Complete Notes on Endocrine Pancreas, Insulin and Glucagon

Endocrine Pancreas

Islets

• The pancreas contains 1-2 million islets, which constitute 1-2% of the pancreatic mass.
• The islets consist of three main cell types:
  • Alpha cells (25%): Secrete glucagon.
  • Beta cells (60%): Secrete insulin.
  • Delta cells (10%): Secrete somatostatin.
• F cells, predominantly found in the posterior portion of the head of the pancreas, secrete pancreatic polypeptide.

Insulin

• Insulin is a 5.8 kDa peptide with 51 amino acids, synthesized by beta cells in the endocrine pancreas.
• It consists of two chains (A and B) linked by disulfide bridges.
• Insulin plays a crucial role in carbohydrate, fat, and protein metabolism.

Structure of Insulin

• The insulin molecule has an A-chain and a B-chain, connected by disulfide bonds between cysteine residues.

Synthesis and Secretion

• Insulin is synthesized as preproinsulin, which is then cleaved to proinsulin in the endoplasmic reticulum (ER).
• The final cleavage into insulin occurs in the Golgi apparatus, where it's packaged into secretory vesicles/granules.
• Insulin is secreted along with C-peptide and small amounts of proinsulin.
• Only insulin has physiological activity.

Transport and Metabolism

• Insulin is transported unbound in plasma.
• It has a half-life of 5-8 minutes.
• Insulin is metabolized by insulinase in the liver, kidney, and muscle.

Process of Secretion

• The primary stimulus for insulin secretion is high blood glucose levels.
  1. Glucose enters the beta cell via the GLUT2 transporter.
  2. It's phosphorylated by glucokinase to glucose-6-phosphate (G6P).
  3. G6P is metabolized, releasing ATP and increasing the ATP/ADP ratio.
  4. ATP closes ATP-sensitive potassium channels (KATP channels).
  5. This causes depolarization of the beta cell.
  6. Opening of voltage-gated calcium channels.
  7. Calcium triggers exocytosis of insulin (excitation-secretion coupling).

Other Factors Affecting Insulin Secretion

• Amino acids and free fatty acids also stimulate insulin secretion.
• Incretin hormones (glucagon-like peptide and gastric inhibitory peptide) trigger insulin secretion via increased cAMP.
• Acetylcholine increases insulin secretion via Gq-coupled M3 muscarinic receptors, while catecholamines decrease it via Gi-coupled α2 adrenergic receptors (↓ cAMP).
• Somatostatin decreases insulin secretion via Gi/↓cAMP.
• Sulfonylureas, a class of oral anti-diabetic drugs, inhibit the KATP channel, triggering insulin release.

Biphasic Insulin Secretion

Insulin Effects

• Insulin affects carbohydrate, fat, and protein metabolism.

Carbohydrate Metabolism

• Promotes uptake, utilization, and storage of glucose by most tissues, mainly the liver, muscle, and adipose tissue.
• Liver:
  • Increases glucose uptake.
  • Stimulates glucokinase (glucose to glucose-6-phosphate), trapping glucose.
  • Stimulates glycogen synthase.
  • Inhibits glycogen phosphorylase.
• Muscle:
  • Increases glucose uptake via GLUT4.
  • Increases glucose utilization (glycolysis).
  • Increases conversion of excess glucose to glycogen.
  • In between meals, muscle mainly relies on fatty acids.
• Adipose tissue:
  • Increases glucose uptake for utilization in the synthesis of glycerol, promoting the synthesis of triglycerides (TGs).
• Insulin promotes glucose uptake in most tissues apart from the brain.

Fat Metabolism

• Insulin does not favor the utilization of fatty acids for energy.
• Excess glucose that cannot be converted to glycogen in the liver is converted to fatty acids, assembled into TGs in VLDL, released into the blood, and transported to adipose tissue for storage.
• Increases lipoprotein lipase in adipose tissue, which breaks down TGs in VLDL to FFAs, which are taken up by the adipose tissue.
• Increases synthesis of TGs in adipose tissue.
• Decreases lipolysis (inhibits hormone-sensitive lipase).

Protein Metabolism

• Increases amino acid uptake.
• Increases protein synthesis.
• Decreases protein catabolism.
• Inhibition of gluconeogenesis indirectly decreases utilization of amino acids/proteins for energy production.

Insulin and Growth

• Insulin works synergistically with growth hormone to promote growth.
• Both hormones enhance amino acid uptake and protein synthesis.
• IGF-I, which mediates the growth effects of GH, has similarities in structure and receptor signaling to insulin.

