Study Notes on Pancreatic Hormones, Insulin, and Glucagon
Pancreatic Hormones (Insulin and Glucagon)
A. Anatomy of the Hepatopancreatic Complex
Dual Role of the Pancreas:
Endocrine Gland: Constitutes only 1–2% of the pancreas's weight. Secretes hormones directly into the bloodstream:
Insulin (produced by β (B) cells)
Glucagon (produced by α (A) cells)
Somatostatin (produced by δ (D) cells)
Pancreatic Polypeptide (PP) (produced by F cells)
Gastrin (produced by G cells, in small amounts)
Exocrine Gland: Constitutes the majority of the pancreas and produces and secretes digestive components into ducts:
Enzymes: Chymotrypsin, Trypsin, Amylase, Lipase
Bicarbonate: Neutralizes gastric acid in the duodenum
Hepatopancreatic Complex Components and Role:
Components: Pancreas, Liver, Gallbladder, Bile ducts, Duodenum.
Function: Works with the gallbladder to integrate the digestion and processing of most dietary nutrients.
A1. Cells of the Pancreatic Islets (Islets of Langerhans)
Human Islet Cells: Secretion of
Insulin: Produced by β (B) cells (
~~60%~~), located in the center. Co-secreted with Amylin.Glucagon: Produced by α (A) cells (
~~25%~~), located in the periphery.Somatostatin: Produced by δ (D) cells (
~~10%~~), located near α-cells.Pancreatic Polypeptide (PP): Produced by F (PP) cells (small %),
scattered. Stimulates gastric acid secretion (HCl) by stomach parietal cells.Gastrin: Produced by G-cells (very small %), scattered.
Amylin (IAPP): Co-secreted with insulin (approx. 1:100 ratio). Deficient in diabetics. Functions: Inhibits glucagon secretion, slows gastric emptying, and acts as a satiety signal.
Blood Flow in Islets: Hormones are secreted into capillaries, then flow through arterioles to venules, and finally into the systemic circulation.
A2. Vascularization and Innervation of Pancreatic Islets
Autonomic Nervous System (ANS) Regulation:
Influences internal organ functions with adrenergic (Sympathetic - SNS) and cholinergic (Parasympathetic - PNS) fibers present in both exocrine acinar and islet regions.
Parasympathetic Stimulation (PNS - Rest & Digest): Promotes insulin secretion, inhibits glucagon secretion.
Sympathetic Stimulation (SNS - Fight or Flight) & Epinephrine: Can enhance glucagon secretion while inhibiting insulin secretion.
Hypothalamic Role:
Major integrator and central regulator in balancing sympathetic and parasympathetic regulation of pancreatic islets, influencing hormone secretion.
B. Insulin
Development of Insulin Chemistry and Physiology: Notable firsts in science related to insulin are discussed.
B1. Insulin Amino Acid Sequence
Forms of Insulin: Preproinsulin (110110 amino acids) transforms into proinsulin, which then becomes mature insulin alongside C-peptide.
Mature Insulin Composition:
A Chain: 2121 amino acids
B Chain: 3030 amino acids
C Peptide: 2121 amino acids, serves as a linker and is cleaved out.
Disulfide Bonds: Three total disulfide bonds:
Two bonds between the A and B chains.
One intrachain bond within the A chain.
Genetic Mutations: Certain mutations disrupt disulfide bond formation or result in incorrect folding, leading to neonatal diabetes, hyperinsulinemia, hyperproinsulinemia, MODY, and Type 1b diabetes.
B2. Conversion of Preproinsulin into Insulin
Proteolytic Cleavage Process:
Involves endopeptidases like prohormone convertase (PC) and carboxypeptidases E (CPE).
Enzyme Pathways:
Major (faster): PC1/PC3 + CPE
Minor (slower): PC2 + CPE
Result: Cleavage at Lys/Arg sites yields a mature insulin composed of the A and B chains linked by disulfide bonds and the separate C-peptide.
B3. Insulin Structure
Structural Conservation:
Fixed positions of all 33 disulfide bonds are conserved across evolution.
Conserved N- and C-termini of the A-chain.
Hydrophobic residues are present at the B-chain C-terminus.
Insulin Exists as:
Monomer (active form)
Dimer
Tetramer
Hexamer (storage form; stabilized by Zn2+Zn2+ and histidines).
B5. Insulin Receptor
Insulin Receptor Composition:
Tetramer Structure: Comprises two smaller extracellular α-subunits and two larger transmembrane β-subunits (containing a tyrosine kinase domain).
Activation Sequence: Two insulin molecules bind to α-subunits, causing a conformational change in the β-subunits, which then autophosphorylate. This tyrosine kinase activity triggers signaling pathways.
B5. Insulin Signal Transduction
Five Major Signaling Pathways:
P1a & P1b (MAPK pathway): SHC → GRB2 → SOS → RAS → RAF → MEK → MAPK. Function: Gene expression and cell growth regulation.
P2 (NO pathway): eNOS → nitric oxide (NO) production. Function: Vasodilation effects.
P3 pathway: PI3K → PDK → Akt → aPKC → FOXO1 → GSK3. Function: Glycogen synthesis (via GSK3 inhibition) and metabolic regulation.
P4 (GLUT4 Translocation Pathway): CAP → Cbl → Crk → C3G → TC10. Function: Moves GLUT4 vesicles to the plasma membrane.
Insulin & GLUT4 Transport Mechanism: Insulin activates the P4 pathway, causing GLUT4 vesicles to fuse with the plasma membrane, thereby increasing glucose uptake.
