Insulin - A hormone from Pancreas Lecture NO : 02nd MBBS Dr Muhammad Ramzan

Insulin – the definition Insulin is a protein hormone(51AAs) secreted by the β cells of the Islets of Pancreas Insulin is a major hypoglycemic agent

Insulin - the background Major action of the Insulin is to regulate metabolism of CHO (glucose) and lipids ↑ glucose uptake by the liver, muscles and adipose Reduces hyperglycemia It facilitates Glycogen storage in the Liver and muscles Insulin Deficiency produces Diabetes mellitus and Excess Hyper insulinemia, Insulin resistance and obesity

Endocrine Pancreas Pancreas is made up of 2 functionally different organs An endocrine Pancreas - the source of Insulin; Glucagon Somatostatin and pancreatic polypeptide 1 The exocrine Pancreas is the major digestive gland. 2

Pancreas – Endo and Exocrine parts

Islets of Langerhans – the composition Endocrine Pancreas consist of .7-1million endocrine glands - Islets of Langerhans – Wt 1- 2 G in adults 4 types of cells are present in Islets: A/α cells = Glucagon's B/ β cells = Insulin – 60% of Islets cells D/ delta cells = Somatostatin F cells = Pancreatic polypeptide

Structure of insulin - 2 peptide chains and C- peptide Insulin has of 51 Amino acids, arranged in 2 peptide chains designated as A and B Chain A = 21 AAs - Chain B = 30 AA Both are linked together by 2 disulfide bridges Insulin molecule is secreted always with equal amount of C – peptide with 31 AAs

Structure of Insulin

Biosynthesis of Insulin - the pathway secreted as Pre Prohormone 86 AAs It is produced as Prepro– insulin (111AA) in the RER of β cells Has Signal sequence; A+ B chain and C- peptide - 4 Cleaved to Proinsulin (86AA) by the Microsomal enzymes after losing Signal Sequence in RER 3 C-peptide (35AA) is excised from the Proinsulin by the Endo - peptidase in the RER, Generating the mature form of Insulin Regulation of Insulin synthesis ------ Current Diabetes Rev; 2014

Biosynthesis of Insulin – the pathway

Insulin secretion as vesicles - Exocytosis in response to CHO ingestion Insulin and free C - peptide is packed in Golgi and stored as secretary vesicles into the β cell cytoplasm C - peptide is also released into circulation in equal amounts along with Insulin Secretary vesicles are released from β cells by Exocytosis and diffuse into Islet capillary blood after : Receiving stimulus from the body like CHO ingestion

Insulin Exocytosis

Significance of C- peptide 35 to 31AAs by cleavage C- peptide (31AA) is produced during Insulin synthesis and is released in the equal amounts with insulin Has no biological Activity but is essential for Insulin folding 1 Good indicator for insulin secretion for having long half life than insulin 8 -12 vs. 4-6 minutes 2 It allows discrimination B/w endogenous and exogenous sources of insulin in the evaluation of hypoglycemia 3

Insulin - the degradation and clearance It is degraded by the Insulinase in the GIT that is why it is given parentally only Is cleared by the kidney and liver Half life of insulin is 4 - 6 minutes C- peptide is cleared later than insulin

Insulin clearance/degradation

Insulin secretion – the regulation 2 pathways direct and indirect Insulin secretion is regulated through 2 pathways : Direct regulation: through hyperglycemia sensed by β cells – the major one and : indirect regulation : Through physiological stimuli, diet and hormones

Direct regulation of Insulin secretion hyperglycemia is the major stimulus Primarily insulin is secreted in response to plasma glucose level and hyperglycemia is sensed by the β cells It stimulate the release of Insulin from the secretary vesicles stored in the cytoplasm of β cells C- peptide is also released along with Insulin

Indirect regulation of Insulin secretion the stimulators Insulin secretion is also regulated through : physiological stimuli : smell, sight and taste of food Diet containing CHOs (glucose) , proteins (AA ). Leucine Hormones: GH; Prolactin, Catecholamines Enteric hormones: Gastrin and Cholicystokinin

