Diabetes mellitus | Renal, endocrine and reproductive system | Pathology

Diabetes mellitus: It is a metabolic disease that results from defects in insulin secretion, action or both, causing hyperglycemia. It presents with polyuria, polydipsia, polyphagia, weight loss and increased susceptibility to infections. Sometimes the presenting feature may be complications such as blurred vision, peripheral neuropathies etc.

Types

Type 1 diabetes mellitus: Also called insulin dependent diabetes mellitus or IDDM or juvenile onset diabetes, is an autoimmune disorder characterized by beta cell destruction by T cells, which sooner or later leads to complete lack of insulin secretion. Cases are typically seen in children and adolescents and show antibodies to insulin, beta cells, glutamic acid decarboxylase or GAD 65 and tyrosine phosphatases. It is associated with HLA DQA, DQB and DRB. Patients are predisposed to ketoacidosis. There is increased risk of other autoimmune disorders such as Grave’s disease, pernicious anemia, myasthenia gravis, Addison’s disease etc.

Type 2 diabetes mellitus: It is the most common type and is also called non-insulin dependent or adult onset diabetes mellitus. It is characterized by insulin resistance and relative insulin deficiency. It is associated with obesity, 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 is not autoimmune in nature. Ketoacidosis is rare and is seen in the presence of infections or stress. Insulin levels may be normal or increased.

Gestational diabetes or GDM: It is diabetes mellitus that occurs during pregnancy, without any previous history of DM. Most cases resolve after delivery. There is increased risk of type 2 DM later on.

Maturity onset diabetes of the young or MODY: It results from defective function of the beta cells. It is characterized by impaired secretion of insulin with minimal defect in insulin action. It presents in childhood or early adolescence and is inherited as AD. Mutations in chromosome 12, glucokinase gene on chromosome 7p, IPF 1 etc are seen.

Other types of diabetes: Genetic syndromes with 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 is an indication of 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. It is associated with 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.

Laboratory criteria for the diagnosis of Diabetes Mellitus (any one of the following can be positive for a diagnosis)

Fasting blood glucose = or > 126 mg/dl
2 hour plasma glucose = or > 200 mg/dl following oral glucose tolerance test with 75 gm glucose
HbA1c = or > 6.5%
Symptoms of hyperglycemia with a random blood glucose = or > 200 mg/dl

Complications: Hyperglycemia is the underlying factor leading to all complications seen in diabetes. Cells like endothelial cells, retinal cells, mesangial cells in the kidney, neurons and Schwann cells in the peripheral nerves are more susceptible to hyperglycemia as they cannot effectively decrease glucose transport into the cell in the presence of hyperglycemia. In the presence of excess glucose, the intracellular enzyme aldose reductase converts glucose to sorbitol, which is then oxidized to fructose, utilizing NADPH during the process. This makes the cell more susceptible to oxidative damage as NADPH is needed to produce reduced glutathione. Hyperglycemia causes the formation of advanced glycation end products in the cell which cause cellular damage by modification of regulators of gene transcription, extracellular matrix changes, modify circulating albumin, increase inflammatory cytokines and growth factors. Hyperglycemia also increases the synthesis of diacylglycerol or DAG which activates protein kinase C. This in turn has multiple deleterious effects such as decreased synthesis of nitric oxide, increased endothelin 1, VEGF, TGF beta, collagen, fibronectin,plasminogen activator inhibitor 1, NF-kB and NADPH oxidase. Result is increased vasoconstriction, decreased fibrinolysis, increased inflammation, angiogenesis, vascular permeability and thrombogenesis and increased free radical damage. Increased synthesis of N-acetyl glucosamine by the hexosamine pathway causes dysregulation of transcription factors, endothelial and myocyte damage. Hyperglycemia also causes overproduction of superoxide by mitochondria.