Metabolism, glucose sparing, push-pull control, islets of L..
Metabolism, glucose sparing, push-pull control, islets of Langerhans, islet cell tumors, insulin synthesis and secretion, fed-state metabolism, fasted-state, type 1 diabetes mellitus

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Colorado State University
Biomedical Science
BMS 460
D.Rao Veeramachaneni

21 October Summary of Metabolism Diet: fats, carbohydrates, proteins Fats Free fatty acids + glycerol → free fatty acids pool, fat stores via lipogenesis, metabolism in most tissues Fat stores → free fatty acid pool via lipolysis Free fatty acid pool → fat stores via lipogenesis, metabolism in most tissues Metabolism in most tissues: excess nutrients → free fatty acid pool Carbohydrates Glucose → glucose pool Excess glucose → fat stores via lipogenesis Glucose pool → urine, metabolism in most tissues, glycogen stores via glycogenesis, brain metabolism Glycogen stores → glucose pool via glycogenolysis Proteins Amino acids → amino acid pool Amino acid pool → body protein via protein synthesis, glucose pool via gluconeogenesis Glucose Sparing (Fat Utilization) Release of energy during the interdigestive period or an extended fast During fasting, both skeletal muscle and adipose tissue contribute directly to circulating blood glucose through the release of gluconeogenic substrates (lactate, amino acids, glycerol) and indirectly through the release of free fatty acids (FFA), which allow skeletal muscle and other tissues to consume less glucose. Finally, release of FFAs and ketogenic amino acids supports ketogenesis by liver. A ketogenic amino acid can be degraded directly into acetyl CoA whereas a glucogenic amino acid is converted into glucose. Push-pull control of metabolism Insulin:glucagon ratio regulates gluconeogenesis and glycogenolysis to maintain blood sugar. High ratio reduces and low ratio increases glucose formation. Fed (absorptive) state: insulin dominates ↑ glucose oxidation ↑ glycogen synthesis ↑ fat synthesis ↑ protein synthesis Fasted (post absorptive) state: glucagon dominates ↑ glycogenolysis ↑ gluconeogenesis ↑ ketogenesis Endocrine Pancreas: Islets of Langerhans α-cells secrete glucagon (which increases glucose blood levels), β-cells secrete insulin (which increases the transport of glucose into cells; such as hepatocytes and skeletal and cardiac muscle cells), δ-cells secrete gastrin (which stimulates production of HCl by parietal cells in the stomach) and somatostatin (which inhibits the release of insulin and glucagon, and the secretion of HCl by parietal cells), and F-cells produce pancreatic polypeptide (which inhibits the secretion of somatostatin and the secretion of pancreatic enzymes) Each islet consists of 2000 to 3000 cells surrounded by a network of fenestrated capillaries and supported by reticular fibers. About a million islets of Langerhans are scattered throughout the pancreas. Endocrine Pancreas: Islet Cell Tumors Islet cell tumors derive from neuroendocrine cells in the islets of Langerhans, which tend to grow in a ribbon pattern Tumors with a hormonal syndrome may present with Hyperglycemia due to glucagon-secreting tumors Hypoglycemia due to insulin-secreting tumors Achlorhydria due to somatostatin-secreting tumors Peptic ulcers due to gastrin-secreting tumors (e.g., Zoellinger-Ellison syndrome) Some less common syndromes Some islet cell tumors are malignant and often present with multiple metastatic tumor deposits in the liver Carcinoid tumors can also develop in the pancreas and behave similarly to other carcinoid tumors of the gastrointestinal tract Removal of localized tumors is usually curative Most islet cell tumors are nonfunctional and often reach a large size before being discovered Most islet cell tumors develop in the tail of the pancreas and do not produce common duct obstruction and jaundice as is common in ductal pancreatic adenocarcinomas Treatment of metastatic tumors with octreotide (a somatostatin analog) may ameliorate hormonal symptoms but does not result in cure Insulin: Synthesis and Secretion C-peptide links the α- and β-chains Equimolar amounts of C-peptide and insulin are stored in secretory granules of beta cells and both are released to the portal circulation C-peptide levels measured as a means of distinguishing type 1 and type 2 diabetes mellitus In type 1 diabetes, the pancreas is unable to produce insulin, and, therefore, they will usually have a decreased level of C-peptide, whereas C-peptide levels in type 2 patients are normal or higher than normal. Insulin secretion Glucose enters β-cells via facilitated diffusion (GLUT2 transporter) Elevated intracellular glucose increases the ATP/ADP ratio, resulting in blockage of the ATP-sensitive K channel in the plasma membrane, which triggers depolarization to cause an influx of calcium Increased intracellular calcium triggers docking and fusion of neurosecretory granules with the plasma membrane, resulting in exocytosis of insulin into the extracellular environment. Mutations of components of the K ATPchannel are seen in neonatal DM Insulin’s cellular mechanism of action Insulin binds to tyrosine kinase receptor Receptor phosphorylates insulin-receptor substrates (IRS) Second messenger pathways alter protein synthesis and existing proteins Membrane transport is modified Cell metabolism is changed Fed-state metabolism under the influence of insulin promotes glucose metabolism by cells ↑ plasma glucose → inhibits α cells of pancreas, effects β cells of pancreas β cells of pancreas → ↑ insulin ↑ insulin → liver; muscle, adipose, and other cells Liver → ↑ glycolysis, ↑ glycogenesis, ↑ lipogenesis → ↓ plasma glucose Muscle, adipose, and other cells → ↑ glucose transport, ↑ glycolysis, ↑ glycogenesis, ↑ lipogenesis → ↓ plasma glucose ↓ plasma glucose has negative feedback on β cells of pancreas Note that insulin acts on liver, muscle, adipose tissue and a variety of other cells Fasted-state: endocrine response to hypoglycemia ↓ plasma glucose inhibits β cells of pancreas, effects α cells of pancreas β cells of pancreas → ↓ insulin → muscle and adipose tissue → lactate, pyruvate, amino acids, fatty acids to liver α cells of pancreas → ↑ glucagon → liver → glycogenolysis, gluconeogenesis → ↑ plasma glucose ↑ plasma glucose has negative feedback on α cells of pancreas, used by brain and peripheral tissues
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