Diabetes mellitus: Diabetes mellitus is a metabolic disease caused by defects in insulin secretion, insulin action, or both. These defects lead to hyperglycemia. Common symptoms include polyuria, polydipsia, polyphagia, weight loss, and increased susceptibility to infections. In some patients, the first presentation may be a complication such as blurred vision or peripheral neuropathy.
Types
Type 1 diabetes mellitus: Also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, type 1 DM is an autoimmune disorder. T cells destroy pancreatic beta cells, which eventually leads to a complete lack of insulin secretion. It typically occurs in children and adolescents. Patients may have antibodies to insulin, beta cells, glutamic acid decarboxylase (GAD 65), or tyrosine phosphatases. It is associated with HLA DQA, DQB, and DRB. Patients are predisposed to ketoacidosis. There is also an increased risk of other autoimmune disorders such as Grave’s disease, pernicious anemia, myasthenia gravis, and Addison’s disease.
Type 2 diabetes mellitus: This is the most common type and is also called non-insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. It is characterized by insulin resistance with relative insulin deficiency. It is associated with obesity, an increased percentage of body fat (especially abdominal fat), lack of physical activity, history of gestational diabetes, hypertension, and dyslipidemia. It has a stronger genetic predisposition than type 1 DM, but it is not autoimmune in nature. Ketoacidosis is rare and is usually seen in the presence of infections or stress. Insulin levels may be normal or increased.
Gestational diabetes or GDM: This is diabetes mellitus that occurs during pregnancy in a person with no previous history of DM. Most cases resolve after delivery. There is an increased risk of developing type 2 DM later.
Maturity onset diabetes of the young or MODY: MODY results from defective beta cell function. It is characterized by impaired insulin secretion with minimal defect in insulin action. It presents in childhood or early adolescence and is inherited as AD. Mutations in chromosome 12, the glucokinase gene on chromosome 7p, IPF 1, etc. are seen.
Other types of diabetes: Genetic syndromes with an increased risk of DM include Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Prader Willi syndrome, Friedreich ataxia, porphyria, huntington chorea, etc. Anti-insulin receptor antibodies may be seen in SLE and autoimmune disorders. DM is also seen in Cushing’s syndrome, acromegaly, glucagonoma, pheochromocytoma, and somatostatinoma. Genetic defects in insulin receptors can cause insulin resistance, hyperglycemia, cystic ovaries, acanthosis nigricans, and DM.
Extensive pancreatic damage from cystic fibrosis, hemochromatosis, chronic pancreatitis, and cancers may cause DM.
Infectious agents associated with DM include congenital rubella, CMV, coxsackie B, adenovirus, and mumps virus.
Drugs associated with DM are glucocorticoids, pentamidine, nicotinic acid, alpha interferon, thyroid hormone, beta adrenergic agonists, and thiazides.
Patients may show elevated HbA1c and impaired glucose tolerance for many years before developing full blown DM. HbA1c indicates average blood glucose levels over the last 2-3 months. Impaired fasting plasma glucose (IFG) levels of 100 to 125 mg/dl, or impaired glucose tolerance (IGT) defined as 2 hour values in the oral glucose tolerance test of 140 to 199 mg/dl, may progress to DM. People with elevated HbA1c (5.7 to 6.4%), IFG, and IGT are called pre-diabetics. This state is associated with an increased risk of DM and cardiovascular disease. Increasing physical activity and decreasing body weight by at least 5-10% can delay the development of diabetes in pre-diabetics.
Complications: Hyperglycemia is the underlying factor leading to all complications seen in diabetes. Certain cells are especially susceptible to hyperglycemia, including endothelial cells, retinal cells, mesangial cells in the kidney, neurons, and Schwann cells in peripheral nerves. These cells cannot effectively decrease glucose transport into the cell during hyperglycemia.
In the presence of excess glucose, the intracellular enzyme aldose reductase converts glucose to sorbitol. Sorbitol is then oxidized to fructose, using NADPH in the process. This increases susceptibility to oxidative damage because NADPH is needed to produce reduced glutathione.
Hyperglycemia also causes the formation of advanced glycation end products in the cell. These cause cellular damage by modification of regulators of gene transcription, extracellular matrix changes, modification of circulating albumin, and increased inflammatory cytokines and growth factors.
Hyperglycemia increases the synthesis of diacylglycerol (DAG), which activates protein kinase C. This has multiple deleterious effects, including decreased synthesis of nitric oxide and increased endothelin 1, VEGF, TGF beta, collagen, fibronectin, plasminogen activator inhibitor 1, NF-kB, and NADPH oxidase. The result is increased vasoconstriction, decreased fibrinolysis, increased inflammation, angiogenesis, vascular permeability, thrombogenesis, and increased free radical damage.
Increased synthesis of N-acetyl glucosamine by the hexosamine pathway causes dysregulation of transcription factors and leads to endothelial and myocyte damage. Hyperglycemia also causes overproduction of superoxide by mitochondria.
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