Pancreatic Hormones

Two types of secretions from pancreas Exocrine function Acinar cells Secretion into acini, ductules Digestive enzymes Used for digestion of food n intestine Endocrine function Islets of Langerhans Secretion into ECF, blood Hormones Regulation of metabolism

The Endocrine Pancreas

Islets of Langerhans 1-2 million islets of Langerhans 0.3 mm diameter of the islets 3 major types of cells Alpha cells – 25% - Glucagon Beta cells - 60% - Insulin and amylin Delta cells – 10% - Somatostatin PP cells – small number - Pancreatic polypeptide

Islets of Langerhans in Pancreas

Insulin First isolated in 1922 by Banting and Best After that tremendous progress in the treatment of Diabetes Mellitus Insulin affects not only carbohydrates metabolism but also has very important effects on protein and fat metabolism Probably , in diabetes mellitus, deranged fat and protein metabolism has more marked and grave effects than the disturbance of carbohydrate metabolism

Insulin secretion Insulin secretion is associated with energy abundance Availability of energy giving nutrient cause insulin secretion Insulin stores the available extra energy giving substances Glucose in the form of glycogen Amino acids in the form of proteins Fatty acids in the form of triglycerides

Chemistry of insulin A small protein MW = 5808 Two amino acid chains linked by disulphide linkages Split linkages, two separated polypeptides have no hormonal activity Insulin synthesized, transcription, translation process as preprohormone

Structure of insulin

Chemistry of insulin Preprohormone MW = 11500 Cleaved in ER to form proinsulin MW 9000 Finally insulin formed in Golgi apparatus and packaged into secretory granules 1/6 hormone still in the form of proinsulin Plasma half life of insulin is only 6 minutes Enzyme Insulinase is responsible for degradation of insulin

Mechanism of action Insulin receptor MW = 300,000 Consisting of 2 alpha subunits – lying outside the CM 2 beta subunits - penetrating through the CM Insulin combines with alpha subunits Beta subunits protruding into the cytoplasm is phosphorylated Activation of cytoplasmic tyrosine kinase Activation of Insulin-receptor substrates (IRS) and many other enzymes Some enzymes are inactivated Altered enzyme system affects the metabolism of carbohydrates, fats and proteins

Mechanism of action

Mechanism of action Cell membrane of 80 % of the cells increase the transport of glucose across This transport is by a carrier protein – facilitated diffusion CM becomes more permeable to amino acids Slowly many metabolic enzymes are altered Alteration of translation of m RNA and transcription of DNA takes place much slowly

Effects of carbohydrate metabolism After meals Glucose absorbed into the blood from GIT Stimulation of insulin production Insulin→ ↑uptake, utilization and storage of glucose Specially in muscles, adipose tissue and liver Between meals ↓ glucose level ↓ insulin Utilization of fatty acids for energy instead of glucose

Glucose uptake Muscle and adipose tissue CM is impermeable to glucose without insulin Resting muscles use fatty acids for energy between meals Muscle use glucose for energy During moderate to heavy exercise In the presence of insulin (which is usually is the case after meals) Insulin →↑uptake of glucose by the adipose and muscle cells

Glucose uptake

Storage of glycogen in the muscles In resting muscle glucose entering into it converted into glycogen This glycogen can be used for energy later Muscle glycogen cannot be converted into free glucose to enter into blood in hypoglycemic conditions Muscles lack the enzyme glucose phosphatase

Liver uptake of glucose Glucose from GIT stored as glycogen by insulin Between meals glycogen reconverted to glucose to be supplied to all the body tissues Liver cell membrane freely permeable to glucose Insulin →↑glucokinase →↑Phosphorylation of glucose (glucose trapped inside) Insulin→ ↓liver phosphorylase→ ↓glycogenolysis Insulin →↑glycogen synthetase →↑glycogen storage Liver glycogen can be stored up to 5-6 % liver cell mass

