2. Peshawar Medical College Regulation of Blood Glucose Level

3. Learning Objectives To define what is normal blood glucose level To describe the sources and utilization of glucose To identify different factors & explain their role in regulation the blood glucose level

4. Regulation of Blood Glucose Level Normal Range4.5 – 5.5 mmol/L (70 – 100 mg / dL) After carbohydrate meal6.5 – 7.2 mmol/L (105– 130 mg/dL) During starvation3.3 – 3.9 mmol/L (60 – 70 mgl/dL)

5. Fasting & Postpradinal state Sudden decrease in blood glucose level causes convulsions (due to diminished supply of glucose to brain) Much lower levels can be tolerated, provided progressive adaptation is allowed. Regulation of Blood Glucose Level

6. Sources Of Blood Glucose 1) DIET Polysaccharides/ Disaccharides / Monosaccharides GIT Glc, Fr, Gal Portal Circulation Liver Glc Glc  Fr Glc  Gal

7. 2) GLYCOGENOLYSIS Glycogen  Glc – I – P  Glc – 6 – P  Glc (Liver) 3) GLUCONEOGENESIS (Liver & Kidney) from glycogenic compounds – 2 types Type-1: Direct conversion of non-carbohydrates to glucose like amino acids, propionate (through TCA cycle & reversal of glycolysis) Sources Of Blood Glucose

8. Type-2: Those which are the products of partial breakdown of glucose e.g. (i) Cori Cycle Glc RBCs & Muscles Lactate  Liver  Pyruvate Energy from Fatty Acids Glucose Anaerobic glycolysis Gluconeogenesis Sources Of Blood Glucose

9. (ii) Glycerol (iii) Glc-alanine Cycle Glc Gly.3.P  Glycerol Adipose Tissue TAG Glucose Liver & Kidney  Glycerol Glycolysis Lipogenesis Lipolysis Gluconeogenesis Glc Muscle Pyurvate Transamination Alanine  Liver  Glucose Glycolysis Gluconeogenesis Sources Of Blood Glucose

10. Diet / Absorption from intestine Hepatic Glycogenolysis Glc obtained from other carbohydrates Gluconeogenesis (liver) Oxidation of glucose for energy Glycogenesis (liver/muscle) Lipogenesis (Adipose tissue) Synthesis of Glycoproteins Glycolipids Lactose Ribose etc Sources Utilization Blood Glucose 60–90 mg/dl If conc. exceeds renal threshold (180 mg/dL) Excreted in urine

11. Metabolic & Hormonal Control (Regulation) Liver cells and pancreatic  islets are permeable to glucose via GLUT 2 Cells of all other tissues are relatively impermeable to glucose and their glucose uptake is regulated by insulin

12. HORMONES Insulin Glucagon Epinephrine and nor-epinephrine Growth hormone ENZYMES (e.g. glucokinase) take part in regulating blood glucose level within a narrow limit. Metabolic & Hormonal Control (Regulation)

13. INSULIN Produced by  -Cells of the islets of Langerhans as a result of hyperglycemia, since these cells are freely permeable to Glc via GLUT 2 transporter Glc GLUT 2 Cells  Glc Glc – 6 – P Glucokinase  ATP  Citric acid Cycle  Glycolysis Metabolic & Hormonal Control (Regulation)

14. RELEASE OF INSULIN Increase in ATP inhibits ATP-sensitive K + channels leading to increased Ca ++ Ions  Stimulating exocytosis of insulin Sulfonylurea drugs increase the secretion of insulin by the same mechanism Amino acids, FFA, Ketone bodies etc cause the release of insulin from pancreas

15. Insulin  Recruitment of GLUT 4   Uptake of glucose by adipose tissue and muscle Insulin has no effect on hepatic uptake of glucose but has an indirect effect by influencing the synthesis of enzymes involved in glycolysis (  ) glycogenesis (  ) and gluconeogenesis (  ) ACTION OF INSULIN

16. Hyperglycemic Factors GLUCAGON: Secreted by  cells of islets of Langerhans of pancreas as a result of hypoglycemia Via portal vein  Liver  activates Phosphorylase  hepatic glycogenolysis

17. GLUCAGON (Contd.) : No effect on muscle phosphorylase Glucagon also enhances gluconeogenesis from amino acids and lactate Net Effect: Hepatic glycogenolysis & gluconeogenesis  Hyperglycemic effect Hyperglycemic Factors

18. GROWTH HORMONE Hypoplycemia  Ant. Pituitary gland  Growth hormone (GH) GH   ed glucose uptake in certain tissues (like muscle) GH  indirect effect by mobilization of FFA from adipose tissue Net Effect: Glucose sparing action ---- Hyperglycemic effect Hyperglycemic Factors

19. GLUCOCORTICOIDS (CORTISOL) Produced by adrenal cortex Cortisol  increased protein catabolism  increased activity of enzymes  increased Gluconeogenesis It also inhibits the utilization of glucose in extra-hepatic tissues (glucose sparing action) Hyperglycemic Factors

20. EPINEPHRINE / NOR – EPINEPHRINE Fear, excitement, hemorrhage, hypoxia, hypoglycemia  adrenal cortex  Epinephrine / Nor-Epinephrine  increased cAMP  activation of Phosphorylase (muscle & liver)  increased Glycogenolysis Hyperglycemic Factors

21. THYROID HORMONES Hyperglycemic effects through experimental evidence T 4 has diabetogenic action since i. Thyroidectomy inhibits the development of diabetes ii. Glycogen is absent in the livers of thyrotoxic animals iii. Humans a. Hyperthyroid patients have  ed fasting blood glucose level b. Hypothyroid patients have  ed fasting blood glucose level Hyperglycemic Factors

22. GLUCOKINASE & HEXOKINASE LIVERGlucose Glucokinase Glc.6.PEXTRAHEPATICGlucose Hexokinase Glc.6.P Role of enzymes in Blood Glucose Regulation

23. Glc.6.P can inhibit Hexokinase but not Glucokinase, thus hepatic glucose uptake is not affected by concentration of Glc.6.P Glucokinase has high Km value or low affinity for glucose thus its activity increases at higher concentration of glucose Role of enzymes in Blood Glucose Regulation

24. When Hyperglycemia  hepatic glucose uptake is increased but glucose output is decreased Hypoglycemia  liver is net producer of glucose (decreased uptake and increased output) During hypoglycemia – Hexokinase can function in the extra-hepatic tissues as it has low Km and high affinity for glucose Role of enzymes in Blood Glucose Regulation

25. Synthesis of Lactose (Mammary glands)