INTRODUCTION
Diabetes mellitus (DM) is a syndrome characterized by hyperglycemia and impaired metabolism of carbohydrates, proteins and fats due to an absolute or relative deficiency of the secretion and/or insulin action.
Its prevalence is 7–8% approximately, of which 90% corresponds to type 2 diabetes and the rest is distributed among the different types of diabetes.
DIAGNOSIS OF DIABETES MELLITUS
The DM is defined by blood glucose levels. They will be considered diabetic those exceeding 126 mg/dL fasting twice or submit above 200 mg/dL values at any time of day or at two hours of testing glucose tolerance.
Normal values are below 100 mg/dL or fasting under 140 mg/dL 2 hours of testing glucose tolerance.
There are some people with glucose levels between 100 mg/dL and 126 mg/dL on the fasting state, or more than or equal to 140 mg/dL but less than 200 mg/dL after 75 g of glucose [oral glucose tolerance test (OGTT)], they are considered nondiabetic but with alterations in carbohydrate metabolism. The first alteration is impaired fasting glucose (IFG), in which insulin resistance plays the most important role; the second disturbance is called impaired glucose tolerance (IGT), in which there is a disturbance in the normal secretion of insulin to the stimulus with glucose (Table 1).
Both alterations in the same individual can also be present. The presence of IFG and IGT indicates a higher probability of evolving to type 2 diabetes mellitus (T2DM).
In the case of presenting one of the alterations, it has been seen that the IGT has a higher incidence of T2DM than the IFG.
Current diagnostic criteria of the American Diabetes Association (ADA) propose adding glycosylated hemoglobin A1c (HbA1c) within them. Values above 6.5% would define the presence of disease. In Argentina, due to the lack of standardization of the method for the determination of HbA1c, Argentine Diabetes Society [Sociedad Argentina de Diabetes (SAD)] decided to exclude this criterion.
Diabetes mellitus diagnostic criteria of the ADA are as follows:
- HbA1c more than or equal to 6.5% (in laboratories with standardized methods)
- Fasting plasma glucose more than or equal to 126 mg/dL (fasting of at least 8 hours)
- Plasma glucose within 2 hours to be more than or equal to 200 mg/dL during an OGTT (according to the technique described by World Health Organization, using a glucose load of 75 g anhydrous dissolved in water)
- Classic symptoms of hyperglycemia or hyperglycemic crisis glucose more than or equal to 200 mg/dL.
CLASSIFICATION OF DIABETES MELLITUS
The former classification of DM based on dependency insulin was modified with the intention of eliminating denominations as insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), taking into account the diversity of response to therapeutic. The current classification of DM is based on the etiology of the disease, considering that type 1 diabetes is the result of the destruction of pancreatic β-cells (autoimmune or unknown cause, etc.) and type 2 diabetes is related to the association of insulin resistance and insulin deficiency.
Etiologic Classification
- Type 1 diabetes (due to β-cell destruction, usually leading to absolute insulin deficiency)
- Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance)
- Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy, that is not clearly overt diabetes)
- Specific types of diabetes due to other causes, e.g. monogenic diabetes syndromes [such as neonatal diabetes and maturity-onset diabetes of the young (MODY)], diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes [such as in the treatment of human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), or after organ transplantation].
TYPE 1 DIABETES MELLITUS
Type 1 diabetes mellitus (T1DM) is characterized by the sudden onset of severe symptoms associated with the absolute deficiency of insulin secretion, tendency to ketosis, and dependence on exogenous insulin to sustain life.
The histopathology of T1DM is defined by a decreased β-cell mass in association with insulitis, a characteristic lymphocytic infiltration limited to the islets of Langerhans and prominent in early stage disease in children.
It has similar characteristics with autoimmune inflammatory processes found in certain thyroid diseases (thyroiditis) and adrenal (adrenalitis). Insulitis is characterized by infiltration and resulting disruption of islets with destruction of β-cells by T lymphocytes of various types.
Pancreatic deficiency of insulin secretion is clearly associated with this type of diabetes and is due to the specific loss of β-cells, with conservation within almost normal mass of α-cells (glucagon), δ-cell (somatostatin) and pancreatic polypeptide (PP cell). This can be demonstrated by measuring blood insulin (in patients who have not received the hormone exogenously), both fasting and basal, as to different stimuli for release (e.g. administration of glucose or glucagon). Also, measure the values of C-peptide, the residual product in the conversion of proinsulin to insulin, since it is not altered or masked by receiving replacement therapy.
