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COUNTERREGULATORYHORMONES

1. COUNTER REGULATORY HORMONES Dr. Mohan T Shenoy

2. One important compensation for hypoglycemia is cessation of the secretion of endogenous insulin. Inhibition of insulin secretion is complete at a plasma glucose level of about 80 mg/dL . In addition, hypoglycemia triggers increased secretion of at least four counterregulatory hormones: Gl ucagon, E pinephrine, G rowth hormone, and C ortisol. COUNTER REGULATORY HORMONES

3. Cell growth and energy metabolism TCA Cycle Kreb’s Cycle CoA Acetyl-CoA Proteins Amino acids Fats Fatty acids Carbohydrates Glucose Pyruvate ATP

4. 4 Intermediary Metabolism of Fuels Clinical Pearl All the fuels are inter changeable in the body It is the total calorie restriction that is important in Obesity and T2DM

5. 5 Glucose-6-Phosphate – The Central Molecule

6. High-carbohydrate meal Rapid increase of glucose 80 → >120 mg/dL Rapid increase of insulin 5 → >120 m U/mL Decrease of glucagon 110 → 90 pg/mL

7. Effect of high-protein meal Stimulates glucagon release Not much insulin Blood glucose not change Mixed meals: get some of each hormone

8. The Counter-regulatory Response INSULIN GLUCAGON EPINEPHRINE NOREPINEPHRINE GROWTH HORMONE CORTISOL GLUCOSE GLUCOSE In normal physiology, GLUCAGON secretion is the main defense against hypoglycemia. Adapted from Cryer PE. Banting lecture. Hypoglycemia: The limiting factor in the management of iddm. Diabetes 1994; 43(11): 1378-89

9. Early response Glucagon Epinephrine Delayed response Cortisol Growth hormone Counter Regulatory Hormones

10. COUNTER REGULATORY HORMONES GLUCAGON EPINEPHRINE GLUCOCORTICOIDS GROWTH HORMONE The epinephrine response is reduced during sleep. Glucagon and epinephrine increase the hepatic output of glucose by increasing glycogenolysis. Growth hormone decreases the utilization of glucose in various peripheral tissues, and cortisol has a similar action.

11. The keys to c ounterregulation appear to be epinephrine and glucagon: if the plasma conc of either increases, the decline in the plasma glucose level is reversed; but if both fail to increase, there is little if any compensatory rise in the plasma glucose level. The actions of the other hormones are supplementary. COUNTER REGULATORY HORMONES

12. Potentially important glucose counterregulatory neurotransmitters include the classic ones (i.e., Sympathetic neural Norepinephrine and Parasympathetic neural Acetylcholine ). Following sympathetic activation, norepinephrine raises glucose levels through mechanisms similar to those of epinephrine. Acetylcholine released from activated parasympathetic neurons decreases hepatic glucose production, an effect demonstrable in humans only in the absence of glucagon release. In addition, it is conceivable that some of the array of neuropeptides released during hypoglycemia might affect glucose metabolism. Counter Regulatory Mechanisms

13. Principles of Glucose Counter-regulation The principles of the physiology of glucose counterregulation are now known . First, the prevention and correction of hypoglycemia involve both dissipation of insulin and activation of glucose counterregulatory systems. The process is not caused solely by dissipation of insulin. Second, whereas insulin is the dominant glucose-lowering factor, there are redundant glucose counterregulatory factors. There is a fail-safe system that prevents failure of the counterregulatory process even when one or perhaps more of the components of the system fail. Third, there is a hierarchy among the counterregulatory factors ; some are more important than others.

