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Regulation of Blood Glucose Level Peshawar Medical College 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 Regulation of Blood Glucose Level Normal Range 4.5 – 5.5 mmol/L (70 – 100 mg / dL) After carbohydrate meal 6.5 – 7.2 mmol/L (105– 130 mg/dL) During starvation 3.3 – 3.9 mmol/L (60 – 70 mgl/dL) Regulation of Blood Glucose Level 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. Sources Of Blood Glucose 1) DIET Polysaccharides/ Disaccharides / Monosaccharides GIT Glc, Fr, Gal Portal Circulation Glc Liver Glc Fr Glc Gal Sources Of Blood Glucose 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 Type-2: Those which are the products of partial breakdown of glucose e.g. (i) Cori Cycle Glc RBCs & Muscles Anaerobic glycolysis Lactate Liver Pyruvate Glucose Energy from Fatty Acids Gluconeogenesis Sources Of Blood Glucose (ii) Glycerol Glc Glycolysis Glucose Gly.3.P Glycerol Gluconeogenesis Adipose Tissue Lipogenesis Liver & Kidney Glycerol TAG Lipolysis (iii) Glc-alanine Cycle Gluconeogenesis Muscle Glc Glycolysis Pyurvate Transamination Alanine Liver Glucose Utilization Oxidation of glucose for energy Sources Diet / Absorption from intestine Glycogenesis Hepatic Glycogenolysis Lipogenesis Glc obtained from other carbohydrates Gluconeogenesis (liver) (liver/muscle) Blood Glucose 60–90 mg/dl (Adipose tissue) Synthesis of Glycoproteins Glycolipids Lactose Ribose etc If conc. exceeds renal threshold (180 mg/dL) Excreted in urine 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 Metabolic & Hormonal Control (Regulation) 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) 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 Glucokinase ATP Citric acid Cycle Glycolysis Glc – 6 – P 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 ACTION OF INSULIN 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 () 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 Hyperglycemic Factors 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 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 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 EPINEPHRINE / NOR – EPINEPHRINE Fear, excitement, hemorrhage, hypoxia, hypoglycemia adrenal cortex Epinephrine / Nor-Epinephrine increased cAMP activation of Phosphorylase (muscle & liver) increased Glycogenolysis Hyperglycemic Factors THYROID HORMONES Hyperglycemic effects through experimental evidence T4 has diabetogenic action since i. Thyroidectomy inhibits the development of diabetes ii. Glycogen is absent in the livers of thyrotoxic animals iii. Humans a. b. Hyperthyroid patients have ed fasting blood glucose level Hypothyroid patients have ed fasting blood glucose level Role of enzymes in Blood Glucose Regulation GLUCOKINASE & HEXOKINASE LIVER EXTRAHEPATIC Glucose Glucokinase Glc.6.P Glucose Hexokinase Glc.6.P Role of enzymes in Blood Glucose Regulation 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 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 Synthesis of Lactose (Mammary glands)