فسلجه البنكرياس

• Islets of Langerhans


  Collections of cells in the pancreas that secrete regulatory polypeptides
• Polypeptides secreted by islets of Langerhans

  • Insulin
  • Glucagon
  • Somatostatin
  • Pancreatic polypeptide
• Islet cell types


  • A cells
  • B cells
  • D cells
  • F cells
• β-Islets make up about 2% of the volume of the pancreas, the exocrine portion makes up 80%, and ducts and blood vessels make up the remainder
• Humans have 1 to 2 million islets
• A cells


  Secrete glucagon

  
• B cells


  Secrete insulin
• D cells


  Secrete somatostatin
• F cells


  Secrete pancreatic polypeptide
• Insulin synthesis and secretion

  1. Synthesized in rough endoplasmic reticulum

  2. Transported to Golgi apparatus

  3. Packaged into membrane-bound granules

  4. Granules move to plasma membrane

  5. Contents expelled by exocytosis

  
• Insulin half-life


  About 5 minutes in humans
• Insulin effects


  • Rapid
  • Intermediate
  • Delayed

  
• Insulin effects on adipose tissue

  • Increases glucose entry, fatty acid synthesis, glycerol phosphate synthesis, triglyceride deposition, activates lipoprotein lipase, inhibits hormone-sensitive lipase, increases K+ uptake

  
• Insulin effects on muscle

  • Increases glucose entry, glycogen synthesis, amino acid uptake, protein synthesis, ketone & K+ uptake, decreases protein catabolism & release of gluconeogenic amino acids

  
• Insulin effects on liver

  • Increases protein & lipid synthesis, decreases ketogenesis, decreases glucose output, increases glycogen synthesis, increases glycolysis

  
• Glucose transporters (GLUTs)


  Facilitate diffusion of glucose across cell membranes

  
• Insulin stimulates glucose entry into muscle, adipose, and some other tissues by increasing the number of glucose transporters (GLUTs) in the cell membranes

  
• Insulin increases the entry of glucose into liver cells by inducing glucokinase, which increases the phosphorylation of glucose, keeping the intracellular free glucose concentration low and facilitating glucose entry

  
• Insulin receptor


  A tetramer made up of two α and two β glycoprotein subunits, with the α subunits binding insulin and the β subunits spanning the membrane
• Insulin deficiency can be produced in animals by pancreatectomy, administration of toxins that destroy B cells, administration of drugs that inhibit insulin secretion, and administration of anti-insulin antibodies

  
• Effects of hyperglycemia


  • Causes hyperosmolality of blood, leads to glycosuria and osmotic diuresis, results in polydipsia
  • Causes non-enzymatic glycation of hemoglobin to form HbA1c, which is used as an index of diabetic control

  
• Effects of hyperglycemia on protein metabolism

  • Increases amino acid catabolism to CO2 and H2O, increases gluconeogenesis from amino acids, decreases protein synthesis in muscle leading to increased blood amino acid levels
• Effects of hyperglycemia on fat metabolism

  • Accelerates lipid catabolism and ketone body formation, decreases fatty acid and triglyceride synthesis
  • Increases plasma free fatty acids, triglycerides, chylomicrons, and cholesterol (VLDL and LDL)
• Regulation of insulin secretion

  1. Glucose enters B cells via GLUT-2

  2. Glucose is phosphorylated by glucokinase and metabolized to pyruvate

  3. Pyruvate enters mitochondria and is metabolized via citric acid cycle, producing ATP

  4. ATP inhibits ATP-sensitive K+ channels, depolarizing B cell and allowing Ca2+ entry

  5. Ca2+ influx causes exocytosis of insulin-containing granules

  
• Metabolism of pyruvate via citric acid cycle also increases intracellular glutamate, which acts on a second pool of insulin-containing granules to produce the prolonged second phase of insulin secretion

  
• Glucagon


  Produced by A cells of pancreatic islets and upper gastrointestinal tract, has glycogenolytic, gluconeogenic, lipolytic, and ketogenic effects

  
• Glucagon mechanism of action

  1. Acts on Gs to activate adenylyl cyclase and increase cAMP in liver, leading to activation of phosphorylase and increased glycogenolysis

  2. Also acts on phospholipase C to increase cytoplasmic Ca2+, which also stimulates glycogenolysis

  
• Factors regulating glucagon secretion


  • Increased by hypoglycemia, sympathetic stimulation, protein meal, amino acid infusion, cholecystokinin, gastrin
  • Decreased by hyperglycemia, somatostatin

  
• Somatostatin


  Secreted by D cells, inhibits secretion of insulin, glucagon, and pancreatic polypeptide

  
• Pancreatic polypeptide


  Secreted by F cells, slows absorption of food in humans
• Hypoglycemia ("insulin reactions") are common in type 1 diabetics and occasional in well-controlled diabetics, can cause incoordination and slurred speech

  
• Functional hypoglycemia is characterized by a normal initial glucose rise but subsequent overshoot to hypoglycemic levels 3-4 hours after meals

  
• Diabetes mellitus


  • Characterized by polyuria, polydipsia, weight loss, hyperglycemia, glycosuria, ketosis, acidosis, coma
  • Fundamental defects are reduced glucose entry into peripheral tissues and increased glucose release from liver

  
• Complications of long-standing diabetes

  • Microvascular: diabetic retinopathy, diabetic nephropathy
  • Macrovascular: accelerated atherosclerosis, increased stroke and myocardial infarction
  • Neuropathic: autonomic and peripheral nerve disease
• Obesity, metabolic syndrome, and type 2 diabetes

  • Obesity increases insulin resistance, associated with hyperinsulinemia, dyslipidemia, and accelerated atherosclerosis
  • Weight reduction decreases insulin resistance