now affecting the children and youth as they tend to spend more time in front of television sets or computers than playing outdoors. The prevalence of diabetes was almost three times higher in individuals with light physical activity compared to those having heavy physical activity (23.2 vs. 8.1%, P < 0.001). It was also noted that prevalence of metabolic syndrome and hypertension was also significantly higher among people with light physical activity. 13
 
The Role of Central Obesity
Obesity also shows familial aggregation among Indian population. Central obesity is common among Indians despite low rates of general obesity and this android pattern of body fat typified by more 5 upper body adiposity measured as WHR was found to be a greater risk factor as compared to general obesity. According to WHO recommendation a BMI of 18.5–22 kg/m2 is considered healthy for Asian population. 14
It was demonstrated that in urban Indian population with a BMI of less than 23 kg/m2, the risk of diabetes is significant for both genders. Asian Indians have higher upper body adiposity measured as WHR. The cut-off values for normal waist circumference for Indians were 85 and 80 cm for WHR in men and women respectively. Visceral fat increases the risk of diabetes and hyperlipidemia by favoring insulin resistance. Increased risk posed by intra-abdominal fat for diabetes and other metabolic diseases could be related to higher fat cell number in the abdominal adipose tissue, higher blood flow, increased receptors for cortisol and testosterone and greater catecholamine induced lipolysis when compared with subcutaneous adipose tissue. 15
 
PREVENTION OF TYPE 2 DIABETES—SOME USEFUL STEPS
Prevention of diabetes mellitus (DM) is the most useful and cost effective way to prevent its complications including diabetic nephropathy.
Several large controlled trials have been completed testing various options for diabetes prevention. The major recent trials completed to date have thrown open some avenues that are worth pursuing.
These can be classified into lifestyle changes, pharmacotherapy and other interventions.
 
Lifestyle Changes
With the rising epidemic of diabetes being commonly linked to the escalation of obesity and inactivity, lifestyle changes have been the logical intervention that has been evaluated in the major diabetes prevention trials. As expected, weight loss, exercise, and diet have all been shown, separately or in combination, to be effective in decreasing the incidence of type 2 diabetes in high-risk patients. 16,17 Interestingly, this beneficial effect appears to last consistently for years after the initial intervention. 17,18
The Diabetes Prevention Program (DPP) trial was a landmark US trial that enrolled 3,234 subjects with prediabetes, defined as an IFG or IGT, randomized to intensive lifestyle modification program, metformin (850 mg twice a day), or matching placebo. Lifestyle changes included low-fat diet and exercise for 150 minutes a week aiming to a 7% body weight reduction. An obvious benefit of lifestyle changes led to the premature discontinuation of the study with a relative risk6 reduction of progression to diabetes at 3 years of 58% in the lifestyle changes group and 31% in the metformin group when compared with placebo. Lifestyle changes were significantly more effective than metformin and were consistent in men and women across ages and ethnic groups.
 
Role of Exercise
Exercise is thought to improve insulin sensitivity and promote peripheral glucose uptake in normal individuals. Long-term moderate exercise, similar to the exercise recommended in the Finnish diabetes prevention study (DPS), results in increased translocation of insulin responsive glucose transporter (GLUT4) from intracellular stores to the cell surface, facilitating glucose uptake. 19
In a systematic review of 10 prospective cohort studies published in 2007, physical activity of moderate intensity such as brisk walking was significantly associated with reduced diabetes incidence in men and women after adjusting for BMI. 20
 
Weight Loss
Weight reduction in subjects with IGT, even at small or moderate scales, has been consistently associated with reduced incidence of diabetes. For example, within the same lifestyle intervention group in the Finnish DPS the participants who were able to achieve more than 5% of initial body weight reduction at 1 year significantly progressed less to diabetes when compared with their peers in the interventional group who had less or no weight loss and to the control group. The amount of weight loss needed to prevent diabetes is quite modest. For example, in the DPP, an average weight loss of only 5.6 kg was associated with a 58% lower incidence of diabetes. Moreover, on further analysis of the DPP trial, and among weight, diet and exercise, diabetes prevention correlated most strongly with weight loss, with an estimated 16% diabetes risk reduction for every single kilogram of weight reduction. 21
 
Metformin—DPP Trial
In the DPP trial, metformin was associated with a diabetes incidence reduction at 3 years of 31%. It seems to be more effective in women with history of gestational diabetes. A recent meta-analysis by Salpeter et al. 22 has confirmed the beneficial preventive effect of metformin, with a reported relative risk reduction of new-onset diabetes of 40%.
7
 
Glitazones­—DREAM Trial
The DREAM trial was one of the largest primary diabetes prevention trials with over 5,000 participants with IFG and/or IGT randomized to rosiglitazone, ramipril and placebo. At 3 years of therapy, rosiglitazone was shown to decrease the incidence of DM by 60% when compared to placebo. 23
The ACT now trial is a randomized and double blinded study enrolling 602 patients with IGT, assigned to pioglitazone, 45 mg daily, or placebo. 24 Over a mean follow-up of 2.6 years, pioglitazone was associated with an 81% decrease of progression to diabetes (1.5% compared with 6.8% in the placebo group, P < 0.0001) with an NNT of 3.5 patients with IGT per year to prevent one case of diabetes.
The recently published CANOE trial examined the effects of low-dose combination therapy in 207 patients with IGT who were randomly assigned to receive combination of metformin (500 mg twice daily) and rosiglitazone (2 mg daily) versus placebo for a median of 3.9 years. 25 As expected, a relative risk reduction of 66% of incidence of diabetes was observed in the treatment group with an NNT of 4.
 
