Glucose homeostasis

The Pancreas Glucose homeostasis

Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism

Actions of insulin and glucagon Insulin Signal of feeding. Target tissues: liver, adipose skeletal muscle Affects metabolism of: carbohydrates, lipidsproteins Actions are anabolic Glucagon Signal of fasting. Target tissues: liver, adipose Affects metabolism of: carbohydrates, lipids Actions are catabolic

Why keep blood glucose concentration constant? Some tissues only metabolise glucose: CNS, PNS, red blood cells, kidney, eye Metabolise glucose at constant rate. Rate of glucose uptake determined by blood [glucose]. • Keep blood [glucose] constant to enable metabolism to proceed at constant rate.

Control of insulin & glucagon secretion Factor Insulin Glucagon Nutrients: glucose  5mM + - glucose  5mM - +  amino acids + +  fatty acids + 0 Hormones/neurotransmitters: GI tract + 0 adrenaline - + noradrenaline - +

Preproinsulin (110aa) S S S S HOOC S S Synthesis of insulin - 1 NH2 ESR10-07

S S S S HOOC S S Synthesis of insulin - 2 Proinsulin (86aa) NH2 ESR10-08

S S S S Synthesis of insulin - 3 Insulin (21 + 30aa)  - chain HOOC NH2  - chain HOOC NH2 S S C - peptide (35aa) ESR10-09

Regulation of glucose transport by insulin Binding of insulin to cell-surface receptors Intracellular vesicles containing membrane-imbedded GLUT4 transporters fuse with the plasma membrane GLUT4 transporters in muscle or adipose cell surface increases capacity of the cell to transport glucose. Basal levels of glucose transport are maintained by GLUT1 and GLUT3 forms of the glucose transporter (in most tissues).

Activation of glycogen synthase and inactivation of glycogen phosphorylase Binding of insulin by the liver or muscle cell leads to stimulation of protein phosphatase-1 Hydrolysis of phosphate catalyzed by protein phosphatase-1 increases the activity of glycogen synthase but deactivates glycogen phosphorylase.

Pi ( + ) ( - ) Insulin switchesONglycogen synthetase (GS) Insulin Phosphoprotein phosphatase GS GS Active cAMP- INDEPENDENT kinase Inactive GSK3 ADP ATP Insulin ESR10-26

Insulin Inhibition of TAG Degradation in Adipose In high insulin/low glucagon state: cAMP falls in adipose HSL is not phosporylated and is inactive Remember: epinephrine as shown here is a counterregulatory hormone

Insulin Action on Cells: Dominates in Fed State Metabolism

Stimulation - insulin secretion • Increased [ glucose ] • Increased [ free aa ] • Increased [ GI hormones ] • (gastrin, secretin, CCK, GIP) Mixed Meal • Increased [ glucagon ] • Noradrenaline • (low [ ]; α-adrenergic receptors) • Acetylcholine ESR10-12

Inhibition - insulin secretion • Decreased [ glucose ] • Increased [ somatostatin ] • (pancreatic + gastric) • Noradrenaline • (high [ ]; β-adrenergic receptors) • Adrenaline • (β-adrenergic receptors) ESR10-13

Hypoglycaemia Blood glucose < 3.0mM Uptake of glucose by glucose-dependent tissues not adequate to maintain tissue function. CNS very sensitive: Impaired vision, slurred speech, staggered walk Mood change – aggressive Confusion, coma, death Stress response (release of adrenaline): Pale Sweating – clammy

Diabetes Mellitus Group of metabolic diseases. Affect 1-2% of population in UK. Characterised by: • chronic hyperglycaemia (prolonged elevation of blood glucose) • leading to long-term clinical complications Caused by: • Insulin deficiency – failure to secrete adequate amounts of insulin from -cells. and/or • Insulin resistance – tissues become insensitive to insulin.

Classification of Diabetes Two major types recognised clinically Type 1 – absolute insulin deficiency (loss of -cells). Type 2 – relative insulin deficiency and/or insulin resistance. Also Gestational Diabetes (only occurs during pregnancy).

Other pancreatic hormones • Glucagon (29aa) - synthesised from preproglucagon • Zn not required for secretion • metal ions decrease clearance • Somatostatin (14aa) • physiological role unclear • can suppress insulin and glucagon ESR10-10

Stimulation - glucagon secretion • Decreased [ glucose ] • Increased [ free aa ]* • Adrenaline Inhibition - glucagon secretion • Increased [ glucose ] ESR10-14

Activation of glycogen phosphorylase and inactivation of glycogen synthase Glucagon as a signal of hunger. In its presence, the liver carries out glycogenolysis to provide glucose to the bloodstream and the rest of the body. Epinephrine is a signal of stress. Stimulates muscle glycogenolysis to provide glucose to support contraction and movement

- P 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/F-2,6-P2ase) Fructose-6-P Glycolysis Gluconeogenesis cAMP-Dependent Protein Kinase Inactive F-2,6-Pase Active F-2,6-Pase Glucagon Active PFK-2 F-1,6-P2ase Inactive PFK-2 PFK-1 Protein Phosphatase-2 - + Fructose-2,6-P2 Fructose-1,6-P2

( + ) Pi ( - ) ( + ) Glucagon switches OFFglycogen synthetase (GS) Glucagon Glycogen phosphorylase a Phosphoprotein phosphatase GS GS cAMP- dependent kinase Active Inactive ADP ATP Glucagon ESR10-25

HSL ( + ) ( - ) ( + ) ( + ) Glucocorticoids HSL and futile cycling Glycerol Cytosolic Acetyl CoA TAG FA Mitochondrial Acetyl CoA Insulin Glycerol cAMP- dependent kinase Glucagon ESR10-32

Somatostatin(somatotropin release-inhibiting factor, SRIF) • Chemistry: • Secreted by hypothalamic anterior periventricular region and by d cells of the pancreatic islets • Secretion  by GH, IGF-I, thyroid hormones S S Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys A single peptide of 14 amino acids A 28-amino acid form is found in the gut

Stimulation - somatostatin secretion • Carbohydrates • Proteins • Fats Mixed Meal • Decreased pH in duodenum • (by gastric acid - bulbogastrone • mechanism) ESR10-15

Somatostatin • Actions: • Inhibits GH secretion but not its synthesis • Inhibits basal and TRH-stimulated TSH secretion • Inhibits secretion of GI peptide hormones: • insulin, glucagon, VIP, gastrin, and others • Mechanism of action: • Gi protein-coupled receptors with tissue-specific expression • Reduces cAMP production and Ca2+

Glucose homeostasis