Blood sugar homeostasis

brief introduction of blood glucose homeostasis

1. Blood Sugar Homeostasis Presented by: Dipesh Tamrakar Msc . Clinical Biochemistry

2. Overview Introduction Hormones of Blood Glucose Homeostasis Fasting state Postprandial state Well feed Starvation Condition of hypo and hyper glycemia Summary

3. Glucose homeostasis Homeostasis is the maintenance of a stable internal environment within an organism, carefully regulate many parameters including glucose levels in the blood. Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium, but neural input, metabolic signals, and other hormones (e.g., glucagon) result in integrated control of glucose supply and utilization.

4. Plasma glucose concentration Hepatic glycogen stores; sufficient to maintain plasma glucose levels for approximately 8 hour This time period can be shorter if glucose demand is increased by exercise or if glycogen stores are depleted by illness or starvation. Fasting Blood Glucose: 70–110 mg/ dL (3.9–6.1 mmol /L) Random Blood Glucose: <140 mg/ dL (<7.8 mmol /L) Post-prandial Blood Glucose: <140 mg/ dL (<7.8 mmol /L)

5. Systemic glucose balance Maintenance of the normal plasma glucose concentration is accomplished by- A network of hormones, Neural signals and Substrate effects that regulate endogenous glucose production and glucose utilization by tissues other than the brain

6. Hormonal regulation of glucose homeostasis Insulin Glucagon Thyroxine Epinephrine ACTH GH

7. Insulin Insulin is a polypeptide hormone produced by the β cells of the islets of Langerhans Its metabolic effects are anabolic and favoring synthesis of glycogen, triacylglycerols , and protein Insulin is composed of 51 amino acids arranged in two polypeptide chains, designated A and B, which are linked together by two disulfide bridges Pig (porcine) and beef (bovine) insulin differ from human insulin at one and three amino acid positions, respectively. Each can be used in humans for the treatment of diabetes; however, antibodies to these foreign proteins can develop

8. Regulation of insulin secretion Stimulation of insulin secretion by Glucose: Ingestion of glucose or a carbohydrate-rich meal leads to a rise in blood glucose, which is a signal for increased insulin secretion Amino acids: Ingestion of protein causes a transient rise in plasma amino acid levels, which, in turn, induces the immediate secretion of insulin. Gastrointestinal hormones intestinal peptides cholecystokinin and gastric-inhibitory polypeptide increase insulin secretion in response to oral glucose, and so are referred to as “incretins.”

9. Inhibition of insulin secretion The synthesis and release of insulin are decreased when: -scarcity of dietary fuels -during periods of stress (for example, fever or infection). These effects are mediated primarily by epinephrine

10. Role of insulin Glucose is the key regulator of insulin secretion by the pancreatic beta cells Glucose levels > 3.9 mmol /L (70 mg/ dL ) stimulate insulin synthesis Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter Insulin promotes peripheral glucose uptake and utilization, and inhibits gluconeogenesis as well as glycogenolysis.

11. Role of other hormones Epinephrine: Secreted by adrenal medulla that increases blood glucose level Acts both on muscle and liver to bring glycogenolysis by increasing phosphorylase activity Secreted in response to stress, trauma, or extreme exercise. Epinephrine has a direct effect on energy metabolism, causing a rapid mobilization of energy-yielding fuels, including glucose from the liver (produced by glycogenolysis or gluconeogenesis) Thyroxine: Hormone of thyroid gland Elevates blood glucose level by stimulating hepatic glycogenolysis and gluconeogenesis

12. Glucocorticoids : Hormones of adrenal cortex Stimulate protein metabolism and increase gluconeogenesis Inhibits glucose utilization by extrahepatic tissues Increases blood glucose level Growth Hormone and adrenocorticotropic hormone (ACTH): Hormones of anterior pituitary gland causing hyperglycemia Glucose uptake by certain tissues decreased by GH ACTH decreases glucose utilization

13. Condition of fasting!!!

14. In the early fasting state The peripheral cells switch to alternative fuels, such as fatty acids and ketone bodies. Ketone bodies are synthesized by the liver but utilized in the peripheral cells. Glycerol and amino acids released form the adipose tissue and muscle respectively are used for glucose production. Glucose is the main fuel for brain. TAG synthesis is decreased in adipose tissues

15. Role of insulin in the fasting state low insulin levels increase glucose production by- Promoting hepatic gluconeogenesis and glycogenolysis and Reducing glucose uptake in insulin-sensitive tissues (skeletal muscle and fat) promotes mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). These effects are mediated by Glucagon.