14. 14 Homeostasis of Glucose Counter Regulation Mechanisms A steady maintenance of blood glucose with in a narrow range Fasting state and fed states – their effects on BG Rate of glucose appearance R a Rate of disappearance R d must be in balance Blood Glucose (BG) = R a - R d Control systems Glucose Receptors, GLUT 1-14 Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine, Growth Hormone. Insulin Signaling sequences, Glucagon signaling Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue Feedback loops Negative feedback Positive feedback

15. Glucose counterregulation. Mean ± SE arterialized venous glycemic thresholds f or t he vario us responses

16. Responses to decreasing Glucose levels Response Glycemic theshhold Physiological effects Role in counter regulation ↓ Insulin 80 - 85 mg% ↑ R a (↓ R d ) Primary First Defense ↑ Glucagon 65 - 70 mg% ↑ R a Primary Second Defense ↑ Epinephrine 65 - 70 mg% ↑ R a ↓ R d Critical Third Defense ↑ Cortisol, GH 65 - 70 mg% ↑ R a ↓ R d Not Critical ↑ Food ingestion 50 - 55 mg% ↑ Exogenous Glucose < 50mg% no cognitive change

17. 17 Insulin – Anabolic Glucagon - Catabolic Metabolic Action Insulin Glucagon Glycogen synthesis ↑ ↓ Glycolysis (energy release) ↑ ↓ Lipogenesis ↑ ↓ Protein synthesis ↑ ↓ Glycogenolysis ↓ ↑ Gluconeogenesis ↓ ↑ Lipolysis ↓ ↑ Ketogenesis ↓ ↑

18. Hormone functions major metabolic paths Insulin promotes storage stimulate glucose storage in muscle, liver promotes growth stimulates protein synthesis, fatty acid synthesis Glucagon mobilizes fuels activates gluconeogenesis and glycogenolysis maintains blood activates fatty acid release glucose in fasting Epinephrine mobilizes fuels stimulate glycogenolysis in acute stress stimulate fatty acid release Cortisol change in long term amino acid mobilization gluconeogenesis

19. I nsulin is glycogenic, antigluconeogenetic, antilipolytic, and antiketotic in its actions. It thus favors storage of absorbed nutrients and is a "hormone of energy storage."   Glucagon, on the other hand, is glycogenolytic, gluconeogenetic, lipolytic, and ketogenic. It mobilizes energy stores and is a "hormone of energy release." Because of their opposite effects, the blood levels of both hormones must be considered in any given situation Insulin – Anabolic Glucagon - Catabolic

20. Secreted by α cells of the pancreas - Acts to increase blood glucose Chemical structure 29 AA,Derived from 160 aminoacid proglucagon precursor, L inear polypeptide with molecular weight of 3485 Rapid half-life of glucagon in plasma ( 5–10 minutes ) ; It is degraded by many tissues but particularly by the liver. Since glucagon is secreted into the portal vein and reaches the liver before it reaches the peripheral circulation, peripheral blood levels are relatively low. T he rise in peripheral blood glucagon levels produced by excitatory stimuli is exaggerated in patients with C irrhosis , presumably because of decreased hepatic degradation of the hormone. Counter Regulatory Hormones : Glucagon

21. Regulators of Glucagon release Major regulators: Effect: Glucose - Insulin - Amino acids + Minor regulators: Cortisol + Neural input (stress) + Epinephrine +

22. Stimulation of Glucagon secretion Blood glucose < 70 mg/dL High levels of circulating amino acids Especially arginine and alanine Sympathetic and parasympathetic stimulation Catecholamines Cholecystokinin, Gastrin and GIP Glucocorticoids Glucagon Secretion

23. 24 Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism (ketogenesis) by decreasing malonyl-CoA levels in the liver Glucagon does not cause glycogenolysis in muscle.. It increases ketone body formation Role of Glucagon Clinical Pearl Glucagon is an established treatment for hypoglycemia Glucagon Kit – 1 mg s/c or IM or IV injection In 2 to 3 minutes recovery

