Glucose homeostasis The Pancreas

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, lipids proteins 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- +

110aa Preproglucagon Preproinsulin A|F 1 KTRR|E 33 KR|G 66 Ins B-chain C-peptide Ins A-Chain 180aa Q|R 1 KR|H 33 KR|N 64 KR|H 72 R|H 78 RGRR|D 111 GRR|H 125 RK 160 GlicentinGlucagon OxyntomodulinGLP-1GLP-2 GLP-1 (7-37amide) 116aa Preprosomatostatin G|A 25 F|L 34 Q|R 89 Antrin ? SS-14 Somatostatin 28 RERK|A aa Prepro Pancreatic polypeptide E|P 33 RPRYGKR|H 69 Pancreatic polypeptide Islet Prohormones

Synthesis of insulin - 1 ESR10-07 S S S S HOOC S S NH 2 Preproinsulin (110aa)

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

Synthesis of insulin - 3 ESR10-09 S S S S HOOC S S NH 2 Insulin ( aa) HOOC NH 2  - chain  - chain C - peptide (35aa)

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.

Insulin switches ON glycogen synthetase (GS) ESR10-26 GS Active Inactive PiPi ATP ADP Phosphoprotein phosphatase cAMP- INDEPENDENT kinase Insulin ( + ) Insulin ( - ) GSK3

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

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

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

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

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

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

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

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

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

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

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: G i protein-coupled receptors with tissue-specific expression Reduces cAMP production and Ca 2+