Diabetes Mellitus: Type 1 and 2 Classification

Diabetes Mellitus (DM)

• Definition: A metabolic disorder caused by an absolute or relative insulin deficiency.

Classification of DM

• Type I (Insulin Dependent Diabetes Mellitus) IDDM
  • Caused by an absolute deficiency of insulin.
  • Typically develops before the age of 40.
  • Not associated with obesity.
  • Treated with insulin and oral antidiabetic drugs if not controlled.

Secondary Causes of DM

• Caused by diseases, such as pancreatitis, Cushing disease.
• Caused by drugs, such as diazoxide, thiazides (water pills).

Insulin

Nature, Regulation, and Insulin Release

• Insulin is a polypeptide hormone secreted from ß-cells of the pancreas.
• Insulin secretion is stimulated by:
  • High plasma concentrations of glucose, free fatty acid, and amino acids.
  • Gastrointestinal hormones, such as secretin, gastrin, and cholecystokinin.
  • Systemic hormones, such as glucagon and growth hormone.
  • Certain drugs, such as sulphonylureas, alpha blockers, Beta 2 agonists, and muscarinic agonists.
• Insulin secretion is inhibited by:
  • Fasting and starvation.
  • Certain drugs, such as alpha agonists, beta blockers, thiazide, diazoxide, anti-cholinergics, and Phenytoin.

Mechanisms of Insulin in the Body

• Brain: Initiates hunger and hepatic glucose production, as well as lipoprotein production.
• Liver: Responds to insulin by mediating peripheral muscle glucose synthesis, glycogen synthesis, and lipid accumulation, alongside inducing inflammation.
• Adipose Tissue: Responds to insulin by mediating glucose metabolism, lipogenesis, glycogen synthesis, muscle mass, mitochondrial dysfunction, inflammation, and the switch from M2 to M1 macrophages.

Insulin Release

• Insulin release is triggered when high blood glucose enters beta cells through the Glut-2 glucose transporter.
• This stimulates glycolysis, generating ATP, which blocks ATP-sensitive K+ channels, resulting in depolarization and stimulation of voltage-dependent Ca++ channels, leading to an influx of Ca++ and exocytosis of insulin.

Kinetics

• Insulin is not effective orally due to digestion by proteolytic enzymes.
• It is administered parenterally, usually subcutaneously (S.C.) or intravenously (I.V.) in emergency situations.
• Insulin undergoes extensive hepatic metabolism, with 50% first-pass metabolism, primarily by the insulinase enzyme.

Dynamics

Mechanism of Action

• Insulin binds to specific membrane receptors consisting of alpha and beta subunits linked by disulphide bridges.
• Alpha-subunits are extracellular, while beta-subunits are transmembrane and have tyrosine kinase activity.
• Insulin binding to alpha-subunits produces conformational changes in beta-subunits, activating tyrosine kinase activity, phosphorylating intracellular proteins, and changing enzyme activity.

Pharmacological Effects

• Insulin facilitates glucose uptake in adipose tissue and skeletal muscles.
• It causes hypoglycemia by facilitating glucose entry, stimulating glycolysis, glucose utilization, glycogenesis, and inhibiting glycogenolysis and gluconeogenesis.
• Insulin increases lipogenesis in the liver and decreases lipolysis, reducing plasma levels of free fatty acids.
• It stimulates ketone body formation in the liver and has anabolic effects by increasing protein synthesis and inhibiting protein breakdown.
• Insulin also increases the uptake of potassium, calcium, and phosphate by cells.