2. Integration of Metabolism (Chapter 23)

3. - Overview - Insulin : o Structure of insulin o Synthesis of insulin o Regulation of insulin secretion Metabolic effects of insulin and glucagon 1 st Lecture: Pages : 305 - 308

4. Overview:  The human body functions as one community.  Communication between tissues is mediated by the nervous system (by the circulating substrates and plasma hormones). (Figure 23.1)  The integration of energy metabolism is controlled primarily by the action of 2 hormones, (insulin & glucagon) and role of catecholamines (epinephrine and norepinephrine).  The four major organs playing important role in fuel metabolism are liver, adipose tissue, muscles and brain.

6. Insulin Insulin is a polypeptide hormone produced by the  -cells of the islets of Langerhans of the pancreas. (Figure 23.2) It is the most important hormone coordinating the use of fuels by tissues. Its metabolic effects are anabolic. stimulating the synthesis of : - glycogen (glycogensis) - triacylglycerol (lipogenesis) - protein.

8. A- Structure of insulin: Insulin is composed of 51 A.A. arranged in 2 polypeptide chains A & B, linked together by 2 disulfide bridges. (Figure 23.3 A) Insulin molecule also contains an intramolecular disulfide bridge in A chain. Beef insulin differs from human insulin at 3 A.A. positions. pork insulin differs from human insulin at only one A.A. position.

9. Figure 23.3 A : structure of Insulin

10. B- Biosynthesis of Insulin: Insulin is first synthesized as preproinsulin which is changed to proinsulin then to insulin as follows: (Figure 23.3 B) Endoplasmic reticulum Golgi apparatus peptide- C + Insulin Proinsulin Preproinsulin Signal peptide Biosynthesis of Insulin

11. Figure 23.3 B : Formation of human insulin from preproinsulin

12. Preproinsulin and proinsulin are inactive. Insulin is stored in the cytosol in granules that are released by exocytosis. (Figure 23.4) Insulin is degraded by the enzyme insulinase present in the liver and to a lesser extent in the kidneys. Insulin has a plasma half-life of about 6 minutes. This short duration of action permits rapid changes in circulating levels of the hormone.

14. C- Regulation of Insulin Secretion: 1-Stimulation of insulin secretion: Insulin secretion by the  -cells is closely coordinated with glucagon release by  -cells of pancreas The relative amounts of insulin and glucagon secreted by the pancreas are regulated so that : the rate of hepatic glucose production = use of glucose by peripheral tissues. The  -cells respond to a variety of stimuli

15. Insulin synthesis and secretion are stimulated by: a) Glucose: ingestion of glucose or a carbohydrate rich meal    blood glucose  stimulates insulin secretion. b) Amino Acids: ingestion of protein    plasma A.A.  stimulate insulin secretion. (  plasma arginine  stimulation for insulin secretion). c) Gastrointestinal hormones: The intestinal peptide Secretin & GIT hormones  stimulate insulin secretion after ingestion of the food. They cause an anticipatory  in insulin level in portal vein before the actual  in blood glucose. (Figure 23.5) (The same amount of glucose given orally stimulates more insulin secretion than if given IV. ).

17. 2. Inhibition of insulin secretion: The synthesis and release of insulin are   during starvation and stress. These effects are mediated by epinephrine, trauma or extreme exercise. Under these conditions, secretion of epinephrine is controlled by the nervous system. Epinephrine stimulates glycogenolysis, gluconeogenesis and lipolysis and inhibits insulin secretion. In emergency, the sympathetic nervous system largely replaces the plasma glucose concentration as the controlling influence over β –cell secretion. (Figure 23.6)

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20. Metabolic effects of insulin and glucagon o Metabolic effects of insulin o Mechanism of insulin action Glucagon : o Stimulation of glucagon secretion o Inhibition of glucagon secretion 2 nd Lecture: Pages : 308 - 311

21. D- Metabolic effects of Insulin: 1-Effects on carbohydrate metabolism: The effects of insulin on glucose metabolism are most prominent in the liver, muscles and adipose tissue. In muscles and adipose tissue : insulin   glucose uptake by increasing the number of glucose transporters in the cell membrane. In muscles and liver, insulin   glycogensis. In the liver, insulin   the production of glucose by inhibiting both glycogenolysis and gluconeogenesis. Insulin is the only hypoglycemic hormone. Insulin   glucose oxidation and utilization by tissues.

