Blood glucose homeostasis

Role of hyperglycemic and hypoglycemic hormones , fed and fast cycle

1. Blood glucose Homeostasis Hormonal regulation of blood glucose Glucose homeostasis in fed and fasting state Fed-fast cycles Hypo and hyperglycemia Difference Between Type I and Type II DM

2. Definition of Glucose Homeostasis The process of maintaining blood glucose at a steady-state level is called “glucose homeostasis ” [ DeFronzo , 1988]. This is accomplished by the finely hormone regulation of peripheral glucose uptake, hepatic glucose production, and glucose uptake during carbohydrates ingestion .

3. Importance of blood Glucose Homeostasis Glucose is an obligate metabolic fuel for many tissues(RBC) and organs(Brain and Kidney). Severe hypoglycemia can cause seizures, loss of consciousness, and death Chronic hyperglycemia leads to ; Diabetes mellitus Gylcation of protein that results in neuropathy, retinopathy and nephropathy Various other complications T herefore, blood glucose concentrations need to be maintained within narrow limits.

4. Normal Blood glucose

5. NORMALBLOOD GLUCOSE REGULATION OF BLOOD GLUCOSE The plasma glucose level depends on the balance between glucose entering and leaving the extracellular fluid GLYCOGENESIS GLYCOLYSIS GLUCONEOGENESIS GLYCOGENOLYSIS LIPOGENESIS DIET Use Storage Conversion Supply

6. FACTORS MAINTAINING BLOOD GLUCOSE

7. HORMONAL REGULATION

8. HORMONAL REGULATION The pancreas detects the change in blood glucose concentration and releases the appropriate hormone

9. Major role of Insulin and Glucagon

10. Insulin & glucagon has opposing action

11. HORMONAL REGULATION - INSULIN INSULIN GLYCOGENESIS GLYCOLYSIS GLUCONEOGENESIS GLUCOSE UPTAKE IN MUSCLE AND ADIPOSE TISSUE GLYCOGENOLYSIS LIPOLYSIS LIPOGENESIS + + + + - - -

12. HYPERGLYCEMIC HORMONES

13. HORMONAL REGULATION

14. Phases of glucose homeostasis 6/17/2017 Biochemistry for medics- Lecture notes 14 Phase 1 Phase 2 Phase 3 Phase 4 Nutritional status Well fed state Post- Absorptive state Fasting Prolonged fasting/ Starvation Source of glucose Diet Hepatic glycogen and Gluconeogenesis Hepatic and Renal gluconeogenesis Renal and hepatic gluconeogenesis Tissues using glucose All All tissues, but in Liver, muscle and adipose tissue, the rate of utilization is slowed. Brain and RBCs and cells lacking mitochondria; small amount by muscle. Brain at a slower rate, RBCs normal rate Major fuel of brain Glucose Glucose Glucose and ketone bodies Ketone bodies and glucose

15. FED STATE Glycolysis Glycolysis

16. FASTING STATE

17. Feed/Fast cycle

18. Liver: Metabolic pathways in absorptive state

19. Carbohydrate metabolism in liver during fed state Insulin /glucagon: Carbohydtate metabolism activity of glucokinase Glucose -6-phosphate Activation of glycogen synthase Glycogenesis activity of HMP shunt for production of NADPH which is used for lipogenesis activity of pyruvate kianse and PDH glycolysis gluconeogenesis Lipid metabolism citrate and NADPH activates acetyl Co A carboxylase fatty acid synthesis TAG synthesis

20. amino acid metabolism amino acids used by liver and other organs for protein synthesis. Excess amino acids catabolized by liver to yield urea.  Carbons used mainly for fatty acid synthesis

21. Adipose tissue : Metabolic pathways in absorptive state

22. Metabolism in adipose tissue in fed state

23. M uscle: : Metabolic pathways in absorptive state

24. Metabolism in resting muscle during fed state

25. Brain: : Metabolic pathways in absorptive state

26. Metabolism in brain during fed state Carbohydrate metabolism In the fed state, the brain uses glucose exclusively as a fuel, completely oxidizing approximately 140 g/day to CO2 and H2O. Fat metabolism fatty acids circulating in the blood make little contribution to energy production

27. Metabolic fuels present in 70 kg man at the beginning of fast

28. Metabolic pathways in liver during starvation

29. Metabolism in liver during starvation Carbohydrate metabolism Increased glucagon/insulin ratio Increased glycogenolysis ; it is early response to fasting and provides blood glucose over a period of 10-18 hours Increased gluconeogenesis ; glucagon activates PEPCK Lipid metabolism Increased fatty acid oxidation Increased ketogenesis during prolonged starvation

