blood sugar control-BY VUREMY IRENE.pptx

blood sugar control mechanism

1. BLOOD SUGAR REGULATION MSC/SM/00101/023

2. OVERVIEW Introduction Sources of glucose Phases of glucose homeostasis Hormones in glucose homeostasis (actions, role in CHO metabolism) Insulin Glucagon Somatostatin Cortisol Growth hormone Epinephrine Other factors Introduction: Regulated between 80-90 mg/100ml of blood After meal-120 to 140 mg/100ml of blood 2hrs meal- glucose levels gets back normal

3. Glucose homeostasis A process that Controls glucose metabolism and Maintains normal blood glucose level in the body Glucose is a major source of body’s energy The liver plays a key role in maintaining blood glucose level It is tightly controlled as the brain constantly needs glucose Severe hypoglycemia can cause coma and death Chronic hyperglycemia results in glycation of proteins, endothelial dysfunction and diabetes mellitus Sources of glucose Dietary sources: Dietary CHOs are digested to monosaccharides Starch provides glucose directly Fructose and galactose are converted to glucose in the liver Metabolic sources (via gluconeogenesis): Glycerol, lactate, pyruvate, glucogenic amino acids

4. Phases of glucose homeostasis Five phases: Phase I (Well-fed state) Phase II ( Glycogenolysis ) Phase III (Gluconeogenesis) Phase IV (Glucose, ketone bodies (KB) oxidation) Phase V (Fatty acid (FA), KB oxidation)

5. Phase I (Well-fed state) Glucose is mainly supplied by dietary CHOs Liver removes about 70% of glucose load after a CHO meal All body tissues use dietary glucose for energy in this phase Some glucose is converted to glycogen for storage in the liver (glycogenesis) Excess glucose is converted to fatty acids and triglycerides in the liver These are transported via VLDL (very low density lipoproteins) to adipose tissue for storage Gluconeogenesis is inhibited in this phase Cori and glucose-alanine cycles are inhibited Phase II ( Glycogenolysis ) Phase II starts during early fasting when dietary glucose supply is exhausted Hepatic glycogenolysis and gluconeogenesis maintain blood glucose level in this phase Major sources of blood glucose in this phase: Glycogenolysis and gluconeogenesis

6. Phase IV (Glucose and KB oxidation) Several days of fasting leads to phase IV Gluconeogenesis starts to decrease FA oxidation increases KB accumulation KBs enter the brain and muscle for energy production Brain uses both glucose and KB for energy Phase III (Gluconeogenesis) Phase III starts when glycogen stores in liver are exhausted (< 20 hours) Duration of phase III depends on Feeding status Hepatic glycogen stores Physical activity Hepatic gluconeogenesis from lactate, pyruvate, glycerol and alanine maintains blood glucose level Major source of blood glucose in this phase: Gluconeogenesis

7. Phase V (FA and KB oxidation) Prolonged fasting leads to phase V Less dependence on gluconeogenesis All body tissues mainly use FA and KB oxidation for energy production Gluconeogenesis somewhat maintains blood glucose level in this phase High KB conc. and glucose levels inhibit proteolysis in muscle (conservation of muscle) When all fat and KBs are used up Body uses muscle protein to maintain blood glucose level

8. Hormones and glucose homeostasis Hormones that regulate glucose metabolism: Insulin (lowers blood glucose level) Glucagon Somatostatin Cortisol Growth hormone Epinephrine INSULIN ACTIONS

9. Mechanism of action The insulin receptor is present on the plasma membrane of cell Composed of a -subunit (extracellular) b -subunit (cytoplasmic) Binding of insulin to a -subunit causes phosphorylation of b -subunit This activates the receptor The activated receptor then phosphorylates intracellular proteins generating a biological response Insulin and CHO metabolism Promotes glucose uptake into cell: Glucose is diffused into cells through hexose transporters such as GLUT4 GLUT4 is present in cytoplasmic vesicles Insulin binding to its receptor causes vesicles to diffuse into plasma membrane GLUT4 is inserted into the membrane Allowing glucose transport into the cell Brain and liver have non-insulin dependent glucose transporter Stimulates glycogen synthesis Decreases blood glucose levels Increases glycolysis Stimulates protein synthesis Insulin deficiency causes diabetes mellitus Hyperinsulinemia is due to insulin resistance in: Diabetes mellitus or Metabolic syndrome

10. Mechanism of insulin secretion Sulfonylurea drugs stimulate insulin secretion by binding to ATP-sensitive potassium channels and blocking their activities. schematic of insulin receptor

11. Glucagon A peptide hormone secreted by a -cells of pancreatic islets Secreted in response to hypoglycemia Increases glucose levels Stimulates glycogenolysis Activates hepatic gluconeogenesis

12. Somatostatin A peptide hormone secreted by d -cells of pancreatic islets, stomach and intestine: Stimulated by increased blood glucose, AA, fatty acids and some GIT hormones An inhibitory hormone Inhibits secretion of both insulin and glucagon Decrease motility of stomach, duodenum and gallbladder Decreases absorption in GIT Affects glucose homeostasis indirectly Glucagon activates adenylyl cyclase in hepatic cells Cyclic AMP formation c AMP activates protein kinase regulator protein Protein kinase A gets activated and activates phosphorylase b kinase which converts phosphorylase b to phosphorylase a Phosphorylase a promotes degradation of glycogen to glucose-1- phosphate Glucose-1-phosphate is dephosphorylated to form glucose.

