lec 4 part 2 Pancreas (Glucagon)

Glucagon and its Functions

  • Secreted by the alpha cells of the islets of Langerhans when blood glucose concentration falls.

  • Its functions are diametrically opposed to insulin and primarily focus on increasing blood glucose concentration.

  • Glucagon is a large polypeptide composed of a chain of 29 amino acids.

Actions of Glucagon

  • Known as a "hyperglycemic hormone."

  • Most actions of glucagon are achieved through the activation of adenylyl cyclase in the hepatic cell membrane.

  • Glucagon binds to hepatic receptors, activating adenylyl cyclase and generating cyclic AMP (cAMP) as a second messenger.

  • cAMP activates protein kinase, leading to phosphorylation that alters the activity of various enzymes.

Mechanism of Action

  • Chemical messenger dynamics:

    • Glucagon binds to receptors on the cell membrane, initiating enzyme activation.

    • Signal transduction occurs, leading to a cellular response.

    • Muscle relaxation and nerve stimulation are influenced by the actions of glucagon.

Effects on Glucose Metabolism

  • Glucagon promotes:

    • Breakdown of liver glycogen (glycogenolysis).

    • Increased gluconeogenesis in the liver.

  • These processes enhance glucose availability to organs.

Other Effects of Glucagon

  • Activates adipose cell lipase, increasing the availability of fatty acids for energy.

  • Inhibits triglyceride storage in the liver, preventing it from removing fatty acids from the bloodstream.

Regulation of Glucagon Secretion

  1. Increased Blood Glucose Inhibits Glucagon Secretion:

    • Blood glucose concentrations must fall significantly (from ~90 mg/100 ml to hypoglycemic levels) to increase glucagon secretion.

  2. Increased Blood Amino Acids Stimulate Glucagon Secretion:

    • Elevated amino acid levels, especially post-meal (e.g., alanine and arginine), stimulate glucagon secretion, alongside insulin.

  3. Exercise Stimulates Glucagon Secretion:

    • Increased glucagon levels during exercise, even without a fall in blood glucose, help prevent glucose drops.

Importance of Blood Glucose Regulation

  • Chronic high blood glucose can lead to tissue damage, particularly in blood vessels.

  • Associated with increased risks of heart attack, stroke, renal disease, and blindness.

Diabetes Mellitus Overview

  • A syndrome of impaired metabolism due to lack of insulin or decreased sensitivity to insulin.

  • Types of Diabetes Mellitus:

    • Type I Diabetes (IDDM): Results from impaired insulin secretion.

    • Type II Diabetes (NIDDM): Results from resistance to insulin's effects.

Clinical Features

Feature

Type I

Type II

Age at Onset

Usually <20 years

Usually >30 years

Body Mass

Low to normal

Obese

Plasma Insulin

Low or absent

Normal to high initially

Plasma Glucagon

High, can be suppressed

High, resistant to suppression

Plasma Glucose

Increased

Increased

Insulin Sensitivity

Normal

Reduced

Therapy

Insulin

Weight loss, medications

Pathophysiology of Type I Diabetes

  • Caused by autoimmune destruction of pancreatic beta cells.

  • Can also result from viral infections or genetic predisposition.

Consequences of High Blood Glucose

  • Leads to glucose loss in urine when levels exceed 180 mg/100 ml, causing osmotic diuresis (polyuria), dehydration, and increased thirst (polydipsia).

  • Chronic high glucose can cause tissue injury, leading to cardiovascular complications, kidney disease, retinopathy, and limb ischemia.

  • Severe untreated diabetes can result in weight loss and energy deficiency despite high food intake (polyphagia).

Type II Diabetes Characteristics

  • More common than Type I (accounting for ~90% cases).

  • Characterized by insulin resistance, often associated with obesity.

Causes of Insulin Resistance

  • Obesity/overweight.

  • Excess glucocorticoids (steroid therapy).

  • Excess growth hormone (acromegaly).

  • Autoantibodies or genetic mutations affecting insulin receptor function.

Diagnosing Diabetes Mellitus

  • Urinary glucose testing and fasting blood glucose (FBG) levels.

  • Normal FBG is 80-90 mg/100 ml; >110 mg/100 ml indicates diabetes.

  • Type I insulin levels are very low or undetectable.

Acetone Breath in Diabetes

  • Acetoacetic acid in the blood converts to acetone, detectable in breath as a sign of Type I diabetes.

Glucose Tolerance Test

  • Test involves glucose ingestion; results vary in diabetic individuals, showing sustained elevated blood glucose levels.

Treatment of Diabetes

  • Type I Treatment: Requires insulin administration.

  • Type II Treatment: Emphasis on lifestyle changes; if ineffective, medications may be used to enhance insulin sensitivity or stimulate pancreas.

Preventive Measures for Complications of Diabetes

  • Management of lipid levels is crucial due to the association of diabetes with vascular complications.