The Endocrine Pancreas Regulation of Carbohydrate Metabolism Copyright

The Endocrine Pancreas Regulation of Carbohydrate Metabolism

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Pancreatic Anatomy n n n Gland with both exocrine and endocrine functions 15 -25 cm long 60 -100 g Location: retro-peritoneum, 2 nd lumbar vertebral level Extends in an oblique, transverse position Parts of pancreas: head, neck, body and tail

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Pancreas

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Head of Pancreas n n n Includes uncinate process Flattened structure, 2 – 3 cm thick Attached to the 2 nd and 3 rd portions of duodenum on the right Emerges into neck on the left Border b/w head and neck is determined by GDA insertion SPDA and IPDA anastamose between the duodenum and the right lateral border

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Neck of Pancreas n n n 2. 5 cm in length Straddles SMV and PV Antero-superior surface supports the pylorus Superior mesenteric vessels emerge from the inferior border Posteriorly, SMV and splenic vein confluence to form portal vein Posteriorly, mostly no branches to pancreas

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Body of Pancreas n n n Elongated, long structure Anterior surface, separated from stomach by lesser sac Posterior surface, related to aorta, lt. adrenal gland, lt. renal vessels and upper 1/3 rd of lt. kidney Splenic vein runs embedded in the post. Surface Inferior surface is covered by transverse mesocolon

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Tail of Pancreas n n n Narrow, short segment Lies at the level of the 12 th thoracic vertebra Ends within the splenic hilum Lies in the splenophrenic ligament Anteriorly, related to splenic flexure of colon May be injured during splenectomy (fistula)

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Pancreatic Duct n n n Main duct (Wirsung) runs the entire length of pancreas Joins CBD at the ampulla of Vater 2 – 4 mm in diameter, 20 secondary branches Ductal pressure is 15 – 30 mm Hg (vs. 7 – 17 in CBD) thus preventing damage to panc. duct Lesser duct (Santorini) drains superior portion of head and empties separately into 2 nd portion of duodenum

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Arterial Supply of Pancreas n n n Variety of major arterial sources (celiac, SMA and splenic) Celiac Common Hepatic Artery Gastroduodenal Artery Superior pancreaticoduodenal artery which divides into anterior and posterior branches SMA Inferior pancreaticoduodenal artery which divides into anterior and posterior branches

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Arterial Supply of Pancreas n n Anterior collateral arcade between anterosuperior and anteroinferior PDA Posterior collateral arcade between posterosuperior and posteroinferior PDA Body and tail supplied by splenic artery by about 10 branches Three biggest branches are n n n Dorsal pancreatic artery Pancreatica Magna (midportion of body) Caudal pancreatic artery (tail)

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Venous Drainage of Pancreas n n Follows arterial supply Anterior and posterior arcades drain head and the body Splenic vein drains the body and tail Major drainage areas are n n n Suprapancreatic PV Retropancreatic PV Splenic vein Infrapancreatic SMV Ultimately, into portal vein

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Lymphatic Drainage n Rich periacinar network that drain into 5 nodal groups n n n Superior nodes Anterior nodes Inferior nodes Posterior PD nodes Splenic nodes

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Innervation of Pancreas n n n Sympathetic fibers from the splanchnic nerves Parasympathetic fibers from the vagus Both give rise to intrapancreatic periacinar plexuses Parasympathetic fibers stimulate both exocrine and endocrine secretion Sympathetic fibers have a predominantly inhibitory effect

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Innervation of Pancreas n n n Peptidergic neurons that secrete amines and peptides (somatostatin, vasoactive intestinal peptide, calcitonin generelated peptide, and galanin Rich afferent sensory fiber network Ganglionectomy or celiac ganglion blockade interrupt these somatic fibers (pancreatic pain)

Production of Pancreatic Hormones by Three Cell Types n n n Alpha cells produce glucagon. Beta cells produce insulin. Delta cells produce somatostatin.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Islet of Langerhans Cross-section n Three cell types are present, A (glucagon secretion), B (Insulin secretion) and D (Somatostatin secretion) A and D cells are located around the perimeter while B cells are located in the interior Venous return containing insulin flows by the A cells on its way out of the islets

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Pancreatic Hormones, Insulin and Glucagon, Regulate Metabolism Figure 22 -8: Metabolism is controlled by insulin and glucagon

Structure of Insulin n Insulin is a polypeptide hormone, composed of two chains (A and B) BOTH chains are derived from proinsulin, a prohormone. The two chains are joined by disulfide bonds.

Roles of Insulin n Acts on tissues (especially liver, skeletal muscle, adipose) to increase uptake of glucose and amino acids. - without insulin, most tissues do not take in glucose and amino acids well (except brain). n Increases glycogen production (glucose storage) in the liver and muscle. n Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue. n Also stimulates potassium uptake by cells (role in potassium homeostasis).

