endocrine and metabolic disorders
Diabetes Mellitus (DM)
Etiology of Diabetes Mellitus
Autoimmune pancreatic beta-cell destruction and absentinsulinproduction Type 1 accounts for<10% of all cases of diabetes mellitus. In type 1 diabetes mellitus (previously called juvenile-onset orinsulin-dependent),insulinproduction is absent because of autoimmune pancreatic beta-cell destruction possibly triggered by an environmental exposure in people who are genetically susceptible. Destruction progresses subclinically over months or years until beta-cell mass decreases to the point thatinsulinconcentrations are no longer adequate to control plasma glucose levels. Type 1 diabetes 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. Autoimmune diabetes that develops in adulthood is often more slowly progressive than childhood type 1 diabetes. Some adults do not needinsulinwhen dysglycemia first develops. This form of diabetes, called latent autoimmune diabetes of adulthood (LADA), may initially be diagnosed as type 2 diabetes. Some cases of type 1 diabetes do not appear to be autoimmune in nature and are considered idiopathic. The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. Susceptibility genesinclude 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 diabetes mellitus—and those outside the MHC, which seem to regulateinsulinproduction and processing and confer risk of diabetes mellitus in concert with MHC genes. Susceptibility genes are more common among some populations than among others and explain the higher prevalence of type 1 diabetes in people with ancestry from certain areas (eg, Scandinavians, Sardinians). Autoantigensinclude glutamic acid decarboxylase,insulin, proinsulin, insulinoma-associated protein, zinc transporter ZnT8, and other proteins in beta cells. It is thought that these proteins are exposed or released during normal beta-cell turnover or beta-cell injury (eg, due to infection), activating primarily a T cell‒mediated immune response that results in beta-cell destruction (insulitis).Glucagon-secreting alpha cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of) beta-cell destruction. (including coxsackievirus, rubella virus, cytomegalovirus, Epstein-Barr virus, SARS-CoV-2 ( Etiology references ), and retroviruses) have been linked to the onset of type 1 diabetes. Viruses may directly infect and destroy beta cells, or they may cause beta-cell destruction indirectly by exposing autoantigens, activating autoreactive lymphocytes, mimicking molecular sequences of autoantigens that stimulate an immune response (molecular mimicry), or other mechanisms. Dietmay also be a factor. Exposure of infants to dairy products (especially cow’s milk and the milk protein beta casein), high nitrates in drinking water, and lowvitamin Dconsumption have been linked to increased risk of type 1 diabetes. Early (<4 months) or late (>7 months) exposure to gluten and cereals increases islet cell autoantibody production. Mechanisms for these associations are unclear. Resistance toinsulin In type 2 diabetes mellitus (previously called adult-onset or non–insulin-dependent),insulinsecretion is inadequate because patients have developed resistance toinsulin. Hepaticinsulinresistance leads to an inability to suppress hepatic glucose production, and peripheralinsulinresistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. Ofteninsulinlevels are very high, especially early in the disease. Later in the course of the disease,insulinproduction 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 years 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 diabetes has become more common among children because childhood obesity has become epidemic. More than 90% of adults with diabetes have type 2 disease. There are clear genetic determinants, as evidenced by the high prevalence of the disease in relatives of people with the disease. Although several genetic polymorphisms have been identified, no single gene responsible for the most common forms of type 2 diabetes has been identified. Pathogenesis is complex and incompletely understood. Hyperglycemia develops wheninsulinsecretion can no longer compensate forinsulinresistance. Althoughinsulinresistance is characteristic in people with type 2 diabetes and those at risk of it, evidence also exists for beta-cell dysfunction and impairedinsulinsecretion that progresses over time, including Impaired first-phaseinsulinsecretion A loss of normally pulsatileinsulinsecretion An increase in proinsulin secretion signaling, indicating impairedinsulinprocessing An accumulation of islet amyloid polypeptide (a protein normally secreted withinsulin) Hyperglycemia itself may impairinsulinsecretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both. Obesity and weight gain are important determinants ofinsulinresistance in type 2 diabetes. 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 impairinsulin-stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also functions as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-alpha, interleukin-6, leptin, resistin) influence glucose metabolism. Intrauterine growth restriction and low birth weight have also been associated withinsulinresistance in later life and may reflect adverse prenatal environmental influences on glucose metabolism. Miscellaneous types of diabetes mellitus account for a small proportion of cases. Causes include Monogenic diabetes due to genetic defects affecting beta-cell function,insulinaction, or mitochondrial DNA (eg, maturity-onset diabetes of youth, neonatal diabetes) Conditions that affect the pancreas (eg, Cystic Fibrosis , Endocrinopathies (eg, Cushing Syndrome , Medications, most notably glucocorticoids, beta-blockers, protease inhibitors, atypical antipsychotics, immune checkpoint inhibitors, and calcineurin inhibitors resistance in all women, but only a fraction will develop Diabetes Mellitus in Pregnancy . 1.Anindya R, Rutter GA, Meur G. New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection.Immunol Cell Biol2023;101(3):191-203. doi:10.1111/imcb.12615 2.D'Souza D, Empringham J, Pechlivanoglou P, Uleryk EM, Cohen E, Shulman R. Incidence of Diabetes in Children and Adolescents During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis.JAMA Netw Open2023;6(6):e2321281. doi:10.1001/jamanetworkopen.2023.21281 