metdi1.pdf

GLUCOSE METABOLISM AND DIABETES MELLITUS GLUCOSE METABOLISM AND DIABETES 7/11/2024 1 MELLITUS  INSULIN SECRETION Insulin is the most important hormone controlling pla...

GLUCOSE METABOLISM AND DIABETES MELLITUS GLUCOSE METABOLISM AND DIABETES 7/11/2024 1 MELLITUS  INSULIN SECRETION Insulin is the most important hormone controlling plasma glucose concentrations. A plasma glucose concentration of greater than about 5 mmol/L acting via the glucose transporter 2 stimulates insulin release from the pancreas β- cell. GLUCOSE METABOLISM AND DIABETES 7/11/2024 2 MELLITUS  INSULIN SECRETION Insulin secretion is stimulated by glucose, some amino acids and fatty acids Insulin is synthesized in the β-cells as preproinsulin which is rapidly cleaved to proinsulin In the secretory granule, proinsulin is cleaved into the 51-amino acid insulin peptide and the 31-amino acid C-peptide. GLUCOSE METABOLISM AND DIABETES 7/11/2024 3 MELLITUS  GLUCOSE METABOLISM AND DIABETES 7/11/2024 4 MELLITUS  INSULIN AND C-PEPTIDE GLUCOSE METABOLISM AND DIABETES 7/11/2024 5 MELLITUS  GLUCOSE TRANSPORTERS Cell membranes are not permeable to glucose. The transport of glucose into cells is modulated by two families of proteins. The sodium-dependent glucose transporters (SGLTs) use the electrochemical sodium gradient to transport glucose against its concentration gradient. SGLTs promote the uptake of glucose and galactose from the lumen of the small bowel and their reabsorption from urine in the kidney. Members of the second family of glucose carriers are called facilitative glucose transporters (GLUT), Insulin-mediated cellular uptake of glucose is regulated through GLUT-4 proteins. 7/11/2024 GLUCOSE METABOLISM AND DIABETES MELLITUS 6  GLUCOSE METABOLISM AND DIABETES 7/11/2024 7 MELLITUS  Glucose transporters Organ Glucose transporter HK coupler Classification Brain GLUT1 HK-I Glucose dependent Erythrocyte GLUT1 HK-I Glucose dependent Adipocyte GLUT4 HK-II Insulin dependent Muscle GLUT4 HK-II Insulin dependent Liver GLUT2 HK-IVL Glucose sensor GK  - cell GLUT2 HK-IVB ( glucokinase ) Glucose sensor Gut GLUT3-symporter ---- Sodium dependent Kidney GLUT3-symporter ---- Sodium dependent GLUCOSE METABOLISM AND DIABETES 7/11/2024 8 MELLITUS  INSULIN SECRETION cont’d Glucose is transported into the β-cells via GLUT-2 (glucose transporter) channels and its metabolism results in the production of ATP. The increased ATP leads to the closure of ATP sensitive K+ -channels in the cell membrane, preventing potassium efflux, leading to depolarization of the β-cell. GLUCOSE METABOLISM AND DIABETES 7/11/2024 9 MELLITUS  INSULIN SECRETION cont’d The cell depolarisation causes a rapid influx of calcium which in turn stimulates the release of insulin. The glucokinase associated with GLUT-2 has very low affinity for glucose (Km=5 mmol/L) Transport of glucose into the beta cell is rapid, but only when the blood glucose concentration exceeds post-meal levels GLUCOSE METABOLISM AND DIABETES 7/11/2024 10 MELLITUS Note the differences in Km of Hexokinase and Glucokinase. What could happen if Km of glucokinase was much lower? GLUCOSE METABOLISM AND DIABETES 7/11/2024 11 MELLITUS  GLUCOSE METABOLISM AND DIABETES 7/11/2024 12 MELLITUS  GLUCOSE METABOLISM AND DIABETES 7/11/2024 13 MELLITUS  INSULIN SECRETION cont’d The same potassium channel can be blocked by sulphonylurea drugs, which are useful for stimulating insulin secretion in diabetics with residual β-cell function. GLUCOSE METABOLISM AND DIABETES 7/11/2024 14 MELLITUS  METABOLIC ACTIONS OF INSULIN Insulin induces: Cellular uptake of glucose. Glycogen and protein synthesis. Fatty acid and triglyceride synthesis. Insulin inhibits: Glycogenolysis. Gluconeogenesis. Proteolysis and lipolysis GLUCOSE METABOLISM AND DIABETES 7/11/2024 15 MELLITUS