24. The second early response hyperglycemic hormone. This effect is mediated through the hypothalamus in response to low blood glucose. Stimulation of sympathetic neurons causes release of epinephrine from adrenal medulla . Epinephrine causes glycogen breakdown, gluconeogenesis, and glucose release from the liver. It also stimulates glycolysis in muscle,Lipolysis in adipose tissue, Decreases insulin secretion and Increases glucagon secretion. Role of Epinephrine

25. 26 These are long term hyperglycemic hormones Activation takes hours to days. Cortisol and GH act to decrease glucose utilization in most cells of the body Effects of these hormones are mediated through the CNS. Role of Cortisol and GH

26. It is synthesized in the adrenal cortex. Synthesis is regulated via the hypothalamus (CRF) and anterior pituitary (ACTH). Glucocorticoids from the adrenal cortex elevate blood glucose and produce a diabetic type of glucose tolerance curve. In humans, this effect may occur only in individuals with a genetic predisposition to diabetes. Clinical correlation: Cushing’s Disease Glucose tolerance is reduced in 80% of patients with Cushing's syndrome and 20% of these patients have frank diabetes. Cortisol

27. The glucocorticoids are necessary for glucagon to exert its gluconeogenic action during fasting. They are gluconeogenic themselves, but their role is mainly permissive. In adrenal insufficiency, the blood glucose is normal as long as food intake is maintained, but fasting precipitates hypoglycemia and collapse. The plasma-glucose-lowering effect of insulin is greatly enhanced in patients with adrenal insufficiency. In animals with experimental diabetes, adrenalectomy markedly ameliorates the diabetes. The major diabetogenic effects are an increase in protein catabolism with increased gluconeogenesis in the liver; increased hepatic glycogenesis and ketogenesis; and a decrease in peripheral glucose utilization relative to the blood insulin level that may be due to inhibition of glucose phosphorylation . PERMISSIVE EFFECT

28. GH is a single chain polypeptide hormone. Source is the anterior pituitary somatotrophs. It is regulated by the hypothalamus. GHRH has a stimulatory effect. Somatostatin (GHIF) has an inhibitory effect. The effects of growth hormone are partly direct and partly mediated via IGF-I . Clinical correlation: Gigantism and Acromegaly cause insulin resistance . Hyperinsulinemia—70% and Glucose intolerance—50% Growth Hormone (GH)

29. Human growth hormone makes clinical diabetes worse, and 25% of patients with growth hormone-secreting tumors of the anterior pituitary have diabetes. Hypophysectomy ameliorates diabetes and decreases insulin resistance even more than adrenalectomy, whereas growth hormone treatment increases insulin resistance. Growth hormone mobilizes FFA from adipose tissue, thus favoring ketogenesis. It decreases glucose uptake into some tissues ( "antiinsulin action" ), increases hepatic glucose output, and may decrease tissue binding of insulin. Indeed, it has been suggested that the ketosis and decreased glucose tolerance produced by starvation are due to hypersecretion of growth hormone. Growth hormone does not stimulate insulin secretion directly, but the hyperglycemia it produces secondarily stimulates the pancreas and may eventually exhaust the B cells.

30. Insulin Therapy “TIGHT” METABOLIC CONTROL HYPOGLYCEMIA Iatrogenic hypoglycemia is the limiting factor in the treatment of insulin-dependent diabetes mellitus.

31. Insulin Preparations Pickup & Williams

32. The Slippery Slope of Hypoglycemia Neuroglycopenic Symptoms Seizures, Coma FREQUENT HYPOGLYCEMIA Autonomic Warning Symptoms BLOOD GLUCOSE (mg/dL)

33. In patients with type 1 diabetes of long duration (> 5 years), epinephrine constitutes the main defense against hypoglycemia, because the pancreatic alpha cell glucagon secretory response to hypoglycemia is irreversibly lost. However, clinical studies have shown that the epinephrine response is also impaired in type 1 patients undergoing intensive insulin treatment. This "double whammy"(lack of glucagon and epinephrine response) places intensively treated type 1 diabetes patients at significant risk for recurrent hypoglycemia. Exercise Impairs Glucose Counterregulation in Type 1 Diabetes. increased insulin levels originating from subcutaneous depots and increased insulin sensitivity that prevent glycogen breakdown to glucose. The Slippery Slope of Hypoglycemia