16. Role of glucagon in the fasting state Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates – Glycogenolysis, Gluconeogenesis by the liver and renal medulla and Prevents glucose uptake by the peripheral cells

17. Condition of well fed!!!

18. Glucose homeostasis in well fed state In the well fed state, glucose absorbed from gut is supplied to all cells it acts as a signal for the release of insulin from Beta cells of pancreas it is oxidized completely to provide energy the surplus is stored as glycogen in liver and muscle. Acetyl co A obtained from pyruvate, can be used for lipogenesis , the triglycerides are stored in adipose tissue.

19. Postprandial glucose homeostasis Postprandially, the glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes. Insulin, an anabolic hormone, promotes the storage of carbohydrate and fat and protein synthesis. The major portion of postprandial glucose is utilized by skeletal muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most notably the brain, utilize glucose in an insulin-independent fashion.

20. Glucose metabolism: Increased phosphorylation of glucose Increased glycogen synthesis Increased activity of the hexose monophosphate pathway Increased glycolysis Decreased gluconeogenesis

21. In post absorptive phase Glucose utilization is decreased in the liver, muscle and adipose tissue Liver glycogenolysis provides the most glucose (75%) gluconeogenesis providing the remainder The glucose-alanine cycle becomes active. 50-60% of glucose is consumed by the brain

22. In the state of starvation Glucose alanine cycle is active. Alanine and glutamine released from muscle are used in liver and kidney respectively for glucose production Ketones play a central role in prolonged starvation, replacing glucose as the primary fuel for the brain and signaling a reduction in protein catabolism and alanine output from muscle.

23. Role of hormones in glucose homeostasis

24. Variations in blood glucose levels A) Hypoglycemia- Decrease in blood glucose below the normal (<45 mg/dl) is called hypoglycemia. A decrease in insulin secretion is the first defense against hypoglycemia. As plasma glucose levels decline just below the physiologic range, glucose counter regulatory (plasma glucose–raising) hormones are released. Among these, pancreatic α cell glucagon, which stimulates hepatic glycogenolysis, plays a primary role. Glucagon is the second defense against hypoglycemia

25. Adreno- medullary epinephrine, which stimulates hepatic glycogenolysis and gluconeogenesis (and renal gluconeogenesis), is not normally critical, however, it becomes critical when glucagon is deficient. Epinephrine is the third defense against hypoglycemia. When hypoglycemia is prolonged, cortisol and growth hormone also support glucose production and limit glucose utilization. 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 .

26. Types of hypoglycemia Spontaneous hypoglycemia in adults is of two principal types: Fasting hypoglycemia : Observed in patients with pancreatic beta cell tumor and hepatocellular damage it is often sub acute or chronic and usually presents with neuroglycopenia as its principal manifestation. 2) Postprandial hypoglycemia : Reactive hypoglycemia with an elevated insulin secretion following a meal it is relatively acute and is often heralded by symptoms of neurogenic autonomic discharge (sweating, palpitations, anxiety, and tremulousness). 3) Insulin-induced hypoglycemia : Hypoglycemia occurs frequently in patients with diabetes who are receiving insulin treatment

27. 4) Hypoglycemia and alcohol intoxication : Alcohol is metabolized in the liver by two oxidation reactions Ethanol is first converted to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is subsequently oxidized to acetate by aldehyde dehydrogenase. In each reaction, electrons are transferred to NAD + , resulting in a massive increase in the concentration of cytosolic NADH. The abundance of NADH favors the reduction of pyruvate to lactate, and of oxaloacetate to malate. Thus, the ethanol-mediated increase in NADH causes the intermediates of gluconeogenesis to be diverted into alternate reaction pathways, resulting in the decreased synthesis of glucose. This can precipitate hypoglycemia, particularly in individuals who have depleted their stores of liver glycogen.

