Diabetes

Learning Objectives:
- Define diabetes mellitus.
- Explain how diabetes affects the body.
- Discuss the mechanisms of treatment.

Diabetes Mellitus is a metabolic disorder caused by a lack of insulin action, either due to insufficient insulin secretion, insulin resistance, or both.
It leads to chronic hyperglycemia, affecting the metabolism of carbohydrates, fats, and proteins.

Insulin Secretion:
- Insulin is produced by beta cells in the pancreas, which are located in the Islets of Langerhans.
- Other cells in the pancreas include:
  - Alpha cells: Produce glucagon, which increases blood sugar.
  - Delta cells: Produce somatostatin, which regulates hormone secretion.
- Diagram Explanation: The pancreas has both endocrine (hormonal) and exocrine (digestive enzyme-producing) roles. The diagram differentiates between these functions.

Mechanism of Insulin Secretion (Step-by-Step):
1. Sensing Blood Glucose Levels:
  - Beta cells sense elevated glucose in the blood after a meal.
  - Glucose enters beta cells through the GLUT2 transporter.
2. ATP Generation:
  - Glucose is metabolized via glycolysis and the TCA cycle, increasing ATP production.
3. Membrane Depolarization:
  - Rising ATP closes ATP-sensitive potassium (K⁺) channels.
  - This depolarizes the cell membrane, opening voltage-gated calcium (Ca²⁺) channels.
4. Calcium Influx:
  - Calcium enters the cell, triggering insulin-containing vesicles to fuse with the membrane.
5. Insulin Release:
  - Insulin is secreted into the portal circulation, reducing blood glucose levels by:
    - Promoting glucose uptake in muscle and fat.
    - Suppressing glucose production in the liver.

Diagram Insights: Feedback loop diagrams show how glucose stimulates insulin secretion and how insulin lowers blood sugar, completing the cycle.

Definition: Low blood glucose levels (typically <3.5 mmol/L).
Symptoms (Diagram List):
- Rapid onset symptoms include shakiness, sweating, confusion, rapid heartbeat, hunger, and in severe cases, seizures or unconsciousness.
Cause: Overuse of insulin, missed meals, or excessive exercise in diabetics.

Chronic hyperglycemia caused by:
1. Defects in insulin secretion.
2. Defects in insulin action or resistance.

Fasting Plasma Glucose: ≥7.0 mmol/L.
Random Plasma Glucose: ≥11.1 mmol/L.
Oral Glucose Tolerance Test (OGTT): ≥11.1 mmol/L after 2 hours of ingesting 75g glucose.

Cause: Autoimmune destruction of pancreatic beta cells.
Features:
- Genetic predisposition (HLA-DR3, HLA-DR4).
- Associated with autoimmune diseases like thyroiditis, Addison’s disease, and vitiligo.
Symptoms: Polyuria (excessive urination), polydipsia (thirst), weight loss, fatigue, and ketoacidosis.

Cause: Insulin resistance combined with beta-cell dysfunction.
Features:
- Associated with obesity and sedentary lifestyle.
- Progressive condition leading to reduced insulin secretion over time.

MODY (Maturity-Onset Diabetes of the Young):
- Caused by genetic defects in beta cells or insulin action.
Gestational Diabetes: Occurs during pregnancy due to hormonal changes affecting insulin sensitivity.

Triggering Autoimmunity:
- Environmental factors (e.g., viral infections) trigger an autoimmune response in genetically susceptible individuals.
Beta Cell Destruction:
- T-cells attack pancreatic beta cells, reducing insulin production.
Hyperglycemia:
- Without insulin, glucose cannot enter cells effectively, leading to elevated blood sugar levels.
Ketoacidosis:
- Fat is broken down for energy, producing ketones, which acidify the blood.

Insulin Resistance:
- Tissues (muscle, liver, fat) fail to respond effectively to insulin.
- Glucose uptake is impaired, and hepatic glucose production increases.
Beta Cell Compensation:
- Beta cells increase insulin production to overcome resistance.
Beta Cell Failure:
- Over time, beta cells become exhausted, leading to reduced insulin secretion.
Chronic Hyperglycemia:
- Persistently high glucose levels damage tissues and lead to complications.

Microvascular:
- Retinopathy (eye damage), nephropathy (kidney damage), and neuropathy (nerve damage).
Macrovascular:
- Increased risk of heart attacks, strokes, and peripheral vascular disease.

Insulin Replacement Therapy:
- Rapid-acting, intermediate, and long-acting insulins mimic natural insulin release.
Emerging Therapies:
- Islet cell transplants and immune modulation therapies.

Drug Classes (Step-by-Step Mechanism):
1. Metformin:
  - Reduces hepatic glucose production and improves insulin sensitivity.
2. Sulfonylureas:
  - Stimulate beta cells to secrete more insulin.
3. GLP-1 Agonists:
  - Enhance glucose-dependent insulin secretion and slow gastric emptying.
4. SGLT2 Inhibitors:
  - Block glucose reabsorption in the kidneys, increasing glucose excretion.
5. Thiazolidinediones:
  - Improve peripheral insulin sensitivity by acting on PPAR-gamma receptors in adipose tissue.

New Drugs: Tirzepatide, a GLP-1/GIP dual agonist, improves blood sugar control and aids weight loss.
Closed-Loop Systems: Artificial pancreas systems monitor glucose and deliver insulin automatically.
Lifestyle Interventions: Public health campaigns promoting diet and exercise.

Pancreatic Function Diagram: Shows the role of insulin in lowering blood sugar and glucagon in raising it.
Feedback Loop Diagram: Illustrates how glucose levels regulate insulin secretion and maintain homeostasis.
Treatment Flowchart: Highlights how different drugs target specific mechanisms, e.g., metformin reduces glucose production while SGLT2 inhibitors increase glucose excretion.