GLUT4 Characteristics: Sodium-independent facilitated-diffusion glucose transporter.
GLUT Classes:
Class I: GLUT1–4 (glucose transporters)
Class II: Fructose transporters
Class III: Atypical GLUTs
General GLUT Structure: Features 1212 transmembrane helices, with both N- and C-termini facing the cytosol.
C. Glucagon and Glucagon-like Peptides
C1. Biosynthesis and Secretion
Main Actions of Glucagon:
In Liver: Promotes gluconeogenesis (glucose synthesis) and glycogenolysis (glycogen breakdown) for maintaining blood glucose levels.
In Adipose Tissue: Stimulates lipolysis, converting stored triglycerides into free fatty acids for energy production.
Origin: All glucagons originate from a single proglucagon gene.
Expression Regulation in Pancreatic α-cells:
Stimulated by: Amino acids (Arg, Ala, Gln), epinephrine, and neuropeptides as agonists.
Inhibited by: Glucose and somatostatin as antagonists.
C2. Proglucagon Gene Products
In Pancreas (α-cells): Primarily processed to full-length glucagon.
In Intestine (L-cells): Processes proglucagon to GLP-1, GLP-2, and oxyntomodulin.
GLP-1: Crucial for regulating insulin secretion (glucose-dependent) and glucose levels. Suppresses glucagon and acts as an antihyperglycemic hormone.
GLP-2: Involved in GI growth with other unclear functions.
Oxyntomodulin: Activates the GLP-1 receptor.
Receptors: All are G-protein–coupled receptors (GPCRs), including the Glucagon receptor, GLP-1 receptor, and GLP-2 receptor.
D. Insulin and Glucagon Interactions
Shared Responsibility: Both hormones collaborate to maintain blood glucose levels.
Goal Blood Glucose Concentration: Normally 80–110extmg/dL80–110extmg/dL.
Abnormal Ranges:
Diabetes-related levels: >130extmg/dL>130extmg/dL (signify chronic elevation, e.g., in Type 2 diabetes).
Hypoglycemia: 50–60extmg/dL50–60extmg/dL.
Glucose Amounts: 100extmg/dL100extmg/dL blood glucose is approximately 5extg5extg of glucose in the entire blood volume. An average meal provides approximately 90extg90extg of glucose, which must be processed.
Handling Glucose After a Meal: Approximately 5050 is stored as glycogen, and 5050 is metabolized (glycolysis → TCA cycle → ATP production).
Insulin Effects (Post-meal):
ext{ } oldsymbol{ ext{ extuparrow }} Glucose uptake (via GLUT4 translocation)
ext{ } oldsymbol{ ext{ extuparrow }} Glycogenesis (glycogen synthesis)
ext{ } oldsymbol{ ext{ extuparrow }} Lipogenesis (lipid synthesis)
ext{ } oldsymbol{ ext{ extdownarrow }} Gluconeogenesis (glucose synthesis)
Glucagon Effects (Between meals/fasting):
ext{ } oldsymbol{ ext{ extuparrow }} Glycogenolysis (glycogen breakdown)
ext{ } oldsymbol{ ext{ extuparrow }} Gluconeogenesis
ext{ } oldsymbol{ ext{ extuparrow }} Lipolysis
Biological Actions: Complex and interdependent, balancing anabolism (building up) and catabolism (breaking down).
D1. Blood Glucose Regulation and Liver Dynamics
Normal Concentrations: 80–110extmg/dL80–110extmg/dL; diabetes-related levels >130extmg/dL>130extmg/dL signify chronic elevation.
Glucose Processing Post-meal: Approximately 90extg90extg provided by an average meal is processed to restore blood glucose levels.
Mechanisms of Action: Involve glucose storage and metabolism through glycolysis and the TCA cycle, leading to ATP production.
Liver Regulation:
Glucagon: Activates key enzymes via phosphorylation, promoting glycogenolysis and gluconeogenesis.
Glucagon stimulates conversion of: Pyruvate → glucose, Lactate → glucose, Alanine → glucose, Glycerol → glucose.
Insulin: Dephosphorylates enzymes to inhibit glycogen breakdown and promote glucose utilization/storage.
D2. Liver and Muscle Dynamics
Key Enzymes: Modulated by insulin and glucagon, affecting glycogenolytic and gluconeogenic pathways in the liver and muscles.
Correlations in Muscle:
Muscle lacks glucose-6-phosphatase, meaning it cannot release glucose directly into the bloodstream.
In low insulin conditions, protein catabolism is practiced, leading to amino acid release for glucose synthesis.
Cori Cycle (Lactic Acid Cycle): Muscle converts glucose → lactate → blood. Liver then converts lactate → glucose → blood.
Glucose-Alanine Cycle: Muscle sends alanine → liver → converted to glucose.
Overall Summary: Insulin and glucagon actions are summarized alongside physiological implications in their respective target tissues: liver, muscle, and adipose.
E. Other Pancreatic Hormones
Pancreatic Polypeptide (PP): Stimulates gastric acid secretion (HCl) by stomach parietal cells.
Somatostatin: Maintains hormone balances by inhibiting the secretion of insulin and glucagon.
Amylin: Secreted with insulin and acts to inhibit glucagon secretion, delays gastric emptying, and acts as a satiety agent.
Conclusion
The synthesis, secretion, and function of pancreatic hormones—primarily insulin and glucagon—are crucial for glucose homeostasis and energy regulation in the body, ensuring body function aligns with nutritional needs and physiological states.