Release of glucose from liver Between meals ↓blood glucose → ↓insulin →↓ storage of glucose ↓insulin →↑ phosphorylase→ ↑glycogenolysis ↓insulin →↑glucose phosphatase → split PO4 to form free glucose Liver cell membrane freely permeable to glucose Glucose from glycogenolysis enters into the blood 60 % of glucose in diet is stored as glycogen an later used to maintain glucose level in the blood

Excess glucose in the liver Glycogen stores up to 5-6 % of liver cell mass Insulin →↑conversion of glucose into FA These FA packaged as triglycerides → transported in blood as VLDL to adipose tissue→ storage in adipose tissue Insulin →↓gluconeogenesis by ↓ enzymes

Lack of Insulin effects on neurons Brain neuronal cell use only glucose for energy Use of other substrates occurs with great difficulty Brain neuronal cell membrane freely permeable to glucose without insulin Brain neurons don’t require insulin for supply and utilization of glucose Hypoglycemia → energy crises in neurons → hypoglycemic shock A critical level of glucose is necessary for neuronal cells

Carbohydrate metabolism in other tissues ↑ transport of glucose into the cell ↑ glycolysis Provision of glycerol for storage of fats in the adipose tissue ↑deposition of triglycerides in adipose tissue

Effects on fat metabolism Insulin promotes fat storage in the fat cells Insulin →↑use of glucose for energy and fats are spared Insulin → FA synthesis in the liver cells Insulin →↑transport of glucose into liver cells→ formation of glycogen up to 5-6 % Extra glucose converted to pyruvate then into Acetyl-CoA Acetyl-CoA converted into FA

Effects on fat metabolism Insulin →↑Glycolysis→ ↑↑citrate and isocitrate ions→ activation of Acetyl- CoA- corboxylase to form melonyl-CoA Most of the FA are synthesized in the liver Converted t into triglycerides Transported in VLDL to adipose tissue Insulin →↑lipoprotein lipase is capillary walls of adipose tissue→ conversion of blood triglycerides into FA → absorption into adipose cells→ reconverted into triglycerides

Effects on fat metabolism Insulin →↓ hormone sensitive lipase→ ↓ hydrolysis of triglycerides Insulin →↑ transport and glycolysis and FA synthesis Insulin →↑ glycolysis → α-glycerophosphate to provide glycerol nucleus for triglyceride synthesis ↓insulin → ↓storage of fats

Insulin deficiency and fat metabolism ↓insulin → ↑ hormone sensitive lipase →↑ hydolysis of triglycrides (mobilization of FA) → ↑FFA ↓insulin →↑β-oxidation of FA ↓insulin → ↑FFA→ conversion into cholesterol and phospholipids → ↑ blood lipoproteins cholesterol and phospholipids ↓insulin →↑ cholesterol → ↑ atherosclerosis

Diabetic Ketoacidosis ↓insulin → ↑FFA →↑carnitine transport system for FA into mitochondria→↑β-oxidation of FA → ↑↑Acetyl-CoA ↑↑Acetyl-CoA→ ↑acetoacetic acid. β-hydroxybutric acid and acetone ↓insulin → Ketosis Ketosis → acidosis Direct Indirect through excretion of Na+ and retention of H+ in the kidney tubules

Effects of removing the pancreas

Effects on Proteins Insulin →↑ protein deposition (effect similar to GH) ↑transport of amino acids into the cells (valine, leucine, isoleucine, tyrosine and phenylalanine) ↑ translation of RNA in the ribosomes ↑ trascription of RNA from DNA ↓ catabolism of protein In the liver Insulin →↓ gluconeogenesis from amino acids Both insulin and GH are required for proper growth of the body

Lack of insulin and protein metabolism ↓synthesis of proteins Stoppage of growth ↑ conversion of amino acids into glucose (gluconeogenesis) ↑catabolism of protein ↑degradation of amino acids ↑excretion of urea Generalized protein wasting Deranged organ and metabolic functions