The Insulin Receptor n n The insulin receptor is composed of two subunits, and has intrinsic tyrosine kinase activity. Activation of the receptor results in a cascade of phosphorylation events: phosphorylation of insulin responsive substrates (IRS) RAS RAF-1 MAP-KK Final actions

Specific Targets of Insulin Action: Carbohydrates Increased activity of glucose transporters. Moves glucose into cells. Activation of glycogen synthetase. Converts glucose to glycogen. Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis.

Specific Targets of Insulin Action: Lipids n Activation of acetyl Co. A carboxylase. Stimulates production of free fatty acids from acetyl Co. A. Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell. lipoprotein lipase

Regulation of Insulin Release n Major stimulus: increased blood glucose levels - after a meal, blood glucose increases - in response to increased glucose, insulin is released - insulin causes uptake of glucose into tissues, so blood glucose levels decrease. - insulin levels decline as blood glucose declines

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Insulin Action on Cells: Dominates in Fed State Metabolism n n glucose uptake in most cells (not active muscle) glucose use and storage protein synthesis fat synthesis

Insulin Action on Cells: Dominates in Fed State Metabolism Copyright © The Mc. Graw-Hill

Other Factors Regulating Insulin Release n n Amino acids stimulate insulin release (increased uptake into cells, increased protein synthesis). Keto acids stimulate insulin release (increased glucose uptake to prevent lipid and protein utilization). Insulin release is inhibited by stress-induced increase in adrenal epinephrine - epinephrine binds to alpha adrenergic receptors on beta cells - maintains blood glucose levels Glucagon stimulates insulin secretion (glucagon has opposite actions).

Structure and Actions of Glucagon n n n Peptide hormone, 29 amino acids Acts on the liver to cause breakdown of glycogen (glycogenolysis), releasing glucose into the bloodstream. Inhibits glycolysis Increases production of glucose from amino acids (gluconeogenesis). Also increases lipolysis, to free fatty acids for metabolism. Result: maintenance of blood glucose levels during fasting.

Mechanism of Action of Glucagon n Main target tissues: liver, muscle, and adipose tissue Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and increased PKA activity. Also activates IP 3 pathway (increasing Ca++)

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Glucagon Action on Cells: Dominates in Fasting State Metabolism n n Glucagon prevents hypoglycemia by cell production of glucose Liver is primary target to maintain blood glucose levels

Targets of Glucagon Action n n n Activates a phosphorylase, which cleaves off a glucose 1 -phosphate molecule off of glycogen. Inactivates glycogen synthase by phosphorylation (less glycogen synthesis). Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis Activates lipases, breaking down triglycerides. Inhibits acetyl Co. A carboxylase, decreasing free fatty acid formation from acetyl Co. A Result: more production of glucose and substrates for metabolism

Regulation of Glucagon Release n n Increased blood glucose levels inhibit glucagon release. Amino acids stimulate glucagon release (high protein, low carbohydrate meal). Stress: epinephrine acts on beta-adrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy). Insulin inhibits glucagon secretion.

Other Factors Regulating Glucose Homeostasis n n Glucocorticoids (cortisol): stimulate gluconeogenesis and lipolysis, and increase breakdown of proteins. Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis. Growth hormone: stimulates glycogenolysis and lipolysis. Note that these factors would complement the effects of glucagon, increasing blood glucose levels.

Hormonal Regulation of Nutrients n Right after a meal (resting): - blood glucose elevated - glucagon, cortisol, GH, epinephrine low - insulin increases (due to increased glucose) - Cells uptake glucose, amino acids. - Glucose converted to glycogen, amino acids into protein, lipids stored as triacylglycerol. - Blood glucose maintained at moderate levels.

Hormonal Regulation of Nutrients n A few hours after a meal (active): - blood glucose levels decrease - insulin secretion decreases - increased secretion of glucagon, cortisol, GH, epinephrine - glucose is released from glycogen stores (glycogenolysis) - increased lipolysis (beta oxidation) - glucose production from amino acids increases (oxidative deamination; gluconeogenesis) - decreased uptake of glucose by tissues - blood glucose levels maintained

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Turnover Rate n n Rate at which a molecule is broken down and resynthesized. Average daily turnover for carbohydrates is 250 g/day. n Some glucose is reused to form glycogen. n n Only need about 150 g/day. Average daily turnover for protein is 150 g/day. n Some protein may be reused for protein synthesis. n Only need 35 g/day. n n 9 essential amino acids. Average daily turnover for fats is 100 g/day. n Little is actually required in the diet. n Fat can be produced from excess carbohydrates. n Essential fatty acids: n Linoleic and linolenic acids.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Energy Metabolism n Energy reserves: n n Molecules that can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat). Circulating substrates: n Molecules absorbed through small intestine and carried to the cell for use in cell respiration. Insert fig. 19. 2

