Classification of Diabetes Mellitus

Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes Other forms:

Pancreatic disease: fibrocalculous pancreatopathy, chronic pancreatitis, pancreatectomy, cystic fibrosis, haemochromatosis, pancreatic carcinoma Endocrine: Cushing's syndrome, acromegaly, thyrotoxicosis, phaeochromocytoma Drug induced: corticosteroids, thiazide diuretics

Conditions with specific genetic causes: e.g., maturity-onset diabetes of the young pancreas of subjects with type 1 diabetes shows infiltration of the islets of Langerhans with inflammatory white blood cells. Blood from subjects with type 1 diabetes has been found to contain a number of autoantibodies to components of the pancreas, including islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD) and insulinoma-associated autoantigen-2 (IA-2) (proteins found in pancreatic P-cells).16 Family studies have shown that these antibodies may be found in a proportion of first-degree relatives of patients with type 1 diabetes, some of whom later develop diabetes.

Genetics. A number of lines of evidence suggest a genetic predisposition to developing type 1 diabetes. The lifetime risk of type 1 diabetes is 0.4% in white populations and rises to 5 to 6% if a first-degree relative is affected. Concordance rates for monozygotic (identical) twins are approximately 50%, but only 6% for dizygotic (nonidentical) twins.17 Genome-wide screens for susceptibility genes for type 1 diabetes have identified more than ten chromosomal loci.18-21 The two loci that contribute most to the risk of type 1 diabetes are the HLA region (tissue compatibility genes) and the insulin gene locus. Detailed analysis of the HLA region on chromosome 6 has shown that HLA DR3 and DR4 haplotypes increase and HLA DR2 haplotype decreases the risk of type 1 diabetes. Because HLA cell surface molecules are involved in activating T-cell immune responses, it is hypothesized that the DR3 and DR4 forms somehow induce an aberrant immune response, perhaps secondary to a viral infection.

Type 2 Diabetes

Type 2 diabetes is a more heterogeneous disease compared to type 1 diabetes. Most subjects with type 2 diabetes have a condition called insulin resistance. This is a state in which more than normal amounts of insulin are needed to produce a normal metabolic response to insulin.22 Insulin resistance is asymptomatic and may be found in subjects years before they develop type 2 diabetes.2324 As long as the pancreas is able to secrete increased amounts of insulin to counter the reduced response to insulin, blood glucose levels stay within the normal range in individuals with insulin resistance. If the pancreas is unable to keep up with the demand for higher insulin secretion rates, blood glucose concentrations start to rise and diabetes may ensue. Biochemical investigation has shown that insulin concentrations are higher than normal in subjects with insulin resistance and are "normal" in patients with type 2 diabetes of short duration.25 Thus, patients with type 2 diabetes have relative insulin deficiency.

Pancreatic defects. In vitro experiments show that insulin release by pancreatic P-cells has an initial first phase lasting about 10 minutes, followed by a more long lasting second phase of gradually increasing insulin release over 2 to 3 hours. The first phase corresponds to release of insulin granules near the plasma membrane and the second to increased synthesis of insulin and transport from storage granules to plasma membrane granules. Both phases of insulin release are blunted in individuals with type 2 diabetes and impaired glucose tolerance (a condition in which blood glucose concentrations rise above normal, but not into the diabetic range).26,27 It has been calculated that P-cell function is impaired by approximately 50% by the time diabetes occurs.28 Dose-response experiments suggest that the defect in insulin secretion is due to a reduced capacity to secrete insulin rather than insensitivity to glucose as a stimulus for insulin secretion. This is partially, but not wholly, explained by the estimated 30% loss of P-cell mass found in type 2 diabetes. First-phase insulin release is also blunted in individuals with a family history of diabetes but normal glucose tolerance, suggesting a genetic contribution to P-cell function.29

Histological examination of pancreatic tissue from subjects with type 2 diabetes shows accumulation of fibrils of amyloid protein, but no inflammatory infiltrate. It is not clear whether the amyloid fibrils play a role in causing pancreatic damage or are a secondary phenomenon.

Genetics. Twin studies show a higher concordance rate for type 2 diabetes for monozygotic compared to dizygotic twins. A number of monogenic causes of apparent type 2 diabetes have been established, such as maturity onset diabetes of the young (MODY), an autosomal dominant form of diabetes affecting adults under the age of 25 years.30-35 These monogenic forms of type 2 diabetes probably represent less than 5% of those with type 2 diabetes. Genome-wide scans for type 2 diabetes susceptibility genes have produced less uniform results compared to studies of type 1 diabetes. One locus on chromosome 2, originally identified as N1DDM1, has been shown to contain a protease (calpain-10) that appears to have a role in pancreatic function.36 Overall, type 2 diabetes is thought to be a polygenic disorder with many genes contributing small effects to lifetime risk of diabetes combined with environmental factors. The difficulty in identifying these genes lies partly with the need for very large-scale studies to exclude the possibility of false positive results.

Insulin resistance. The most common associations with insulin resistance are obesity and lack of physical fitness. A wide range of other conditions is associated with insulin resistance (see Table 1.2) and many also increase the risk of developing diabetes. In prospective studies, obesity is the strongest modifiable risk factor that predicts future risk of diabetes in nondiabetic populations.37 Body fat distribution is important also; visceral (abdominal) obesity, as measured by the waist:hip ratio, is a stronger predictor than body mass index.38 It is thought that the increased fat mass in obese individuals augments insulin resistance by a number of different mechanisms, including increased release of free fatty acids and a number of adipocytokines including tumor necrosis factor-a, leptin, resistin, and interleukin-6. Some workers have also proposed, in the "lipotoxicity theory" that obesity not only affects insulin sensitivity, but also pancreatic function, with excess fatty acids inhibiting insulin release.39

Fetal nutrition. Epidemiological studies initiated by Barker and coworkers have suggested a novel theory of pathogenesis for type 2 diabetes.40,41 Prevalence of type 2 diabetes has been shown to be higher in low-birth-weight babies compared to high-birth-weight babies. It has been suggested

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