Insulin Physiology Overview

Insulin Physiology Review

• Insulin is a hormone produced by beta cells in the islets of Langerhans in the pancreas.
• It regulates carbohydrate and lipid metabolism, but has minor impact on protein metabolism.
• Insulin has a short half-life and is cleared from the body within 15 minutes of secretion.

Insulin Synthesis

• Preproinsulin: The initial, larger protein form of insulin.
• Proinsulin: Preproinsulin is processed, creating three peptide chains (A, B, and C).
• Insulin: Proinsulin is further processed, removing the C peptide, leaving only the A and B chains bonded together, forming the active insulin.
• C-peptide: The removed peptide; it's a measure of insulin production and may decrease complications in those with diabetes.

Insulin Secretion

• Stimulated by: Higher glucose levels, amino acids, and free fatty acids in the blood.
• Inhibited by: Lower glucose levels and higher levels of insulin itself; this is a feedback mechanism to prevent overproduction.
• Other stimuli: Gastrointestinal hormones (e.g., gastrin, CCK, secretin) and parasympathetic nervous system stimulation can also influence insulin release.

Insulin Action

• Receptors: Found on most cell membranes, enabling cells to receive the insulin signal.
• Structure: Two alpha subunits bind insulin and two beta subunits have tyrosine kinase activity.
• Activation cascade: Binding to the receptor activates tyrosine kinase, triggering further cellular signaling involving other intracellular enzymes like PKB and MAP kinase.
• Glucose uptake: Crucial; Insulin binding moves glucose transporters (GLUT4) to the cell surface.
• General effects:
  • Control of postprandial plasma glucose levels: Insulin promotes glucose uptake and lowers blood sugar after eating.
  • Promotes glucose storage as glycogen: Excess glucose is stored in liver and muscles as glycogen.
  • Fatty acid synthesis and triglyceride formation: Promotes fat storage in adipose tissue.
  • Transport of amino acids; stimulates protein synthesis: Transports essential nutrients; builds and repairs tissue.
  • Stimulates cell growth and differentiation.
  • Facilitates K+ transport: Influences potassium levels.

Glucagon

• Glucagon is a hormone produced by alpha cells in the pancreas.
• It's an antagonist to insulin: It opposes insulin's effects, increasing blood glucose levels primarily through liver action.
• Secretion: Triggered by low blood glucose levels.
• Effects: Promotes glycogen breakdown (glycogenolysis), glucose production from other sources (gluconeogenesis), fat breakdown (lipolysis), and ketone production (ketogenesis).
• Circulation: Primarily affects the liver with limited circulation to other tissues.

Diabetes Mellitus

• Diabetes mellitus: A group of disorders characterized by high blood glucose (hyperglycemia) and difficulty regulating glucose metabolism.
• Diagnostic criteria: HbA1c >6.5% (average blood glucose over 2-3 months), and FPG >126 mg/dL (fasting blood glucose after at least 8 hours). Random plasma glucose >200mg/dL (regardless of timing) also suggest diabetes, especially if symptoms present.

Type 1 Diabetes Mellitus

• Type 1A: Autoimmune-mediated; most common type. The immune system attacks and destroys beta cells, leading to a complete lack of insulin production.
• Autoantibodies and cytotoxic T cells target beta cells for destruction.
• Type 1B: Nonimmune-mediated; Not due to an autoimmune response. Could be related to chronic pancreatitis or cystic fibrosis.
• Causes: A combination of genetic predisposition and environmental factors (e.g., viral infections, dietary aspects, and early introduction of gluten).

Type 2 Diabetes Mellitus

• Type 2 diabetes: Chronic condition where the body doesn't produce enough insulin or doesn't use insulin properly (insulin resistance).
• Risk factors: Genetic predisposition, obesity, older age, ethnicity, PCOS, metabolic syndrome.

Pathophysiology of Type 2 Diabetes Mellitus

• Insulin resistance: Cells don't respond properly to insulin.
• High-calorie/carbohydrate diet: Contributing factor to hyperinsulinemia (high insulin levels).
• Adipokines: Hormones released by fat cells that can contribute to insulin resistance.
• Consequences of insulin resistance: hyperglycemia, osmotic diuresis, hyperosmolarity, dyslipidemia.

Chronic Complications of Diabetes Mellitus

• Advanced glycation end products (AGEs): Formed in the presence of high blood sugar, causing damage to blood vessels.
• Nonenzymatic glycosylation: Modification of proteins, lipids, and nucleic acids in the presence of high blood sugar, altering their structure and function.
• High blood glucose: Leads to advanced glycation end products (AGEs).
• Cause capillary basement membrane thickening: Blocking nutrient exchange between blood and tissues.
• Increased capillary permeability: Leads to fluid leakage from capillaries into surrounding tissues (edema), potentially causing further tissue damage.

Microvascular Disease

• Severity: Influenced by factors such as age, duration of diabetes, and blood glucose control.
• Complications: Retinopathy, nephropathy.
• Pathophysiology: Advanced glycation end products (AGEs), Polyol pathway, inappropriate protein kinase C activation.

Macrovascular Disease (Atherosclerosis)

• Atherosclerosis: Fatty deposits (plaque) build up in arteries, narrowing them and restricting blood flow.
• Contributing factors: Hyperglycemia, dyslipidemia, AGEs.
• Consequences: Coronary artery disease, myocardial ischemia/infarction, cerebral infarct (stroke), renal artery stenosis, intestinal vascular insufficiency, peripheral arterial disease (including skin ulceration, gangrene, amputation).

Neuropathy

• Peripheral neuron dysfunction: Problems in nerves outside the brain and spinal cord, affecting sensation, movement, and organ function.
• Pathophysiology: polyol pathway activation, AGEs, PKC activation, ischemia of peripheral neurons, axonal degeneration, demyelination.
• Clinical consequences: Sensory deficits (tingling, burning, numbness), motor deficits (changes in gait, weakness).

Increased Risk of Infection

• Decreased perfusion: Reduced blood flow in tissues, making them more vulnerable to damage from injury and infection.
• Skin breakdown, impaired vision and sensation are common consequences.
• Glucose as a fuel source, and decreased WBC supply are risk factors for bacterial infections.
• Impaired WBC function: Hyperglycemia can negatively impact white blood cell function, making them less effective at combating infection.