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Pancreatic Islets within Pancreas

Pancreatic Islets within Pancreas. Modulators of Insulin Secretion. Insulin Secretion. Phospholipase A 2 Cleavage Sites. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic B cell dysfunction Krauss et al JCI 112:18311842, 2003. Chronic Hyperglycemia

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Pancreatic Islets within Pancreas

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  1. Pancreatic Islets within Pancreas

  2. Modulators of Insulin Secretion

  3. Insulin Secretion

  4. Phospholipase A2 Cleavage Sites

  5. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic B cell dysfunctionKrauss et al JCI 112:18311842, 2003 • Chronic Hyperglycemia • Mitochondrial Produced Superoxide • Superoxide Activates UCP2 (Uncoupling Protein 2) • UCP2-mediated proton leak • Lowered B-cell ATP • Loss of Glucose Stimulated Insulin Secretion

  6. Control of Insulin mRNA Stability in Rat Pancreatic Islets: Regulatory Role of a 3’-Untranslated Region Pyrimidine-Rich SequenceTillmar et al, J. Biol Chem 277:1099-1106 • Beta Cell insulin mRNA: 40,000-100,000 molecules, total cell approx 360,000 mRNAs • Max insulin mRNA synthesis: 2,500/ hour • Glucose increases mRNA stability • 3’UTR of insulin gene binding of Polypyrimidine tract-binding protein (PTB) • PTP binding to insulin mRNA increased with glucose, probably enhancing stability

  7. PTB controls granule biogenesisKnock et al. Polypyrimidine tract-binding protine promotes insulin secretory granule biogenesisNat Cell Biol 2004 6:207-214. • Beta cell stimulation induces translocation of PTP from nucleus to cytoplasm • Activated cytosolic PTP binds to mRNA for multiple proteins (including insulin) that form insulin secretory granules • Binding of PTB stabilizes RNA increasing translation • Lack of PTB results in lack of granules

  8. A Pancreatic islet-specific microRNA regulates insulin secretionPoy et al Nature 432:226-230, 2005 • Micro-RNA 375 restricted to islet cell lines and islet cells • Over-expression of miR-375 results in 40% decrease in insulin secretion • Inhibits insulin secretion at distal stage with increase in docked granules • Mtpn (myotrophin) is a target gene involved in vesicle transport

  9. microRNAs synthesis and function • RISC (RNA-induced silencing complex) guides miRNAs to their target mRNA • miRNAs recognizes complementary sequences in the target mRNA UTR (seed sequences) • miRNAs cleave target mRNAs or repress translation Pugliese

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