30. amino acid metabolism amino acids are utilized for guconeogenesis

31. Metabolic pathways in adipose tissue during starvation

32. Metabolism in adipose tissue during starvation Increased glucagon/insulin ration Carbohydrate metabolism decreased utilization of glucose by depress activity of GLUT -4 Lipid metabolism Increased degradation of TAG due to activation of hormone sensitive lipase by glucagon Increased release and oxidation of fatty acid Glycerol part of fat is substrate for gluconeogenesis

33. Metabolic pathways in resting muscle during starvation

34. Metabolism in resting muscle during starvation Resting muscle uses fatty acids as its major fuel source. By contrast, exercising muscle initially uses its glycogen stores as a source of energy . G-6-p from glycogenolysis is converted to lactic acid in exercising muscle Carbohydrate metabolism Low insulin glucagon ration leads to decreased transport of glucose by GLUT -4

35. Lipid metabolism During the first 2 weeks of fasting, muscle uses fatty acids from adipose tissue and ketone bodies from the liver as fuels After about 3 weeks of fasting, muscle decreases its use of ketone bodies and oxidizes fatty acids almost exclusively. Amino acid metabolism In early days of fasting muscle protein breaks down rapidly for gluconeogenesis Glutamate and alanine are predominent glucogenic amino acid After several days of fasting rate of proteolysis decreases because now more ketone bodies are utilized by brain compared to glucose from gluconeogenesis

36. Metabolic pathways in brain during starvation

37. Metabolism in brain during starvation carbohydrate metabolism During the first days of fasting, the brain continues to use glucose exclusively as a fuel provided by hepatic gluconeogenesis . Ketolysis In prolonged fasting(greater than 2–3 weeks), plasma ketone bodies reach significantly elevated levels, and replace glucose as the primary fuel for the brain

38. Metabolism in kidney during starvation during starvation about 50% of gluconeogenesis occurs here .

39. G-6-P Pyruvate Acetyl CoA TCA Glycogen HMP shunt Glucose Fatty acid TAG Amio acid protein VLDL Glucose GLUT-4 Glucose G-6-P Pyruvate ACetyl CoA TCA Fatty acid VLDL TAG Chylomicrons Glucose GLUT-4 G-6-P Glycogen Glycolysis Amino acid Protein G-6-P Glycolysis HMP shunt Insulin/glucagon Intertissue relationships in the absorptive state. GLUT-2 GLUT-3 Liver Muscle Brain Adipose tissue

40. Glycogen G-6-P Glucose TCA Glucose Acetyl CoA Ketone bodies TCA TAG Fatty acid Glycerol Fatty acid Ketone bobies Ketone bodies Ketone bodies Acetyl CoA TCA protein Amino acid Acetyl CoA TCA Liver Adipose tissue Muscle Brain Intertissue relationships during starvation Glucagon Epinephrine Cortisol Blood

41. Glucose transporters

42. Hypoglycemia Hypoglycemia - Decrease in blood glucose below the normal is called hypoglycemia. Hypoglycemia is a laboratory ‘diagnosis’ which is usually considered a blood glucose level below 60 mg/ dL . Symptoms begin at plasma glucose levels in the range of 60 mg/ dL and Impairment of brain function at approximately 50 mg/ dL .

43. Common causes of hypoglycemia 6/17/2017 Biochemistry for medics- Lecture notes 43 Endogenous hyperinsulinism Insulinoma Ectopic insulin secretion Congenital hyperinsulinism and Enzyme deficiencies- Glycogen storage disease  Hormonal deficiencies:Cortisol , growth hormone, or both, Glucagon and epinephrine

44. Hyperglycemia Increase in blood glucose level above the normal physiological limit is called as Hyperglycemia Causes of hyperglycemia Diabetes mellitus Diseases of pancreas(pancreatitis, hemochromatosis , carcinoma head of pancreas,) Acromegaly , Cushing's syndrome, Glucagonoma and Pheochromocytoma Hyperthyroidism

45. Definition of Diabetes Mellitus Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

46. Classification of Diabetes mellitus Diabetes can be classified into the following general categories: 1 . Type 1 diabetes (due to ᵦ -cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) 3. Other specific diabetes Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) IGT(Impaired Glucose tolerance) IFG(Impaired Fasting Glucose)

47. Typical progression of type 2 Diabetes mellitus