34. The onset of neuroglycopenia in the absence of prior autonomic warning symptoms HYPOGLYCEMIA UNAWARENESS

35. Hierarchy of autonomic responses to progressive stepwise reduction in plasma glucose concentration in healthy volunteers

36. In addition, frequent antecedent hypoglycemia reduces the counterregulatory responses to future hypoglycemia by 50% , hence creating a vicious cycle of iatrogenic hypoglycemia-associated autonomic failure, where hypoglycemia induces further hypoglycemia.

37. Hypoglycemia- Associated Autonomic Failure 3 syndromes - defective glucose counterregulat ion , hypoglyc emia unawareness , and elevat ed glycemic thresholds during effective intensive therapy —have muc h in common. A functional disorder distinct from classic diabetic autonomic neuropathy. First, they are all associated with a high frequency of severe Iatrogenic hypoglycemia. Second, they tend to segregate together clinically but they do not segregate together with classic diabetic autonomic neuropathy. Third, they share several pathophysiologic features,including elevated glycemic thresholds for autonomic —adrenomedullary (epinephrine), parasympathetic neural (pancreatic polypeptide) and perhaps sympathetic neural (neurogenic symptoms)—responses to hypoglycemia.

38. Somogyi Phenomenon Multiple Insulin Injection Therapy Cause Counter regulatory hormones response to hypoglycemia at midnight. Increase in hepatic glucose production. Insulin resistance because of the Counter regulatory hormones. Treatment Decrease pre-supper intermediate insulin. Defer the dose to 9 PM. Change or start pre-bed snack.

39. Dawn Phenomenon Multiple Insulin Injection Therapy E C T I O N Cause: Less insulin at bed time. More food at bed time. Not using NPH at night. Treatment: Use enough dose. Reduce bed time snack. Add NPH pre-supper.

40. Cause: antihypoglycemic mechanisms are insufficient Result: hypoglycemia develops without warning symptoms and signs Pathomechanism involved in HU development: • Primary defect is localised to the CNS -  or loss of neurotransmiter production on hypoglycemic stimulus -  reactivity of peripheral tissues counterregulatory hormones Consequences: Deep hypoglycemia  hypoglycemic coma   death Hypoglycemia unawareness (HU)

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42. Symptoms of Hypoglycemia “Warning symptoms of hypoglycemia”

43. The Counterregulatory Response INSULIN GLUCAGON EPINEPHRINE NOREPINEPHRINE GROWTH HORMONE CORTISOL GLUCOSE GLUCOSE Type 1 DM Adapted from Cryer PE. Banting lecture. Hypoglycemia: The limiting factor in the management of iddm. Diabetes 1994; 43(11): 1378-89

44. The Slippery Slope of Hypoglycemia BLOOD GLUCOSE (mg/dL) Autonomic Warning Symptoms

45. The Slippery Slope of Hypoglycemia BLOOD GLUCOSE (mg/dL) Autonomic Warning Symptoms Neuroglycopenic Symptoms

46. Autonomic Nervous System Response to Hypoglycemia Alpha-Adrenergic Effects   Inhibition of endogenous insulin release Increase in cerebral blood flow (peripheral vasoconstriction ) Beta-Adrenergic Effects   Hepatic and muscle glycogenolysis Stimulation of plasma glucagon release Lipolysis to raise plasma-free fatty acids Impairment of glucose uptake by muscle tissue Increase in cerebral blood flow (increase in cardiac output ) Adrenomedullary Discharge of Catecholamines   Augmentation of all of the above alpha- and beta-adrenergic effects Cholinergic Effects   Raises level of pancreatic polypeptide Increases motility of stomach Produces hunger Increases sweating