Insulin Receptor

• Receptor Tyrosine-Kinase (enzyme-linked/catalytic receptor).
• Four subunits (two alpha and two beta).
• Alpha subunits are on the external side of the membrane and have the hormone-binding site.
• Beta subunit spans the membrane and has tyrosine kinase on the cytosolic side.
• Insulin binding triggers autophosphorylation of the beta subunits.
• Leads to recruitment and phosphorylation of adaptor proteins, key among them Insulin Receptor Substrates (IRS).
• IRS phosphorylation activates phosphoinositide-3-kinase (PI3K), which then activates protein-kinase-B pathway (Akt), responsible for the metabolic effects of insulin.

Downstream Effects include:

• Insertion of transport proteins e.g., GLUT4 that enhances glucose uptake.
• Change in the activity of intracellular enzymes.
• Alteration in gene transcription (several hours to days).

Glucagon

• The primary "counter-regulatory hormone" to insulin, increases blood glucose.
• A 29 amino acid peptide hormone, secreted by the alpha cells of the pancreatic islet.
• Released in between meals when blood glucose levels begin to fall.
• Insulin levels also fall during this period, hence less inhibition on glucagon secretion.

*Synthesized as preproglucagon.
*Cleavage in ER and Golgi apparatus before secretion.
*Circulates unbound, short half-life of 6 minutes.
*Degraded by the liver.
*Most of it degraded as it goes through the liver from the portal vein, hence very small amounts enter the general circulation.
*Primary site of action is the liver.
*Effects opposite to those of insulin.

Effects of Glucagon

Carbohydrate Metabolism (MAIN)

• Glycogenolysis
• Gluconeogenesis
  *Other effects are minor, at high glucagon levels

Lipid Metabolism

• Increases Lipolysis in adipose tissue
• Inhibits lipid storage in the liver

*Factors That INFLUENCE GLUCAGON Secretion

Stimulants

• Low blood glucose (hypoglycemia) (MAIN)
• High blood amino acid levels
  • Glucagon enhances amino acid uptake by the liver to be utilized in gluconeogenesis
• Exercise

Inhibitors

• Insulin
• Somatostatin

Mechanism of Action

• Binds to a GPCR
• Activates Gs/cAMP/PKA cascade
• PKA activates phosphorylase kinase (PPK)
• PPK activates glycogen phosphorylase/PYG (converts phosphorylase b to a)
• PYG breaks down glycogen (glycogenolysis)

Other Hormones That Increase Blood Glucose (Counter-Regulatory Hormones)

• Catecholamines
• Glucocorticoids (Cortisol)
• Growth Hormone

Catecholamines

• Secreted as hormones by the adrenal medulla or neurotransmitters by sympathetic nerves

Stimuli for secretion

• Hypoglycemia
• Exercise
• Stress

*Effects via β2 adrenergic receptors in the liver, muscle, and adipose tissue
*GS/cAMP/PKA signaling cascade, just like glucagon

Effects:

• Gluconeogenesis
• Lipolysis: stimulates hormone-sensitive lipase in adipose tissue
• Proteolysis and decreased protein synthesis in skeletal muscle

Diabetes Mellitus

• A chronic disease characterized by hyperglycemia resulting from lack of insulin or impaired sensitivity to insulin (insulin resistance)
• Most common endocrine disorder
• One of the most prevalent non-communicable diseases (NCD), and a major risk factor for cardiovascular disease, renal failure, blindness, limb amputation, and neurodegenerative disease
• Associated with dysregulation of carbohydrate, fat, and protein metabolism

Type I DM

• Less common
• Due to a lack of insulin secretion
• Main cause: Autoimmune destruction of the beta cells of the pancreas
• Diagnosed in childhood/adolescence/young adulthood
• Rapid onset

Type II DM

• Common
• Due to insulin resistance
• Gradual onset
• Onset normally after 30 years
• Lifestyle-related

Differences Between Type I and Type II

Symptoms of Diabetes

• Polyuria
• Polydipsia
• Polyphagia
• Weight loss
• Fatigue
• Blurring of vision
• Poor wound healing
• Recurrent infections

Complications of DM

Acute

• Diabetic Ketoacidosis (DKA)
• Hyperosmolar Hyperglycemic State

Chronic/Long-term

• Microvascular complications
• Macrovascular complications

Complications of Type 2 Diabetes

Microvascular Complications

• Diabetic Retinopathy
  • Leading cause of blindness in working-age adults
• Diabetic Nephropathy
  • Leading cause of end-stage renal disease
• Diabetic Neuropathy
  • Leading cause of nontraumatic lower extremity amputations

Macrovascular Complications

• Stroke
  • 2- to 4-fold increase in cardiovascular mortality and stroke
• Heart Disease
• Peripheral Vascular Disease

Management

• Lifestyle modification: Diet, Exercise, Weight loss

Medical treatment

• Type I DM
  • Insulin
• Type II DM
  • Sulfonylureas
  • Biguanides
  • Thiazolidinediones
  • Alpha-glucosidase inhibitors
  • Insulin