Type 1 diabetes mellitus usually occurs abruptly, with overt signs of hyperglycemia, and sometimes with significant deterioration of clinical status.
Hyperglycemia is the result of destruction of 80–90% of the mass of β-cell functioning.
Only the clinical manifestation is acute. There is a silent preclinical period and can be recognized by different immunological markers that reveal the underlying autoimmune process.
Most cases of T1DM are due to the autoimmune process and the destruction of β-islet cells in genetically susceptible individuals. Type 1 diabetes secondary to the autoimmune process are called type 1a in the classification. It should be noted that not all type 1 diabetes have the same clinical evolution.
Not all individuals with pathogenic autoimmune process of T1DM progress to clinical T1DM or they do it slowly, with a prior relatively long period without insulin dependence.
Antibodies have been detected years before the onset of hyperglycemia. Functional studies, such as intravenous glucose tolerance test, reveal a decrease in the first phase of insulin secretion months or weeks before the clinical onset of the disease or the presence of fasting hyperglycemia, according to the magnitude and extent of damage caused in the β-cells.
It must be considered a preclinical period in the natural history of disease, which can be identified through different immunological and genetic markers.4
Genetic Determinism
Autoimmune diabetes is a T-dependent specific organ disease, which is polygenic and mainly restricted by the human leukocyte antigen (HLA). HLA-DR (Human Leukocyte Antigen-antigen D Related) is a major histocompatibility complex class II cell surface receptor encoded by the HLA on chromosome 6 region 6p21.31. The complex of HLA-DR and its ligand, a peptide of nine amino acids in length or longer, constitutes a ligand for the T-cell receptor (TCR). HLA-DR molecules are upregulated in response to signaling.
While HLA genes are the most important genetic factors that determine predisposition or protection to T1DM, it is clear that predisposition is necessary, but is not enough.
It has been found that other important genes also confer susceptibility to T1DM. The variable number tandem repeat region which is adjacent to the 5’ end of the insulin gene is also related to T1DM predisposition.
The gene encoding the protein CTLA-4 (Cytotoxic T Lymphocyte Antigen 4) also has importance in the determinism of T1DM.
The HLA region is located in the short arm of chromosome 6. The association between HLA and T1DM was initially demonstrated by Nerup. Patients with T1DM have DR3 and/or DR4 by 94% compared with 60% in the healthy population.
People with positive HLA-DR3 have a relative risk (RR) to develop diabetes of 6.4, and in the carriers of HLA-DR4, the RR is 3.7.
The presence of both markers increases the susceptibility to develop the disease, more than the sum of the RRs of DR3 and DR4.
There are also markers that express a lower chance of developing diabetes. There is a lower frequency of HLA-DR2 in patients with T1DM, determining an RR for the disease of 0.26, so is considered as a protection factor, so people who has this HLA is protected from developing T1DM.
HLA-DQB1 belongs to the HLA class II β-chain paralogs. This class II molecule is a heterodimer consisting of an alpha (DQA) and a β-chain (DQB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen-presenting cells (APC)—B lymphocytes, dendritic cells, and macrophages.
Different allelic variants of polymorphic gene DQB are circumscribed to the second exon of the gene and are encoding the amino terminal region of the antigen-presenting molecule.
Several alleles of HLA-DQB1 are associated with an increased risk of developing T1DM. The locus is the highest genetic risk for type 1 diabetes. Again, the DQB1*0201 and DQB1*0302 alleles, particularly the phenotype DQB1*0201/*0302, has a high risk of late onset type 1 diabetes. This nomenclature can individualize each allele with 4. The risk is partially shared with the HLA-DR locus (DR3 and DR4 serotypes) (Fig. 1).5
Autoimmunity
Type 1 diabetes mellitus can be induced by a process of autoimmunity directed against the insulin-producing β-cells. This mechanism could be triggered by certain environmental factors in genetically determined individuals. The suspicion of an autoimmune process came from the striking association between T1DM and other endocrine autoimmune diseases, such as those affecting thyroid and adrenal, as the high percentage of specific antibodies was present in the serum of patients. The first description of autoimmunity in diabetes was made in 1974, they are ICA antibodies (islet cell antibodies). ICAs are present in 0.5–1.7% of the general population and 15–30% in T1DM, but at the time of onset of the disease, in patients less than 30 years, this percentage rises to 60–85%, descending to lower values after 2–3 years.