Insulin and GH required for growth

Mechanism of insulin secretion Beta cells membrane has glucose transporter protein Glucose enters the beta cells Glucose -6 phosphate formed Utilized to produce ATP ATP inhibits ATP- sensitive Potassium channels Depolarization of cell membrane Voltage gated calcium channels open Calcium enters into beta cells Amino acids have similar mechanism of stimulation of insulin secretion

Mechanism of insulin secretion

Regulation of insulin secretion

Factors causing increased insulin secretion Hyperglycemia Increased amino acid level in the blood GIT hormones Gastrin Secretin CCK GIP Glucagon, GH, Cortisol Parasympathetic stimulation, acetylcholine β-adrenergic stimulation

Factors causing decreased insulin secretion Hypoglycemia Fasting Somatostatin α-adrenergic stimulation

Hyperglycemia Hyperglycemia is the most powerful stimulus for beta cells for insulin secretion At fasting Blood glucose level of 80 mg/100ml insulin secretion is 25 ng/min/kg body weight Increasing blood glucose concentration stimulates the secretion Sustained hyperglycemia → ↑insulin secretion proportionate to level of blood glucose This increase rate of secretion is in phases

Phasic increase in insulin secretion 10 fold increase within 3-5 minutes after elevation of blood glucose Due to release of preformed/ stored insulin This increase in not sustained Returns half way down within 5-10 minutes Gradual increase after 15-20 minutes of hyperglycemia Reaches a new plateau within2-3 hours The level is higher than the initial rise Results from additional release and new synthesis Further slow elevation in days Due to hypertrophy of beta cells

Phasic increase in insulin secretion

Feed back regulation Insulin secretion increases in direct proportion to increase in the blood glucose level Above 100 mg/100ml blood glucose level → very rapid rise in insulin secretion 400-600 mg/100ml blood glucose level →10-25 times the basal level Reduction in blood glucose level → rapid reduction in secretion Blood glucose level is very rapidly controlled by this feed back mechanism

Insulin secretion at different blood glucose levels

Mechanism of insulin secretion Glucagon, acetylcholine and gastric inhibitory peptide increase intra cellular calcium by some other mechanism Somatostatin and nor-epinephrine activate -adrenergic receptors and inhibit secretion of insulin Sulphonylurea (e.g. Daonil) drugs stimulate insulin secretion by combining with ATP-sensitive Potassium channels to block them and to produce depolarization to open calcium channels to secrete insulin

Mechanism of insulin secretion

Amino acids Elevated amino acid level also stimulates the beta cells Amino acid Lysine is most potent stimulus among amino acids Very weak stimulus in absence of simultaneous hyperglycemia Very strong effect in the presence of hyperglycemia Effect of hyperglycemia is potentiated by increase in amino acid level Feed back control of amino acids and insulin

GIT hormones Gastrin Secretin Cholecystokinin GIP All increase insulin secretion moderately Anticipatory elevation of insulin Even before elevation of blood glucose or amino acid level

Other hormones Glucagon Growth hormone Cortisol Progesterone Estrogen All of these elevate the blood glucose level and stimulate insulin secretion Uncontrolled oversecretion of any one of these → burning out of the beta cells → diabetes mellitus

Autonomic nervous system Parasympathetic stimulation causes in crease secretion of insulin β-adrenergic stimulation also increase insulin secretion

Switching between CHO & fats metabolism ↑Insulin (present at times of availability of glucose) → Utilization of glucose Fats spared Protein spared Absence of insulin (state of hypoglycemia) → Excessive fat utilization Glucose spared Other hormones affecting the switch GH Glucagon Cortisol Epinephrine

Regarding action of insulin on target cells, the correct statement is: a) Insulin receptor has one alpha an 2 beta subunits b) Beta subunits lie entirely outside the cell membrane c) Insulin receptor is voltage gated d) Autophosphorylation of beta subunits activate tyrosine kinase e) Dephosphorylation of insulin receptor substrates occur

ACTH and MSH