22. 2-Effects on Lipid Metabolism: Insulin   the release of fatty acids from adipose tissue by: a)  in triacylglycerol degradation: Insulin  inhibition of the activity of hormone- sensitive lipase in adipose tissue. b)  triacylglycerol synthesis: - Insulin   the transport and metabolism of glucose into adipocytes,  providing glycerol 3 - phosphate for triacylglycerol synthesis. - Insulin   lipoprotein lipase activity of adipose tissue by  the enzyme synthesis,  providing fatty acids for esterification.

23. 3-Effects on protein synthesis: Insulin  stimulation the entry of A.A. into cells and  protein synthesis in most tissues. E- Mechanism of Insulin Action: - Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle and adipose tissue. - This is the first step in a cascade of reactions leading to many biological actions.

24. 1- Insulin receptor (IR): It is synthesized as a single polypeptide that is glycosylated and cleaved into  - and  - subunits which is assembled into a tetramer linked by disulfide bonds. (Figure 23.7) The extracellular  -subunit contains the insulin binding site. The cytosolic domain of the  -subunit is a tyrosine kinase, which is activated by insulin.

25. 2- Signal transduction : Binding of insulin to  - subunits of insulin receptor  conformational changes to the  - subunits  rapid auto-phosphorylation of a specific Tyrosine Residue on each  - subunits. (Figure 23.7) Auto-phosphorylation  cascade of cell signaling responses (Phosphorylation of Insulin Receptor Substrate (IRS) proteins ). At least 4 IRSs show similar structures but different tissue distributions. The actions of insulin are terminated by dephosphorylation of the receptors.

27. 3-Membrane effects of Insulin: Glucose transport in many tissues (skeletal muscle and adipocytes)  in the presence of insulin. (Figure 23.8) Insulin  the recruitment of insulin-sensitive glucose transporters (GLUT-4) from a pool present in intracellular vesicles. Some tissues have insulin independent systems for glucose transport e.g. - hepatocytes - erythrocytes - cells of the nervous system - intestinal mucosa - renal tubules - cornea (Figure 23.9).

30. 4- Receptor regulation: Binding of insulin  intracellular hormone-receptor complex  insulin degradation in the lysosomes. The receptors may be degraded but most are recycled to the cell surface.  levels of insulin   the degradation of receptors,   the number of surface receptors. This is one type of “ down regulation “.

31. 5-Time course of insulin actions: - After insulin binding to the receptors, there will be: a)  glucose transport into adipocytes & skeletal muscles (seconds). b) Change in enzyme activity (phosphorylation states) (minutes to hours). c)  in the amount of enzymes (e.g. glucokinase, phosphofructokinase, and pyruvate kinase) (hours to days). - These changes  gene transcription & enzyme synthesis

32. Glucagon  Glucagon is a polypeptide hormone secreted by the α-cells of islets of Langerhans of the pancreas.  Glucagon is composed of 29 amino acids arranged in a single polypeptide chain.  Unlike insulin, the A.A. sequence of glucagon is the same in all mammalian species.  Glucagon maintains blood glucose levels by  hepatic glycogenolysis & gluconeogenesis.  Epinephrine, glucagon, cortisol, and growth hormone are anti-insulin ( Counterregulatory hormones ).