They are immunoglobulin G class autoantibodies produced by activated T lymphocytes, are not specific to β-cell. They are determined by indirect immunofluorescence (IFA) and measured in JDF units, values under 10 UJDF are considered negative. Currently, this determination has been replaced by other antibodies described here.
The glutamic acid decarboxylase antibodies (GADA) are the most useful because of the ease of its determination. They are measured by radiobinding assay (RBA). There are two isoforms, 65 kD (specific for diabetes) and 67 kD. GAD antigen is not specific β-cell, participates in the formation of gamma-aminobutyric acid (GABA).
Islet antigen-2 (IA-2), previously also known as ICA-512, is a major target of islet cell autoantibodies.
They are present in 45–75% of the cases at the beginning of the disease. They are determined by RBA.
Insulin autoantibodies (IAA) are positive in 20–50% of patients with recent onset diabetes. They are positive previous the treatment with insulin. The use of insulin determines the presence of insulin antibodies (IA) to the exogenous insulin (IA instead of IAA) as they would be related of the exogenous antigen of the hormone injection. They are measured by RBA. They have inverse correlation with age, being more common at younger ages.
It has recently been discovered antibodies against the zinc transporter-8 islet (ZnT8-A) also predicts T1DM. ZnT8 is specifically expressed in the pancreatic β-cells and has been identified as a novel target autoantigen in patients with T1DM. Antibodies to ZnT8 have been detected in 60–80% of Caucasian and 33–58% of Asian population with T1DM.
The sensitivity and predictive capacity increase with the association of markers. The association of GADA, IA-2A and IAA determines a sensitivity of 90% and a positive predictive value close to 100% for the next 5 years (Table 2).6
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The appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations. Diabetes autoantibodies are now being used in studies of high-risk populations (first-degree relatives) as well as the general population. Following the antibodies prospectively in genetically at-risk subjects affords the opportunity to identify environmental triggers and introduce preventative measures.
These antibodies are informative markers of humoral immunity that aid in prediction, prevention, classification, and intervention strategies.
Environmental Factors
Given the evidence of the genetic predisposition for diabetes and autoimmune origin, is still in search those factors that act as trigger determining the process of aggression to the pancreas to generate diabetes.
The mechanism of action involved in environmental factors is not known precisely, but it is postulated that they may act in two different ways: (1) by direct toxicity against β-cell; and (2) triggering the autoimmune mechanism against β-cell.
Age is an important factor, being less common to develop T1DM in the first nine months of life, probably related to the protection provided by the maternal antibodies to the newborn. There is an increase in incidence at 5–6 years, a peak at 12–14 years, and a slight decrease between 20 years and 35 years comes later. There are also geographical variations, with significant differences between different areas; (e.g. in Finland, the incidence is 29.5/100,000 people per year while in Hokkaido, Japan, it is 1.6/100,000 per year). Migrant studies indicate that the incidence of T1DM has increased in population groups who have moved from a low incidence region to a high incidence area, also emphasizing the influence of environmental conditions.
There have been described factors as chemical agents and specific drugs (alloxan, streptozotocin, pentamidine and a rodenticide Vacor).7
A large number of epidemiological studies were conducted to determine the influence of viral infections in the development of T1DM in humans, accepting its association mainly with four viruses: mumps, coxsackie, rubella and Cytomegalovirus, which would act as a trigger for immune process.
Currently, although genetic and immunological markers present, is not approved the use of immunosuppressants in the preclinical period, since is not demonstrated its safety and effectiveness, and that might be unnecessary in patients who undergo to a spontaneous remission without developing the disease.
TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus is a chronic disease with a polygenic origin of variable expression, where environmental factors play an important role in its determinism.
The variable expression of genes implies that the presence of the predisposition not invariably determines an evolution towards the disease, and that their presence only involves the risk of developing T2DM. This risk is enhanced with some environmental factors as unhealthful food, refined carbohydrates, and barriers to physical activity and stress.
This accounts for 90 to 95% of all diabetes. This form encompasses individuals who have insulin resistance and usually relative (rather than absolute) insulin deficiency. Insulin resistance alone is insufficient to develop diabetes, so it requires the alteration in insulin secretion. The insulin resistance has two determining factors, the genetic and the environmental, which is influenced by lifestyle, diet, sedentary lifestyle, overweight, medication, etc. It is more common in adults; its onset is insidious by the lack of symptoms, being common to ignore the presence of the disease.
