Metabolic effects of insulin & glucagon

1. Metabolic effects of insulin & glucagon ENDO412

2. Introduction Fuels are biomolecules (as carbohydrates, lipids & proteins) that can yield energy in the form of ATP on (catabolism or degradation). This energy (ATP) that can be used for all biological processes of the cells. Fuels can be also stored in certain sites of the body in the form of larger molecules (anabolism or building) to be released in case of demand. These procedures (catabolism & anabolism) are called energy metabolism. Energy metabolism occurs mainly in 4 organs; liver, adipose, muscles & brain, in which energy is stored, produced & released according to needs of the body. These 4 organs communicate in a way that one of them produces substrates for another. Among these 4 organs, energy metabolism is integrated & regulated primarily by the action of insulin & glucagon (with catecholamines plays a supporting role).

3. Organ map during the absorptive stateshowing intertissue relationship

4. Organ map during the fasting stateshowing intertissue relationship

6. Introduction(cont.) • In conclusion: In case of well-fed state (directly after ingestion of a meal): There is a abundance of energy yielding fuels (glucose etc..) more than actual body needs for energy. Excess of fuels (energy) is stored by help of INSULIN hormone. (anabolic pathways) In case of stress or prolonged fasting (post absorptive): These is a lack in energy-yielding fuels to give sufficient energy to all body. Stored fuels are released to be available for used by cells of the body by the help of GLUCAGON hormone. Also, epinephrine plays a role in this status. (catabolic pathways)

7. Insulin Generally, insulin hormone is: • a polypeptide hormone • produced by b-cells of islets of Langerhands (1-2% of cells of the pancreas). • the most important hormone coordinating the use of fuels by tissues. • of anabolic metabolic effects favoring synthesis of glycogen, triacylglycerol (storing of energy) & proteins

8. Structure of insulin • Insulin is protein composed of 51 amino acids, • which are arranged in 2 polypeptide chains A & B linked together by 2 disulfide bridges (in addition to intrmolecular disulfide bridges between amino acids of the A chain)

9. Synthesis & secretion of insulin Preproinsulin(inactive precursor) in ER Proinsulin(inactive precursor) Golgi apparatus Insulin + C-peptide Insulin & C-peptide are stored in cytosol as granules To be released by certain stimulus by exocytosis to blood C-peptide has a longer half-life in the plasma more than insulin. & hence is a good indicator of insulin production & secretion in early cases of DM

10. Synthesis & secretion of insulin

11. Regulation of secretion of insulin • Insulin secretion by b-cells is coordinated with the release of glucagon by a-cells. • Relative amounts of insulin & glucagon released from the pancreas are regulated so that the rate of liver glucose production is equal to use of glucose by peripheral tissues. • In short: Insulin is required for storing of glucose in liver. Glucagon is required for releasing glucose from its stores in liver. So, both hormones secretion from pancreas has to be regulated according to needs of the body.

12. Regulation of secretion of insulin (cont.) 1-Factors stimulating of insulin secretion: - Glucoseingestion (or carbohydrate rich meals) - Amino Acids - Gastrointestinal hormones (as cystokinines & gastric-inhibitory polypeptides) increase insulin secretion in response to oral glucose 2-Factors inhibiting insulin secretion: Decrease of synthesis of insulin occurs when there is a scarcity of diet fuel & during periods of stress. These effects are mediated by epinephrine, which causes rapid mobilization of energy-yielding fuels (including glucose from liver & fatty acids from adipose tissue). Epinephrine binds to a-adrenergic receptors on b-cells resulting in decrease of insulin secretion.

13. Regulation of secretion of insulin (cont.)

14. Metabolic effects of insulin Carbohydrates Metabolism Promotes storage of glucose LiverMusclesadipose Glycogen Glycogen uptake of Synthesis Synthesis glucose Gluconeogenesis Intake of glucose Glycogenlysis Lipids Metabolism TAG TAG Degrad. Synth Protein Synthesis Entry of AA into cells Protein Synth.

16. Mechanism of action of insulin Binding Of Insulin on a-cells Phosphorylationof b-subunits Phosphorylation of IRS CHANGES IN Gene Metabolism Growth Expression

17. Mechanism of action of insulin(Membrane effects of insulin) Glucose transport in some tissues as skeletal muscles & adipocytes increase in the presence of insulin Insulin promotes the recruitment of insulin-sensitive glucose transporters (GLUT-4) from a pool located in intracellular vesicles N.B. Some tissues do not depend on insulin for glucose transport As Liver cells, RBCs, neurons, intestinal mucosa, renal tubules & cornea

18. Time course of action of insulin Binding of insulin to its receptors on various cells provoke a wide range of actions that varies in time course. Some may occur immediately within few seconds, while others need days Immediate(within seconds): increased glucose transport into adipose tissue & sk. ms. (membrane effect) Within minutes to hours: changes in activity of enzymes. (phosphorylation of proteins i.e. enzymes) Within hours to days: increase amounts of many enzymes (increase in gene expression with increase in mRNA & enzyme synth.)

19. Down regulation of action of insulin(Receptor Regulation) Binding of insulin to its receptors is followed by internalization of hormone- receptor complex. Once inside cells, insulin is degraded in lysosomes. Receptors are either degraded or recycled to cell surface. Elevated levels of insulin promote the degradation of receptors, with a decrease in the number of surface receptors (a type of down regulation)

20. Glucagon • Glucagon is a single polypeptide chain hormone secreted by a-cells of islets of Langerhands of the pancreas. • It is one of a group of hormones (glucagon, epinephrine, cortisol & growth hormone) that oppose many actions of insulin (anti-insulin hormones or diabetogenic hormones). • Glucagon mainly acts by maintaining blood glucose level by increasing glycogenlysis & gluconeogenesis in liver cells.

21. Stimulation of glucagon actions a-cells are responsive to a variety of stimuli that signal hypoglycemia (actual or about to occur) Glucagon secretion is increased by: 1- Low blood glucose in blood: During an overnight or prolonged fasting, elevated glucagon levels prevent hypoglycemia. 2- Amino acids: Amino acids released from meals containing protein stimulate both glucagon & insulin. In this case, glucagon prevents the hypoglycemia that would occur as a result of increased insulin secretion after a protein meal. 3- Epinephrine: Epinephrine is released either by adrenal medulla or by sympathetic innervations of pancreas or both) in cases of stress, trauma or severe exercise. In these cases, glucagon levels are elevated to be ready for the possibility of increased glucose use.

22. Inhibition of glucagon actions Glucagon secretion is significantly decreased by : - Elevated blood glucose - Insulin Both substances are increased following ingestion of glucose or carbohydrate-rich meal

23. Stimulation & Inhibition of glucagon release

24. Metabolic effects of glucagon Carbohydrates Metabolism Increases blood glucose Liver Glycogenlysis Gluconeogenesis Lipids Metabolism TAG Degrad. in adipose tissue fatty acids in liver ketone bodies (ketpgenesis) Protein Metabolism Uptake of AA by liver Carbon skeleton for gluconeogenesis

25. Mechanism of action of glucagon