Insulin – the mechanism of action like peptide hormones Insulin is a polypeptide and it acts through extra cellular receptors - Tyrosine Kinas (Tetramer, α and β subunits. 4 units) Tyrosine Kinas also functions as an enzyme that transfers phosphate group from ATP to the : Tyrosine residues in the intracellular target proteins Binding of Insulin to α subunit causes the β subunit to phosphorylate itself - (Auto Phosphorylation)

Insulin – Phosphorylation of proteins an activator of receptor It, thus activates the catalytic activity of the receptor The activated receptor, Phosphorylates a no of intracellular proteins which alter their activity and : generates biological effects Several of these proteins act as Insulin Receptor Substrate like Insulin Receptor Substrate 1 or IRS -1 (Skeletal muscles) IRS activate Glucose transporters (GLUT) to ↑ entry of Glucose

Insulin receptor – the mechanism

Insulin - mechanism of action

Phospho and dephosphorylation of Proteins/enzymes When these Receptor Substrates are Phosphorylated they phosphorylate other proteins/enzymes to : mediate insulin effects Action of insulin is terminated by Dephosphorylation of Receptor and IRS - 1 or degradation by Insulinase

Metabolic effects of Insulin These include effects on : Carbohydrate (CHO)metabolism Lipid metabolism and Protein metabolism

Insulin effects on CHO metabolism produces hypoglycemia Major effect of Insulin is to increase the Glucose uptake by the Liver, muscles and Adipose tissue the Insulin sensitive tissues This decreases the blood glucose level especially after dietary intake to prevent hyperglycemia after : GIT absorption (Post parandial hyperglycemia)

CHO metabolism – Excess of glucose Glycogen in liver Insulin increases Synthesis and Storage of glycogen in liver and muscles - ↑Glycogenesis 1 ↓es breakdown of glycogen – Glycogenolysis 2 Production of ATP from aerobic metabolism of glucose

Conversion of excess glucose to Glycogen

Insulin -– further excess of Glucose TG and Lipoprotein Synthesis Further excess is used for FA synthesis in liver and Glycerol in Adipose tissues FAs and glycerol are used by the liver to synthesize TG and lipoproteins (VLDL – C) TG and lipoproteins are exported to the peripheral tissues for energy production and consumption - ATP

Insulin - Effects on lipid metabolism promotes Lipogenesis It increases triglyceride (TG) synthesis from the FAs and storage in fatty tissue (FAs from excess glucose) 1 It reduces breakdown of fats in adipose tissue- Lipolysis by inhibiting intracellular lipase to hydrolyze TG 2

Insulin – metabolic effects on CHO and lipids

Insulin effects on lipid metabolism – the benefits prevents fats consumption for energy Insulin prevents the use of fats as an energy source by inhibiting the release of Glucagon It prevents FA oxidation and Ketogenesis Instead, Insulin facilitates the breakdown of glycogen in liver and muscles As insulin is always present in the body

Insulin - Effects on Protein metabolism Increases protein synthesis Insulin is an anabolic hormone and stimulates the entry of AAs in the cell to increase protein synthesis It ↑ genetic expression by Replication of DNA leading to (transcription) mRNA synthesis and leads to : Translation for protein synthesis and enzymes ↑ growth by cell proliferation in Liver land embryo

Insulin – secretion abnormalities the deficiency Insulin may be secreted in excess or there can be deficiency of Insulin Both conditions lead to the development of significant clinical conditions Insulin deficiency leads to the development of Diabetes Mellitus – A hyperglycemic state It is the inability of the body tissues to utilize Glucose

Excess of Insulin – the Clinical Significance Insulin excess causes the development of : Hyperinsulinemia, Insulin resistance, obesity and Metabolic syndrome Dyslipidemia Cardiovascular disease