OTHER SPECIFIC TYPES
Among the other specific types of diabetes, it is worth noting the MODY diabetes, which is characterized by diabetes that appears early in life, but behaves like type 2 diabetes and not as type 1, is characterized by impaired insulin secretion with minimal or no defects in insulin action. It is inherited in an autosomal dominant pattern, so the sons of a person with MODY have a 50% chance of inheriting this type of diabetes.
It commonly appears before 25 years of age, usually occurs in three or more generations of the same family. It is monogenic type, with dominant inheritance.
There are six types of MODY whose recognition is difficult to perform, but is important to consider the presence of this type of DM because their treatment and prognosis differ from the T1DM.
MODY 2: Glucokinase enzyme gene chromosome 7p (GCK)
MODY 3: Hepatocyte Nuclear Factor, gene chromosome 12q 1α Liver (HNF 1α)
MODY 4: Factor 1β Hepatic gene (chromosome 17)
MODY 5: Gene Insulin Promoter Factor-1 on chromosome 13q (IPF-1)
MODY 6: NeuroD1 transcription factor chromosome 2.
The diagnosis of monogenic diabetes should be considered in children with the following findings:
- Diabetes diagnosed within the first 6 months of life
- Strong family history of diabetes but without typical features of type 2 diabetes (nonobese, low-risk ethnic group)
- Mild fasting hyperglycemia (100–150 mg/dL [5.5–8.5 mmol/L]), especially if young and nonobese
- Diabetes with negative autoantibodies and without signs of obesity or insulin resistance.
GESTATIONAL DIABETES MELLITUS (GDM)
Gestational diabetes mellitus has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Although most cases resolve with childbirth, the definition applies regardless of whether the condition persists after pregnancy, and does not exclude the possibility that glucose intolerance precede pregnancy. It has a prevalence of 7% with a range from 1 to 14%, depending on the population studied and the diagnostic criteria used. For the diagnosis of GDM, an oral glucose tolerance test is performed between 24 weeks and 28 weeks of pregnancy; if negative and there are risk factors for, is repeated between 31 weeks and 33 weeks. It is made with 75 g of anhydrous glucose dissolved in 375 mL of water, to be ingested in 5 minutes.
The diagnostic criteria are different according to different medical societies that are considered (Table 3).
Classical risk factors for developing gestational diabetes are:
- Polycystic ovary syndrome
- A previous diagnosis of gestational diabetes or prediabetes, IGT, or impaired fasting glycemia
- A family history revealing a first-degree relative with T2DM
- Maternal age: A woman's risk factor increases as she gets older (especially for women over 35 years of age).
- Ethnicity (those with higher risk factors include African-Americans, Afro-Caribbeans, Native Americans, Hispanics, Pacific Islanders, and people originating from South Asia)
- Being overweight, obese or severely obese increases the risk by a factor 2.1, 3.6 and 8.6, respectively.
- A previous pregnancy which resulted in a child with a macrosomia [high birth weight: >90th centile or >4000 g (8 lb or 12.8 oz)]
- Previous poor obstetric history
- Other genetic risk factors: There are at least 10 genes where certain polymorphisms are associated with an increased risk of gestational diabetes, most notably TCF7L2.
Latent autoimmune diabetes in adults (LADA) in the classification of the ADA is not considered in this type of diabetes pathogenesis that could be included in type 1 diabetes. It is known as LADA for its acronym in English. It is characterized, as indicated by its name, by its autoimmune origin that occurs in adults, but with a less abrupt onset and may not require the use of insulin for at least 6 months period. It is important to consider this possibility in adult individuals (over 35 years) and who are not overweight. GADA determination is indicated in this group of patients, being important to understand the type of diabetes present because they tend to insulin dependence and must be distinguished from type 2 diabetic with failure to oral agents. Other antibodies that may be useful for diagnosis include IA-2A and ZnT8-A. The determination of IAA is not recommended (less frequent in adults).
CONSIDERATIONS
Diabetes is the generic name of a syndrome that is defined by a blood glucose value; however, it can be concluded that there are different causes of this condition, so should be identified the type of diabetes in a newly diagnosed diabetic patient, to understand the nature of the disease, since this knowledge will make a difference in the treatment, prognosis and complications.
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