28. Normal gluconeogenesis in the absence of ethanol consumption. B. Inhibition of gluconeogenesis resulting from hepatic metabolism of ethanol

29. Common causes of hypoglycemia A) Physiological- Pronged fasting or starvation. B) Pathological 1. Fasting hypoglycemia Drug induced- Insulin, oral hypoglycemic drugs, alcohol, sulfonamides etc. Critical illnesses - Hepatic, renal, or cardiac failure, and sepsis. Hormone deficiencies- Cortisol, growth hormone, or both, Glucagon and epinephrine (in insulin-deficient diabetes)

30. Endogenous hyperinsulinism Insulinoma Autoimmune (autoantibodies to insulin or the insulin receptor) Ectopic insulin secretion Congenital hyperinsulinism and Inherited enzyme deficiencies 2. Postprandial (reactive) hypoglycemia Alimentary (Post-gastrectomy) Hereditary fructose intolerance, Galactosemia Idiopathic.

31. 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, Cystic fibrosis) Infections and sepsis Anesthesia Asphyxia

32. Hormonal tumors- Acromegaly, Cushing's syndrome, Glucagonoma and Pheochromocytoma Pharmacologic agents (corticosteroids, sympatho mimetic drugs, thiazide diuretics and niacin) Liver disease (cirrhosis, hemochromatosis) Muscle disorders (myotonic dystrophy) Adipose tissue disorders (Lipodystrophy and truncal obesity)

33. Clinical implication of disturbed glucose homeostasis-glycosuria Although normal urine contains virtually no sugar but under certain circumstances, glucose or other sugars may be excreted in urine. This condition is called ‘ Melituria ’. The term Glucosuria, Fructosuria , Galactosuria , Lactosuria and Pentosuria are applied specifically for urinary excretion of glucose, fructose, galactose, lactose and pentose respectively. Glycosuria (Glucosuria) can be classified in to two main groups A) Hyperglycemic glycosuria B) Renal glycosuria

34. A. Hyperglycemia glycosuria Alimentary Glycosuria(Excessive ingestion of carbohydrates) Emotional Glycosuria(Excessive catecholamine release)- Stress, anxiety etc. Glycosuria due to endocrinal disorders e.g. o Diabetes Mellitus o Hyperthyroidism o Epinephrine hyper secretion o Hyperactivity of anterior pituitary(Acromegaly) o Hyperactivity of Adrenal cortex (Cushing’s syndrome/disease) o Increased secretion of glucagon

35. B. Renal glycosuria Renal Tubular disease Fanconi's Syndrome Toxic renal tubular disease Lead Toxicity Mercury Toxicity Inflammatory renal disease: acute glomerulonephritis, nephrosis Increased GFR without tubular damage Hereditary renal glycosuria (Carrier protein deficiency) Lowering of renal threshold (pregnancy)

36. Diabetes mellitus Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate. Type 1 diabetes is due to pancreatic islet B cell destruction predominantly by an autoimmune process, and these patients are prone to ketoacidosis. Type 2 diabetes is the more prevalent form and results from insulin resistance with a defect in compensatory insulin secretion

37. Dawn Phenomenon The dawn phenomenon and the Somogyi effect cause high blood sugar levels, especially in the morning before breakfast , in people who have  diabetes . In the early morning hours, hormones ( growth hormone ,  cortisol , and  catecholamines ) cause the liver to release large amounts of sugar into the bloodstream. For most people, the body produces insulin to control the rise in blood sugar. If the body doesn't produce enough insulin, blood sugar levels can rise. This may cause high blood sugar in the morning (before eating).

38. Somogyi Effect  If the blood sugar level drops too low in the early morning hours, hormones (such as growth hormone, cortisol, and catecholamines) are released. These help reverse the low blood sugar level but may lead to blood sugar levels that are higher than normal in the morning. An example of the Somogyi effect is: A person who takes insulin doesn't eat a regular bedtime snack, and the person's blood sugar level drops during the night. The person's body responds to the low blood sugar by releasing hormones that raise the blood sugar level. This may cause a high blood sugar level in the early morning.

39. DRUGS USED IN DIABETES MELLITUS

40. Summary Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium. In the fasting state, low insulin levels increase glucose production by promoting hepatic Gluconeogenesis and glycogenolysis and reduce glucose uptake in insulin-sensitive tissues. Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla . Postprandially, the glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes. Other tissues, most notably the brain, utilize glucose in an insulin-independent fashion.

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