PL3 Physiology of Endocrine Pancreas

• Islets of Langerhans

  Cells in the pancreas

  
• Cells in the pancreatic islet

  • Alpha: 25%, secrete glucagon (located at the periphery)
  • Beta: 60%, secrete insulin and amylin (located centrally)
  • Delta: 10%, secrete somatostatin (scattered around the cell)
  • Others: PP cell, secrete pancreatic polypeptide

  
• Islet of Langerhans

  • Allow close interrelations and cell to cell communications
  • Insulin inhibit glucagon
  • Amylin inhibit insulin
  • Somatostatin inhibit insulin + glucagon

  
• Neural control of insulin secretion

  1. Vagal innervation of the pancreas controls the release of insulin release from its beta cells

  2. It is inhibited by norepinephrine released under sympathetic control from the splanchnic nerve
• Insulin


  Synthesized from the proinsulin by the action of convertase and carboxypeptidase E that remove the center portion of the molecule from the C- and N- terminal ends
• Glucagon


  When bind to liver glucagon receptor, trigger glycogenolysis and gluconeogenesis
• Insulin release (β-cells)

  1. Two phases: 1st - rapid release in response to high blood glucose levels, 2nd - sustained, slow release of newly formed vesicles triggered independently of sugar

  2. Glucose enters β-cells through the GLUT2

  3. Glucose goes into glycolysis → ATP molecules

  4. The ATP-controlled K+ channel close and the cell membrane depolarizes

  5. On depolarization, voltage controlled Ca2+ channel open and Ca2+ flows into the cells

  6. Increased Ca2+ level activate of phospholipase C, which cleaves the phosphatidyl inositol 4,5-bisphospahate → inositol 1,4,5-triphospahate (IP3) + diacylglycerol

  7. IP3 binds to receptor of ER and release Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of Ca2+

  8. Significantly increased amounts of Ca2+ in the cells causes release of previously synthesized insulin (stored in secretory vesicles)
• Glucose transport

  The pancreas releases insulin carries glucose to cells that need extra energy<|>The glucose enters the cell by glucose transporters<|>The cells that need glucose have specific insulin receptors on their surface so that insulin can bind to them, encouraging glucose entry and utilization in the cells<|>Need to regulate base on availability of glucose
• Glucose transporter (GLUT)

  • GLUT1 = fetal tissue, erythrocytes
  • GLUT2 = renal tubular cell & small intestine
  • GLUT3 = mostly in neurons
  • GLUT4 = adipose tissue & striated muscle
• Glucose metabolism

  • Glucose transport
  • Glucose catabolism

  
• Glucose catabolism

  1. Aerobic: Glycolisis, Krebs cycle, Electron transport chain (ETC), Oxidative phosphorylation

  2. Anaerobic: produces the by-product lactic acid

  
• Inefficient transport of glucose from blood to inner cells

  • Insulin resistant by insulin receptors
  • Lack of insulin secretions
  • When control of insulin levels fails, diabetes mellitus will result

  
• Hypoglycemia


  Low blood glucose level

  
• Hyperglycemia

  High blood glucose level
• Type 1 diabetes mellitus: The beta cells in the pancreas are destroyed by autoimmune, pancreas make less insulin

  
• Type 2 diabetes mellitus: Body cells don't respond well to insulin

  
• Leptin

  When leptin binds to its receptor, adenosine monophosphate kinase (AMPK) is phosphorylated and activated<|>Phosphorylates and inactivates ACC, leading to a reduction in malonyl-CoA formation<|>Deinhibition of carnitine palmitoyltransferase (CPT1) and increase in fatty acid oxidation, reduces the formation of a diacylglycerol (DAG) pool from long-chain fatty acyl-CoA (FA-CoA) and prevents the toxic effects of lipid intermediates<|>In the absence of leptin or under conditions of leptin resistance, nonesterified fatty acids (NEFA) accumulate in the cell, DAG is formed and the insulin signaling cascade follows an abnormal pathway, DAG serves to activate a serine kinase, possibly protein kinase C (PKC)<|>PKC phosphorylates the insulin receptor substrate (IRS)-1 on a serine residue and interferes with the ability of insulin (through its receptor, IR) to phosphorylate IRS-1 on a tyrosine residue and recruit and activate phosphatidylinositol 3-kinase (PI3-K)<|>The net effect is loss of the stimulus for GLUT4 translocation to the cell surface promoted by PI3-K and impairment of insulin-stimulated glucose uptake and metabolism
• Mice without the leptin gene are morbidly obese compared to normal mice
• Endurance athletes have higher levels of glut-4 protein in their muscles, glut-4 has also been found to enhance the action of insulin, which might allow endurance athletes to store more glycogen in their muscle cells, then release it progressively as glucose during sustained exercise

  
• Exercise has long been recognised as a useful adjunct to managing insulin dependent diabetes (IDDM), maybe exercise, induce the glut-4 glucose transport system, bypasses the insulin pathway

  
• In overweight or obese individuals, a malfunction in the insulin-signaling pathway renders cells insensitive to insulin; excess glucose, instead of being converted into glycogen, is converted into fat and placed in long-term storage, worsening the individual's weight problem. Untreated, insulin resistance can result in non-insulin dependent diabetes (IDDM)

  
• 2 tissue in pancreas

  1. Acini = secrete digestive juices into duodenum
  2. Islet of Langerhans = secrete insulin and glucagon directly into the blood
• mechanism of glucagon action

  1. The binding of glucagon to its G protein-coupled receptor on hepatocytes increases intracellular levels of cAMP, leading to
  2. activation of protein kinase A, phosphorylase kinase, and phosphorylase & Inactivation Glycogen synthase.
  3. The result is stimulation of gluconeogenesis and glycogenolysis and inhibition of glycolysis

  
• Activation of Glucose transporter (GLUT) by Insulin***


  insulin bind to a subunit of it receptors cause autophosphorylation of the B sub unit -> induce tyrosine kinase activity (phosphorylation) lead expression/translocation of glut4 to cell membrane.

  
• Type 1 DM vs Type 2 DM

  1. the beta cell destroyed by autoimmune // no expression or translation of GLUT4