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Pancreatic Islets (Islets of Langerhans) n Alpha cells secrete glucagon. n n Stimulus is decrease in blood [glucose]. Stimulates glycogenolysis and lipolysis. Stimulates conversion of fatty acids to ketones. Beta cells secrete insulin. n n Stimulus is increase in blood [glucose]. Promotes entry of glucose into cells. Converts glucose to glycogen and fat. Aids entry of amino acids into cells.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Energy Regulation of Pancreas n Islets of Langerhans contain 3 distinct cell types: n a cells: n n b cells: n n Secrete glucagon. Secrete insulin. D cells: n Secrete somatostatin.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon n n Mainly regulated by blood [glucose]. Lesser effect: blood [amino acid]. n n n Regulated by negative feedback. Glucose enters the brain by facilitated diffusion. Normal fasting [glucose] is 65– 105 mg/dl.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon (continued) n When blood [glucose] increases: n n Glucose binds to GLUT 2 receptor protein in b cells, stimulating the production and release of insulin. Insulin: n Stimulates skeletal muscle cells and adipocytes to incorporate GLUT 4 (glucose facilitated diffusion carrier) into plasma membranes. n Promotes anabolism.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Oral Glucose Tolerance Test n n n Measurement of the ability of b cells to secrete insulin. Ability of insulin to lower blood glucose. Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs. Insert fig. 19. 8

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon n Parasympathetic nervous system: n n Stimulates insulin secretion. GLP-1: n n Stimulates glucagon secretion. GIP: n n Stimulates insulin secretion. CCK: n Stimulates insulin secretion.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. n Glucose homeostasis – Putting it all together Insulin Beta cells of pancreas stimulated to release insulin into the blood High blood glucose level STIMULUS: Rising blood glucose level (e. g. , after eating a carbohydrate-rich meal) Body cells take up more glucose Liver takes up glucose and stores it as glycogen Homeostasis: Normal blood glucose level (about 90 mg/100 m. L) Blood glucose level rises to set point; stimulus for glucagon release diminishes Figure 26. 8 Blood glucose level declines to a set point; stimulus for insulin release diminishes Liver breaks down glycogen and releases glucose to the blood STIMULUS: Declining blood glucose level (e. g. , after skipping a meal) Alpha cells of pancreas stimulated to release glucagon into the blood Glucagon

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Hormonal Regulation of Metabolism n Absorptive state: n n Absorption of energy. 4 hour period after eating. Increase in insulin secretion. Postabsorptive state: n n n Fasting state. At least 4 hours after the meal. Increase in glucagon secretion.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Absorptive State n n Insulin is the major hormone that promotes anabolism in the body. When blood [insulin] increases: n n Promotes cellular uptake of glucose. Stimulates glycogen storage in the liver and muscles. Stimulates triglyceride storage in adipose cells. Promotes cellular uptake of amino acids and synthesis of proteins.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Postabsorptive State n n Maintains blood glucose concentration. When blood [glucagon] increased: n n Stimulates glycogenolysis in the liver (glucose-6 -phosphatase). Stimulates gluconeogenesis. Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone-sensitive lipase). Stimulates lipolysis and ketogenesis.

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Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Diabetes Mellitus n n Chronic high blood [glucose]. 2 forms of diabetes mellitus: n n Type I: insulin dependent diabetes (IDDM). Type II: non-insulin dependent diabetes (NIDDM).

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Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Type I Diabetes Mellitus n b cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent. n n Killer T cells target glutamate decarboxylase in the b cells. Glucose cannot enter the adipose cells. n Rate of fat synthesis lags behind the rate of lipolysis. n n Fatty acids converted to ketone bodies, producing ketoacidosis. Increased blood [glucagon]. n Stimulates glycogenolysis in liver.

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Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Type II Diabetes Mellitus n n Slow to develop. Genetic factors are significant. Occurs most often in people who are overweight. Decreased sensitivity to insulin or an insulin resistance. n n n Obesity. Do not usually develop ketoacidosis. May have high blood [insulin] or normal [insulin]. Insert fig. 19. 12

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Treatment in Diabetes n Change in lifestyle: n Increase exercise: n n Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells. Weight reduction. Increased fiber in diet. Reduce saturated fat.

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Hypoglycemia n n Over secretion of insulin. Reactive hypoglycemia: n n Caused by an exaggerated response to a rise in blood glucose. Occurs in people who are genetically predisposed to type II diabetes. Insert fig. 19. 13

Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Regulation n Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary. n Insulin, T 3, and GH can act synergistically to stimulate protein synthesis.