HORMONAL SECRETION OF PANCREAS (PANCREAS 1)

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1 HORMONAL SECRETION OF PANCREAS (PANCREAS 1) LEARNING OBJECTIVE: At the end of lecture student should be able to know: What is pancreas. Endocrine and exocrine portion of pancreas, Insulin secretion. Insulin effects. Diabetic mellitus PANCREAS A triangular gland, A ions which has both exocrine and endocrine cells, located behind the stomach. A dual organ having two functions: o Exocrine Functions. o Endocrine Functions o EXOCRINE FUNCTIONS: o The exocrine function of the pancreas is localized in the acinar cells. o Acinar cells involves synthesis and secretion of digestive juices pancreatic juice.

2 o Plays an important role in the digestion of proteins and lipids. o Has mild digestive action on carbohydrates. ENDOCRINE FUNCTIONS: o Performed by the islets of Langerhans. o Involves production of hormones. o Human pancreas contain 1 2 million islets. ISLETS OF LANGERHANS ORGAN SYSTEMS PANCREAS A triangular gland. There are two distinct within the pancreas The exocrine portion of the pancreas is made up of acini and ductal systems. ACINAR CELLS CONTAIN ZYMOGEN

3 ORGAN SYSTEMS PANCREAS The endocrine portion of the pancreas is served by structures called the islet of Langerhans

4 o The islet of Langerhans have several distinct cell types Alpha cells-produce glucagon and constitute approximate 25% of the total islet cell number. Beta cells-the insulin producing cells (majority of the cells) Delta cells-produce somatostatin INSULIN Hormone of nutrient abundance A protein hormone consisting of two amino acid chains linked by disulfide bonds Synthesized as part of proinsulin (86 AA) and then excised by enzymes, releasing functional insulin (51 AA) and C peptide (29 AA). Insulin is secreted in response to high blood sugar, although a low level of insulin is always secreted by the pancreas. After a meal, the amount of insulin secreted into the blood increases as the blood glucose rises. Likewise, as blood glucose falls, insulin secretion by the pancreatic islet beta cells decreases. In response to insulin, muscle cells,, and fat cells take glucose in from the blood, which ultimately lowers the high blood glucose levels back to the normal range. Insulin Structure Large polypeptide 51 AA (MW 6000) Tow chains linked by disulfide bonds. A chain (21 AA)

5 B chain (30 AA) 3 disulfide bonds. NORMAL INSULIN METABOLISM Insulin is a peptide hormone composed of 51 aminoacids that is synthesized, packaged and secreted in the pancreatic beta cells. The major regulator of insulin secretion is glucose which acts both directly and by augmenting the action of other insulin secretagogues. A rise in the blood glucose levels, causes an immediate release of insulin, presumably that is stored in the beta-cell granules. If the secretory stimulus persists, a delayed response follows, which involves active synthesis of insulin from the beta-cells. Other agents, including intestinal hormones and certain aminoacids (leucine and arginine), as well as sulfonylureas, stimulate insulin release. INSULIN SYNTHESIS Insulin gene encodes a large precursor of insulin (preproinsulin) During translation, the signal peptide is cleaved (proinsulin) During packaging in granules by Golgi, proinsulin is cleaved into insulin and C peptide Protein and Polypeptide Synthesis and Release Insulin synthesis is stimulated by glucose or feeding and decreased by fasting. Threshold of glucose-stimulated insulin secretion is 100 mg/dl. Glucose rapidly increase the translation of the insulin mrna and slowly increases transcription of the insulin gene.

6 PROTEIN AND POLYPEPTIDE SYNTHESIS AND RELEASE INSULIN SYNTHESIS LEVELS Blood glucose is normally maintained between 70 mg/dl and 110 mg/dl.

7 Blood glucose levels below 70mg/dl, denote the situation of "hypoglycemia". Although blood glucose levels of 110mg/dl can be normal, this is only the case if a meal has been taken within 2 to 3 hours. A blood glucose level of 180mg/dl or more, is termed "hyperglycemia. Diagnosis is made if blood glucose levels are above 200mg/dl after drinking a sugar-water drink (glucose tolerance test). Insulin excess causes hypoglycemia, which leads to convulsions and coma. Insulin deficiency, either absolute or relative, causes diabetes mellitus (chronic elevated blood glucose), a complex and debilitating disease that if untreated is eventually fatal ISLETS OF LANGERHANS Islets of Langerhans consists of four types of cells : o A cells or α cells o B cells or β cells o D cells or δ cells. o F cells or PP cells. o Alpha cells - release the hormone glucagon, which

8 o triggers the release of glycogen form liver stores and o helps to raise the level of glucose (sugar) in the o bloodstream. o Beta cells - release the hormone insulin, which help regulate carbohydrate metabolism into the bloodstream. FUNCTIONS OF INSULIN Insulin is a major anabolic hormone. It is necessary for: o Transmembrane transport of glucose and aminoacids o Glycogen formation in the liver and skeletal muscles o Glucose conversion to triglycerides o Nucleic acid synthesis o Protein synthesis Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body. These are the striated muscle cells, including myocardial cells,

9 fibroblasts, and fat cells, representing collectively about 2/3 of the entire bodyweight. GLUCOSE IS THE PRIMARY STIMULATOR OF INSULIN SECRETION

10 REGULATION OF INSULIN SECRETION No insulin is produced when plasma glucose below 50 mg/dl Half-maximal insulin response occurs at 150 mg/dl A maximum insulin response occurs at 300 mg/dl Insulin secretion is biphasic: o Upon glucose stimulation an initial burst of secretion (5-15 min.) o Then a second phase of gradual increment that lasts as long as blood glucose is high INSULIN SECRETION IS BIPHASIC

11 INSULIN SIGNALING INSULIN ACTION ON CELLS:

12 INSULIN ACTION ON CARBOHYDRATE METABOLISM: Liver: Stimulates glucose oxidation Promotes glucose storage as glycogen Inhibits glycogenolysis Inhibits gluconeogenesis Muscle: Stimulates glucose uptake (GLUT4) Promotes glucose storage as glycogen Insulin Action on Carbohydrate Metabolism Adipose Tissue: Stimulates glucose transport into adipocytes Promotes the conversion of glucose into triglycerides and fatty acids GLUCOSE TRANSPORT GLUT2 (liver, pancreas) GLUT4, insulin sensitive transporter (muscle, adipose tissue)

13 GLUT3 (brain) GLYCOGEN SYNTHESIS Short term storage of glucose Activates glycogen synthase Inhibit glycogen phosphorylase Glycolysis is also stimulated by insulin Lipogenic and antilipolytic Insulin promotes lipogenesis and inhibits lipolysis o Promotes formation of α-glycerol phosphate and fatty acid synthesis o Stimulates fatty acid synthase (FAS) o Inhibits hormone sensitive lipase (HSL) o Activates lipoprotein lipase (LPL) Protein Synthesis and Degradation Insulin promotes protein accumulation: Stimulates amino acid uptake Increases the activity of protein synthesis Inhibits protein degradation ACTION OF INSULIN ON LIVER: ACTION OF INSULIN ON FAT

14 ACTION OF INSULIN ON MUSCLE

15 INSULIN ACTION (SUMMARY): Dominates in Fed State Metabolism. glucose uptake in most cells glucose use & storage protein synthesis fat synthesis DIABETES MELLITUS

16 DIABETES MELLITUS is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. TWO GENERAL TYPES: o Type I diabetes, insulin-dependent diabetes mellitus (IDDM): Caused by lack of insulin secretion.

17 o Type II diabetes, non insulin-dependent diabetes mellitus (NIDDM): o Caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance.

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