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Dr. Ravi Kant Associate Professor Dept. of Medicine AIIMS, Rishikesh Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86 amino acid precursor polypeptide, preproinsulin. Subsequent Proteolytic proces the amino terminal signal peptide, giving rise to proinsulin . Proinsulin is structurally related to insulin-like growth I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generate the C peptide and the A (21 amino acid ) and B (30 amino acid) chain of insulin , which are connected by disulfide bonds the mature insulin molecule and C peptide are stored together and co secreted from secretory granules in the beta cells Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose levels > 3.9 mmol/L (70 mg/dl) stimulate insulin synthesis, primarily by enhancing protein translation and processing . Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is the rate limting step that controls glucose-regulated insulin secretion. Insulin secretory profiles reveal a pulsatile pattern of harmone release , with small secretory bursts occuring about every 10 min, superimposed upon greater amplitude oscillations of about 80-150 min. Incretins are released from neuroendrocrine cells of the gastrointestinal tract following food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion. Once insulin is secreted into the portal venous system 50% is degraded by the liver . Un extracted insulin enters the systemic circulation where it binds to receptors in target sites. Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). . IRS and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. Activation of other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells Functions of Insulin 1. 2. 3. 4. 5. Insulin stimulates Glucose uptake by the cells ( thru GLUT-4!!!) Insulin stimulates Glycogenesis in both the Liver & the skeletal muscles. It inhibits Glycogenolysis It inhibits Gluconeogenesis It promotes liver uptake, use & storage of Glucose Throughout the day the muscles use Fatty Acids. This is because under resting conditions, the cells are dependent on GLUT-4 for glucose uptake ! With moderate or severe exercise, special GLUT-4 vesicles (present only in muscles) move into cell membrane in response to exercise only & do not require Insulin ↓ That is why EXERCISE LOWERS BLOOD SUGAR Insulin inhibits Gluconeogenesis by altering the quantity & activity of Liver enzymes required for the reaction Insulin inhibits Glycogenolysis by inactivating Liver phosphorylase: GLYCOGEN__________→ GLUCOSE (catalyzed by Liver phosphorylase) Glycogen stored in the liver is not broken down into Glucose for further use. Insulin enhances Glycogenesis by increasing the activity of Glycogen synthase & phosphofruktokinase enzyme. ◦ Net effect is increased synthesis of Glycogen in the liver Insulin promotes conversion of excess Glucose into Fatty acids ◦ When the Glycogen content exceeds 5-6% of the liver mass (about 100gms), then the excess glucose entering the liver cells is converted into Fatty acids. ↓ Triglycerides, which is taken to the adipocytes & stored there Glucose is released from the Liver between meals. It increases the translation of mRNA forming new proteins & the transcription of DNA. Insulin inhibits protein catabolism & decreases the rate of amino acids released from the cells. In the liver, it decreases the rate of gluconeogenesis & thus conserves amino acids for protein synthesis. INSULIN PROMOTES FAT SYNTHESIS & STORAGE: Insulin increases Glycogenesis but when 5-6% of liver mass is Glycogen, then additional Glucose entering the liver is converted to Fat. FA synthesized by liver cells are used by them for TG synthesis. Insulin inhibits lipolysis by inhibiting action of hormone-sensitive lipase. Thus, TG present in the fat cells are not metabolized to yield FA. Insulin promotes glucose transport into the fat cells- this glucose is used to synthesize FA & more importantly to form large quantities of alpha glycerolphosphate. This supplies the glycerol that forms the TG after combining with FA in the fat cells. Glycerol+ FA----------Triglycerides Insulin PROMOTES uptake of Glucose by different cells of the body. In doing so it lowers the blood glucose levels post meal. Insulin increases Glycogenesis, Lipogenesis & protein formation. Insulin inhibits Glycolysis, Gluconeogensis, Lipolysis & protein breakdown. It promotes growth. Factors Stimulating Glucose Insulin Release Amino acids Free fatty acids Gastrointestinal hormones: gastrin, secretin, GIP Parasympathetic stimulation: