Pancreatic Islets within Pancreas Modulators of Insulin Secretion

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 • Mitochondrial Produced Superoxide • Superoxide Activates UCP 2 (Uncoupling Protein 2) • UCP 2 -mediated proton leak • Lowered B-cell ATP • Loss of Glucose Stimulated Insulin Secretion

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

PTB controls granule biogenesis Knock et al. Polypyrimidine tract-binding protine promotes insulin secretory granule biogenesis Nat Cell Biol 2004 6: 207 -214. • Beta cell stimulation induces translocation of PTP from nucleus to cytoplasm • Activated cytosolic PTP binds to m. RNA 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

A Pancreatic islet-specific micro. RNA regulates insulin secretion Poy et al Nature 432: 226 -230, 2005 • Micro-RNA 375 restricted to islet cell lines and islet cells • Over-expression of mi. R-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

micro. RNAs synthesis and function • RISC (RNA-induced silencing complex) guides mi. RNAs to their target m. RNA • mi. RNAs recognizes complementary sequences in the target m. RNA UTR (seed sequences) • mi. RNAs cleave target m. RNAs or repress translation Pugliese