Define and classify Diabetes mellitus. Discuss the pathophysiology of Type-2 diabetes. What are the complications of uncontrolled diabetes?

Defining and Classifying Diabetes Mellitus

Diabetes mellitus is not a single disease but a group of metabolic disorders sharing the common thread of hyperglycemia. The classification of diabetes has evolved over time, but the current categorization, as defined by the American Diabetes Association (ADA), includes:

• Type 1 Diabetes: An autoimmune disease leading to the destruction of pancreatic beta cells, resulting in absolute insulin deficiency. Typically presents in childhood or adolescence.
• Type 2 Diabetes: Characterized by insulin resistance and progressive beta-cell dysfunction. Strongly associated with obesity, physical inactivity, and family history.
• Gestational Diabetes (GDM): Glucose intolerance diagnosed during pregnancy.
• Specific Types of Diabetes: Due to other causes, such as genetic defects, drug-induced diabetes, or diseases of the exocrine pancreas (e.g., cystic fibrosis).
• Monogenic Diabetes Syndromes: Caused by mutations in a single gene (e.g., Maturity-Onset Diabetes of the Young - MODY).

Pathophysiology of Type 2 Diabetes

The development of Type 2 diabetes is a complex process involving multiple factors. The core defects are insulin resistance and impaired insulin secretion. The pathophysiology can be described in stages:

1. Insulin Resistance

Initially, tissues (muscle, liver, and adipose tissue) become resistant to the effects of insulin. This means that a normal amount of insulin is unable to effectively stimulate glucose uptake and utilization. Several factors contribute to insulin resistance:

• Obesity: Excess adipose tissue, particularly visceral fat, releases adipokines that interfere with insulin signaling.
• Physical Inactivity: Reduces insulin sensitivity in muscle tissue.
• Genetic Predisposition: Certain genes increase susceptibility to insulin resistance.
• Inflammation: Chronic low-grade inflammation contributes to insulin resistance.

2. Compensatory Hyperinsulinemia

In response to insulin resistance, the pancreatic beta cells initially increase insulin production to maintain normal blood glucose levels. This state of compensatory hyperinsulinemia can persist for years, often without noticeable symptoms.

3. Beta-Cell Dysfunction

Over time, the beta cells become exhausted and unable to sustain the increased insulin demand. This leads to progressive decline in insulin secretion. Factors contributing to beta-cell dysfunction include:

• Glucotoxicity: Chronic hyperglycemia damages beta cells.
• Lipotoxicity: Excess free fatty acids impair beta-cell function.
• Amyloid Deposition: Islet amyloid polypeptide (IAPP) can accumulate in the islets, contributing to beta-cell death.
• Genetic Factors: Certain genetic variations increase susceptibility to beta-cell dysfunction.

4. Hyperglycemia and Disease Progression

As insulin secretion declines, blood glucose levels rise, leading to the development of hyperglycemia and ultimately, Type 2 diabetes. The chronic hyperglycemia further exacerbates beta-cell dysfunction, creating a vicious cycle.

Complications of Uncontrolled Diabetes

Uncontrolled diabetes can lead to a wide range of acute and chronic complications affecting multiple organ systems:

Acute Complications

• Diabetic Ketoacidosis (DKA): Primarily occurs in Type 1 diabetes, characterized by hyperglycemia, ketonemia, and metabolic acidosis.
• Hyperosmolar Hyperglycemic State (HHS): More common in Type 2 diabetes, characterized by severe hyperglycemia, dehydration, and altered mental status.
• Hypoglycemia: Low blood glucose levels, often caused by excessive insulin or oral hypoglycemic agents.

Chronic Complications (Microvascular and Macrovascular)

Complication	Mechanism	Affected Systems
Diabetic Retinopathy	Damage to blood vessels in the retina due to chronic hyperglycemia.	Eyes
Diabetic Nephropathy	Damage to the glomeruli in the kidneys due to chronic hyperglycemia.	Kidneys
Diabetic Neuropathy	Damage to nerves due to chronic hyperglycemia.	Peripheral nerves, autonomic nervous system
Cardiovascular Disease	Accelerated atherosclerosis due to hyperglycemia, dyslipidemia, and hypertension.	Heart, blood vessels, brain
Peripheral Artery Disease (PAD)	Narrowing of arteries in the limbs, leading to reduced blood flow.	Legs, feet
Foot Ulcers and Amputations	Combination of neuropathy, PAD, and impaired wound healing.	Feet