Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It is one of the most common metabolic diseases worldwide, with serious microvascular and macrovascular complications.
Type 1 Diabetes
Type 1 diabetes results from autoimmune destruction of the pancreatic beta cells, leading to absolute insulin deficiency. Genetic susceptibility involves HLA-DR3 and HLA-DR4 haplotypes, and environmental triggers such as viral infections may initiate the autoimmune response. Autoantibodies against insulin, GAD65, IA-2, and zinc transporter 8 appear months to years before clinical onset, marking the preclinical phase.
The loss of insulin secretion leads to uncontrolled gluconeogenesis and glycogenolysis, increasing hepatic glucose output. Reduced glucose uptake in muscle and adipose tissue worsens hyperglycemia. When blood glucose exceeds the renal threshold, glucosuria causes osmotic diuresis, polyuria, and polydipsia. The absence of insulin also allows unchecked lipolysis, increasing fatty acid delivery to the liver and promoting ketogenesis. Diabetic ketoacidosis develops when ketone bodies accumulate, causing metabolic acidosis.
Type 2 Diabetes
Type 2 diabetes is characterized by insulin resistance combined with progressive beta cell dysfunction. Insulin resistance impairs glucose uptake in muscle, increases hepatic gluconeogenesis, and reduces suppression of lipolysis in adipose tissue. The beta cells initially compensate by increasing insulin secretion, producing hyperinsulinemia. Over time, beta cell function declines, and insulin secretion becomes insufficient to maintain normoglycemia.
Obesity, particularly visceral adiposity, is a major risk factor. Adipose tissue dysfunction increases release of free fatty acids and inflammatory adipokines such as TNF-alpha, IL-6, and resistin, which impair insulin signaling. Adiponectin, which enhances insulin sensitivity, is reduced. Ectopic lipid accumulation in muscle and liver further impairs insulin action.
Metabolic Consequences
In both types, insulin deficiency or resistance causes widespread metabolic abnormalities. In muscle, glucose uptake and glycogen synthesis are reduced. In the liver, gluconeogenesis is unrestrained, and the normal suppression of glucose production by insulin is lost. In adipose tissue, lipolysis is increased, elevating plasma free fatty acids. These abnormalities contribute to fasting and postprandial hyperglycemia.
Chronic Complications
Chronic hyperglycemia causes microvascular complications through several mechanisms. Increased flux through the polyol pathway converts glucose to sorbitol, causing osmotic damage in tissues that do not require insulin for glucose uptake. Advanced glycation end products form from non-enzymatic glucose reactions with proteins, altering their function. Activation of protein kinase C increases vascular permeability and promotes inflammation. Increased hexosamine pathway flux alters gene expression.
Diabetic retinopathy is the leading cause of blindness in working-age adults. It progresses from non-proliferative changes including microaneurysms and hemorrhages to proliferative retinopathy with neovascularization. Diabetic nephropathy causes progressive kidney damage, starting with microalbuminuria and progressing to end-stage renal disease. Diabetic neuropathy affects peripheral nerves, causing sensory loss, pain, and autonomic dysfunction.
Macrovascular complications include accelerated atherosclerosis, coronary artery disease, stroke, and peripheral arterial disease. Diabetes confers a two- to four-fold increased risk of cardiovascular events.
Diagnosis and Monitoring
Diabetes is diagnosed by fasting plasma glucose over 7.0 mmol/L, hemoglobin A1c over 6.5%, or an oral glucose tolerance test with 2-hour glucose over 11.1 mmol/L. HbA1c reflects average blood glucose over the preceding 2 to 3 months and is the primary monitoring tool. The diabetes treatment goal is HbA1c below 7.0% for most adults.
Treatment
Type 1 diabetes requires lifelong insulin therapy, with multiple daily injections or continuous subcutaneous infusion. Type 2 diabetes is managed with lifestyle modification, oral medications, and eventually insulin. Metformin reduces hepatic gluconeogenesis and improves insulin sensitivity. Sulfonylureas stimulate insulin secretion. GLP-1 receptor agonists enhance incretin signaling and promote weight loss. SGLT2 inhibitors reduce renal glucose reabsorption and have cardiovascular benefits. Insulin therapy is indicated when oral agents no longer achieve glycemic targets.