Ach Sulfonylurea drugs Factors Inhibiting Insulin Decreased blood Release Glucose Fasting Somatostatin Sympathetic stimulation: epinephrine Leptin 1. Hyperglycemia 2. Glycosuria 3. Polyuria 4. Polydipsia & Polyphagia 5. Weight Loss 6. Increase in plasma Cholesterol & Phospholipid conc. Hyperglycemia Glycosuria Polyuria Polydipsia & Polyphagia Weight loss Increase in plasma cholesterol & phospholipid conc. THE NET EFFECT OF INSULIN LACK IS A SEVERE REDUCTION IN THE ABILITY TO STORE GLCOSE, FAT & PROTEIN The End I. Type 1 diabetes (beta cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance) III. Other specific types of diabetes A. Genetic defects of beta cell function characterized by mutations in: 1. Hepatocyte nuclear transcription factor (HNF) 4 (MODY 1) 2. Glucokinase (MODY 2) 3. HNF-1 (MODY 3) 4. Insulin promoter factor-1 (IPF-1; MODY 4) 5. HNF-1 (MODY 5) 6. NeuroD1 (MODY 6) 7. Mitochondrial DNA 8. Subunits of ATP-sensitive potassium channel 9. Proinsulin or insulin B. 1. 2. 3. 4. Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipodystrophy syndromes C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase D. Endocrinopathies—acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma E. Drug- or chemical-induced—glucocorticoids, vacor (arodenticide), pentamidine, nicotinic acid, diazoxide, adrenergic agonists, thiazides, hydantoins, asparaginase, interferon, protease inhibitors, antipsychotics (atypicals and others), epinephrine. F. Infections—congenital coxsackievirus rubella, cytomegalovirus, G. Uncommon forms of immune-mediated diabetes— "stiff- person" syndrome, anti-insulin receptor antibodies H. Other genetic syndromes sometimes associated with diabetes— Wolfram's syndrome, Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, PraderWilli syndrome. Two features of the current classification of DM diverge from previous classifications. First, the terms insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia, the use of the term NIDDM generated considerable confusion. It is estimated that between 5 and 10% of individuals who develop DM after age 30 years have type 1 DM. Other etiologies for DM include specific genetic defects in insulin secretion or action, metabolic abnormalities that impair insulin secretion, mitochondrial abnormalities, and a host of conditions that impair glucose tolerance. Maturity-onset diabetes of the young (MODY) is a subtype of DM characterized by autosomal dominant inheritance, early onset of hyperglycemia (usually <25 years), and impairment in insulin secretion. Cystic fibrosis-related DM is an important consideration in this patient population. Glucose intolerance developing during pregnancy is classified as gestational diabetes. Insulin resistance is related to the metabolic changes of late pregnancy, and the increased insulin requirements may lead to IGT or diabetes. GDM occurs in 7% (range 2–10%) of pregnancies in the United States; most women revert to normal glucose tolerance postpartum but have a substantial risk (35–60%) of developing DM in the next 10–20 years. The International Diabetes and Pregnancy Study Groups now recommends that diabetes diagnosed at the initial prenatal visit should be classified as "overt" diabetes rather than gestational diabetes. Glucose tolerance is classified into three broad categories: normal glucose homeostasis, diabetes mellitus, and impaired glucose homeostasis. Glucose tolerance can be assessed using the fasting plasma glucose (FPG), the response to oral glucose challenge, or the hemoglobin A1C (A1C). An FPG <5.6 mmol/L (100 mg/dL), a plasma glucose <140 mg/dL (11.1 mmol/L) following an oral glucose challenge, and an A1C <5.6% are considered to define normal glucose tolerance. The International Expert Committee with members appointed by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation has issued diagnostic criteria for DM based on the following premises: (1) The FPG, the response to an oral glucose challenge (OGTT—oral glucose tolerance test), and A1C differ among individuals. (2) DM is defined as the level of glycemia at which diabetesspecific complications occur rather than on deviations from a population-based mean. For example, the prevalence of retinopathy in Native Americans (Pima Indian population) begins to increase at an FPG >6.4 mmol/L (116 mg/dL) Symptoms of diabetes plus random blood glucose concentration 11.1 mmol/L (200 mg/dL)a Fasting plasma glucose 7.0 mmol/L (126 mg/dL)b A1C > 6.5%c Two-hour plasma glucose 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testd Thank You