Pancreatic Islets within Pancreas

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Pancreatic Islets within Pancreas
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Modulators of Insulin Secretion
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Insulin Secretion
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Phospholipase A2 Cleavage Sites
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Superoxide-mediated activation of uncoupling
protein 2 causes pancreatic B cell
dysfunctionKrauss et al JCI 11218311842, 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

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Control of Insulin mRNA Stability in Rat
Pancreatic Islets Regulatory Role of a
3-Untranslated Region Pyrimidine-Rich
SequenceTillmar et al, J. Biol Chem 2771099-1106

• 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
• 3UTR of insulin gene binding of Polypyrimidine
  tract-binding protein (PTB)
• PTP binding to insulin mRNA increased with
  glucose, probably enhancing stability

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PTB controls granule biogenesisKnock et al.
Polypyrimidine tract-binding protine promotes
insulin secretory granule biogenesisNat Cell
Biol 2004 6207-214.

• 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

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A Pancreatic islet-specific microRNA regulates
insulin secretionPoy et al Nature 432226-230,
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

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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
  

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