Insulin production absent because of autoimmune pancreatic β-cell destruction
In Type 1 DM (previously called juvenile-onset or insulin -dependent), insulin production is absent because of autoimmune pancreatic β-cell destruction possibly triggered by an environmental exposure in genetically susceptible people. Destruction progresses subclinically over months or years until β-cell mass decreases to the point that insulinconcentrations are no longer adequate to control plasma glucose levels. Type 1 DM generally develops in childhood or adolescence and until recently was the most common form diagnosed before age 30; however, it can also develop in adults (latent autoimmune diabetes of adulthood, which often initially appears to be type 2 DM). Some cases of type 1 DM, particularly in nonwhite populations, do not appear to be autoimmune in nature and are considered idiopathic. Type 1 accounts for < 10% of all cases of DM.
The pathogenesis of the autoimmune β-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors.
Susceptibility genes include those within the major histocompatibility complex (MHC)—especially HLA-DR3,DQB1*0201 and HLA-DR4,DQB1*0302, which are present in > 90% of patients with type 1 DM—and those outside the MHC, which seem to regulate insulinproduction and processing and confer risk of DM in concert with MHC genes. Susceptibility genes are more common among some populations than among others and explain the higher prevalence of type 1 DM in some ethnic groups (Scandinavians, Sardinians).
Autoantigens include glutamic acid decarboxylase, insulin , proinsulin, insulinoma-associated protein, zinc transporter ZnT8, and other proteins in β cells. It is thought that these proteins are exposed or released during normal β-cell turnover or β-cell injury (eg, due to infection), activating primarily a T cell‒mediated immune response resulting in β-cell destruction (insulitis). Glucagon -secreting α cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of)β-cell destruction.
Several viruses (including coxsackievirus, rubella virus, cytomegalovirus, Epstein-Barr virus, and retroviruses) have been linked to the onset of type 1 DM. Viruses may directly infect and destroy βcells, or they may cause β-cell destruction indirectly by exposing autoantigens, activating autoreactive lymphocytes, mimicking molecular sequences of autoantigens that stimulate an immune response (molecular mimicry), or other mechanisms.
Diet may also be a factor. Exposure of infants to dairy products (especially cow’s milk and the milk protein β casein), high nitrates in drinking water, and low vitamin D consumption have been linked to increased risk of type 1 DM. Early (< 4 mo) or late (> 7 mo) exposure to gluten and cereals increases islet cell autoantibody production. Mechanisms for these associations are unclear.
Resistance to insulin
In type 2 DM (previously called adult-onset or non– insulin -dependent), insulin secretion is inadequate because patients have developed resistance to insulin . Hepatic insulinresistance leads to an inability to suppress hepatic glucose production, and peripheralinsulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. Often insulin levels are very high, especially early in the disease. Later in the course of the disease, insulin production may fall, further exacerbating hyperglycemia. The disease generally develops in adults and becomes more common with increasing age; up to one third of adults > age 65 have impaired glucose tolerance. In older adults, plasma glucose levels reach higher levels after eating than in younger adults, especially after meals with high carbohydrate loads. Glucose levels also take longer to return to normal, in part because of increased accumulation of visceral and abdominal fat and decreased muscle mass.
Type 2 DM is becoming increasingly common among children as childhood obesity has become epidemic: 40 to 50% of new-onset DM in children is now type 2. Over 90% of adults with DM have type 2 disease. There are clear genetic determinants, as evidenced by the high prevalence of the disease within ethnic groups (especially American Indians, Hispanics, and Asians) and in relatives of people with the disease. Although several genetic polymorphisms have been identified over the past several years, no single gene responsible for the most common forms of type 2 DM has been identified.
Pathogenesis is complex and incompletely understood. Hyperglycemia develops wheninsulin secretion can no longer compensate for insulin resistance. Although insulinresistance is characteristic in people with type 2 DM and those at risk of it, evidence also exists for β-cell dysfunction and impaired insulin secretion, including impaired first-phase insulin secretion in response to IV glucose infusion, a loss of normally pulsatileinsulin secretion, an increase in proinsulin secretion signaling impaired insulinprocessing, and an accumulation of islet amyloid polypeptide (a protein normally secreted with insulin ). Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize β cells, cause β-cell dysfunction (glucose toxicity), or both. These changes typically take years to develop in the presence of insulin resistance.
Obesity and weight gain are important determinants of insulin resistance in type 2 DM. They have some genetic determinants but also reflect diet, exercise, and lifestyle. An inability to suppress lipolysis in adipose tissue increases plasma levels of free fatty acids that may impair insulin -stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also appears to function as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-α, IL-6, leptin, resistin) influence glucose metabolism. Intrauterine growth restriction and low birth weight have also been associated with insulin resistance in later life and may reflect adverse prenatal environmental influences on glucose metabolism.
Miscellaneous causes of DM that account for a small proportion of cases include genetic defects affecting β-cell function, insulin action, and mitochondrial DNA (eg, maturity-onset diabetes of youth); pancreatic diseases (eg, cystic fibrosis, pancreatitis, hemochromatosis); endocrinopathies (eg, Cushing syndrome, acromegaly); toxins (eg, the rodenticide pyriminyl [Vacor]); and drug-induced diabetes, most notably from glucocorticoids, β-blockers, protease inhibitors, and therapeutic doses of . Pregnancy causes some insulin resistance in all women, but only a few develop the symptoms.
REFERENCE: Mercks Manual.