33. A-Regulation of Glucagon Secretion: 1-Stimulation of glucagon secretion: a- Low blood glucose: hypoglycemia is the primary stimulus for glucagon secretion. (Figure 23.10) b- Amino acids:  the secretion of both glucagon and insulin (Glucagon prevents hypoglycemia caused by  insulin) c-  Epinephrine and nor epinephrine (during stress, trauma or severe exercise)   glucagon secretion. In contrast insulin levels are  2-Inhibition of glucagon secretion : (Figure 23.11) Glucagon secretion is markedly  by  blood sugar and by insulin following carbohydrate-rich meal.

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37. Metabolic effects of insulin and glucagon o Metabolic effects of glucagon o Mechanism of action of glucagon Hypoglycemia : o Symptoms of hypoglycemia o Glucoregulatory systems 3 rd Lecture: Pages : 311 - 314

38. B- Metabolic Effects of Glucagon: 1-Effects on carbohydrate metabolism: I.V. administration of glucagon   blood glucose levels by   hepatic glycogenolysis and  gluconeogenesis. 2 -Effects on lipid metabolism: - Glucagon   hepatic oxidation of fatty acids  formation of ketone bodies from acetyl CoA. - Glucagon  minimal lipolytic effect in adipose tissue in humans. 3- Effects on protein metabolism: Glucagon   A.A. uptake by the liver for gluconeogenesis   plasma A.A

39. C-Mechanism of action of glucagon : Glucagon binds to high-affinity receptors on the cell membrane of the hepatocyte  activation of the adenylate cyclase in the plasma membrane   cAMP (second messenger). (Figure 23.12) cAMP  activation of cAMP–dependent protein kinase   phosphorylation of specific enzymes or other proteins. Phosphorylation  activation or inhibition of the key regulatory enzymes of carbohydrate and lipid metabolism.

41. Hypoglycemia Hypoglycemia is a medical emergency characterized by: 1) Central nervous system symptoms, including confusion, aberrant behavior, or coma. 2) Simultaneous blood glucose level equal to or less than 40 mg/dl. 3) Symptoms being corrected within minutes following the administration of glucose.

42. CNS has an absolute need for a continuous supply of blood glucose as a fuel for energy metabolism. Transient hypoglycemia  cerebral dysfunction, Severe, prolonged hypoglycemia  brain death. The most important hormonal changes to correct hypoglycemia are:   glucagon and epinephrine combined with   insulin secretion.

43. A. Symptoms of hypoglycemia: 1) Adrenergic symptoms: Anxiety, palpitation, tremor, and sweating. These symptoms are due to  epinephrine secretion regulated by the hypothalamus due to hypoglycemia. These symptoms occur when the blood glucose levels fall rapidly. 2) Neuroglycopenic Symptoms:  glucose supply to the brain  brain dysfunction  headache, confusion, slurred speech, seizures, coma and death. -- It results from a gradual  in blood glucose(<40mgdl)

44. B. Glucoregulatory Systems: Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia: 1) The islets of Langerhans (  - cells),  glucagon. 2) The glucoreceptors in the hypothalamus   secretion of both epinephrine (through the autonomic nervous system) and ACTH and growth hormone (GH) by the anterior pituitary gland. (Figure 23.13) - Glucagon, epinephrine, cortisol and GH are called the counter-regulatory hormones because they antagonize the action of insulin on glucose utilization.

46. 1.Glucagon and Epinephrine: Hypoglycemia is corrected by  insulin secretion and  secretion of glucagon, epinephrine, cortisol, and growth hormone.  Glucagon and epinephrine are most important in the acute, short- term regulation of blood glucose levels.  Glucagon :   hepatic glycogenolysis and gluconeogenesis.  Epinephrine:   glycogenolysis and lipolysis,   insulin secretion, and   insulin dependent uptake of glucose by tissues.

47. 2.Cortisol and Growth hormone:  These hormones are less important in the short term regulation of blood glucose levels, but they are important in the long term regulation of glucose metabolism.  They   gluconeogenesis.

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