13. Glucocorticoids (Cortisol) Cortisol is a steroid hormone secreted by adrenal gland Contributes to glucose homeostasis-Decrease rate of glucose utilization by most cells, enhanced utilization of fatty acids Maintains normal glucose levels in fasting Stimulates gluconeogenesis in the liver Mobilizes amino acids for gluconeogenesis Stimulates fat breakdown in adipose tissue Growth hormone A protein hormone secreted by anterior pituitary gland Interact synergistically with insulin to promote growth Decrease rate of glucose utilization by most cells, enhanced utilization of fatty acids Maintains blood glucose levels by: Inhibiting insulin action Stimulating gluconeogenesis in the liver a

14. Epinephrine A catecholamine hormone secreted by adrenal gland Stimulates lipolysis in adipose tissue when glucose blood levels fall Promotes glycogenolysis in skeletal muscle Help in preventing severe hypoglycemia Other factors : Some AA-arginine and lysine act in a similar manner as excess insulin to stimulate insulin secretion-AA strongly potentiate glucose stimulus for insulin secretion Some GIT hormones- gastrin,secretin,CCK , glucagonlike peptide-1(GLP-1) and glucagon-dependent insulinotropic peptide(GIP)-moderately increase insulin production. GLP-1 and GIP are incretins -enhance insulin secretion rate . Progesterone and estrogen levels also affect insulin secretion Insulin deficiency: Increased use for fat for energy Lipolysis of storage fat ad release of free fatty acids-phospholipid and cholesterol formation in liver that result in atherosclerosis Excess use of fats leads to ketosis and acidosis

15. TYPES OF DIABETES : Type 1 diabetes -insulin-dependent diabetes-lack of insulin secretion- 5%-10% of people with diabetes Also called juvenile diabetes-onset at 14 years of age Caused by viral infections or autoimmune disorders-involved in destruction of beta cells Sequence of abrupt development: Increased blood sugar level, low insulin levels Increased utilization of fats for energy and formation of cholesterol by liver Depletion of body proteins Treated using insulin- rapid-acting, short-acting, intermediate-acting, long-acting, and ultra-long-acting insulins . Sypmtoms : Loss of glucose in urine-excess glucose that cannot be reabsorbed by renal tubes Dehydration due to increased osmotic pressure and osmotic diuresis in renal tubules Polyuria-increased urine excretion Tissue injury due to chronic high glucose-heart attack, stroke, end stage kidney disease, retinopathy, limb gangrene Polydipsia- increased thirst Polyphagia-increased hunger: excess loss of glucose in urine that leads the body to crave for more glucose . Utilization of fats and metabolic acidosis can cause diabetic coma and death Depletion of body protein

16. Type 2 diabetes -non insulin dependent diabetes mellitus. Cause by decreased sensitivity of target tissues to metabolic effects of insulin-insulin resistance. Disease develops slowly-after age between 50-60 years-adult onset diabetes. Obesity,insulin resistnce and metabolic syndrome-precede development of type 2 diabetes Other factors that may cause insulin resistance-polycystic ovary syndrome(PCOS) Excess formation of glucocorticoids( cushing’s sundrome ) Excess formation of growth hormone(acromegaly) Treatment of type 2 diabetes: Changes in lifestyle-physical activity; caloric restriction, weight reduction Thiazolidinediones - increase insulin sensitivity Metformin-suppress liver glucose production Sulfonylureas: cause additional release of insulin by pancreas. Later stages of management may need insulin administration Incretin drugs: mimic actions of GLP-1 and increase insulin secretion, used in combination with other drugs Inhibition of enzyme dipeptidyl peptidase 4(DPP-4) which inactivates GLP-1 and GIP- incretin effects GIP and GLP-1 is prolonged thus increased insulin production

17. Cont … Gliflozins : Inhibition of sodium glucose transporter(SGLT2)-reduce renal glucose reabsorption thus large amounts of glucose is released in urine-reducing blood glucose levels SGLT2 inhibitors cause marked diuresis due to osmotic effect of glucose remaining in renal tubules. This may be beneficial in reducing hypertension in type 2 diabetes. Lipid-lowering drugs Bariatric surgery procedure may reduce fat mass and achieve improved control of blood glucose. Metabolic surgery-Gastric bypass and ventral sleeve gastrectomy DIAGNOSIS : Urinary glucose Fasting blood glucose and insulin concentrations Glycated hemoglobin Glucose tolerance test Acetone breath Glycated albumin Insulinoma - adenoma of islets of Langerhans- causes hyperinsulinism THE END