Alpha-Glucosidase Inhibitors
A multicenter placebo-controlled randomized trial, the STOPNIDDM, examined the efficacy of acarbose in reducing the occurrence of diabetes in 1,429 subjects with IGT, who were randomly assigned to receive acarbose, 100 mg three times a day, or placebo. 26 At 3 years of follow-up, the use of acarbose significantly decreased the occurrence of DM by 25% (relative risk of 32.4% vs 41.5% in the acarbose and the placebo groups, respectively) with an NNT of 11. Limitations of this study were significant gastrointestinal adverse effects of the medication, probably leading to the high observed discontinuation.
 
Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers
Several major hypertension trials have consistently suggested, through secondary or post hoc analysis, a beneficial effect of inhibition of the renin-angiotensin system (RAS) in preventing diabetes in cardiovascular patients treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), e.g. ramipril (in the HOPE study), captopril (compared with diuretics and b blockers in the CAPP study), 27 lisinopril (compared with amlodipine and chlorthalidone in the ALLHAT trial), losartan (compared with atenolol 8 in the LIFE trial), and multiple other randomized controlled trials. In summary, ACE inhibitors or ARBs do probably have a beneficial effect on glucose metabolism, especially in the cardiovascular population. This effect is thought to be related to different mechanisms; inhibition of the postreceptor insulin signaling abnormalities, increased blood flow to the skeletal muscle facilitating insulin action, enhanced differentiation of pre-adipocytes into mature adipocytes and increased pancreatic islet blood perfusion leading to appropriate insulin release and possible partial PPAR-g activity. 28,29
To sum up, two of these measures namely therapeutic lifestyle change (TLC) and metformin have shown definite benefits. The recently published guidelines of the American Diabetes Association (ADA) recommend, as a first-line preventive measure in the prediabetic population, a 5–10% body weight reduction and at least 150 minutes a week of moderate physical activity for patients with IFG, IGT, or HbA1c levels of 5.7–6.4%. Metformin may be considered in those who are at very high risk for diabetes, who are obese, or who are under 60 years of age. 30
 
WHAT IS OUR PROGRESS?
On 21 December 2006, the United Nations General Assembly unanimously declared diabetes to be an international public health issue and identified World Diabetes Day as a United Nations Day–the second disease (after HIV/AIDS) to attain that status. For the first time, governments acknowledged that a non-infectious disease poses as a serious threat to world health as infectious diseases such as HIV/AIDS, tuberculosis and malaria. The problems of diabetes are now seen as a major global public-health concern; especially in developing countries that can least afford it.
 
Evidences Included
  • Mohan V, Gokulakrishnan K, Deepa R, et al. Association of physical inactivity with components of metabolic syndrome and coronary artery disease—the Chennai Urban Population Study (CUPS). Diabet Med. 2005;1206-11.
  • Lindstrom J, Peltonen M, Eriksson JG, et al. Finnish Diabetes Prevention Study (DPP). Lancet. 2006;368(9548);1673-9.
  • Diabetes prevention program research group, Knowler WC, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes prevention program outcomes study. Lancet. 2009;374(9702);1677-89.9
  • DREAM trial investigators, Gerstein HC, Yusuf S. Diabetes reduction assessment with ramipril and rosiglitazone medications. Lancet. 2006;368:1096-115.
  • DeFronzo RA. ACT Now: Acts Now for Prevention of diabetes, 68th ADA mut 6 June 2008–Abstract.
  • Zinmen B, Harris SB, Neuman J, et al. CANOE–Canadian normoglycemia outcomes evaluation. Lancet. 2010;376(9735):103-17.
  • Chiasson Jh, et.al. STOP-NIDDM: study to prevent NIDDM. Lancet. 2002;359:2072-7.
  • Hansson L, Lindholm LH, Niskanen L, et al. CAPP study–captopril prevention project. Lancet. 1999;353:611-6.
  • ADA Guideline. Diabetes care. 2010;33:511-61.
 
Essential at a Glance
  • Incidence on the rise: Prediction for India in 2025—69.9 million Diabetics.
  • Onset of DM in Indian a decade earlier than rest of the world. Asian Indian Phenotype, Thin fat Phenotype and Thirfty Phenotype—play a role.
  • Chennai Urban Population Study showed 12.5% of urban population to be diabetic in comparison to 6.5 of rural population.
  • Prevention–is the need of the hour by life style modification.
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