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: , 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

Control of Insulin mRNA Stability in Rat Pancreatic Islets: Regulatory Role of a 3’-Untranslated Region Pyrimidine- Rich Sequence Tillmar et al, J. Biol Chem 277: Beta Cell insulin mRNA: 40, ,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

PTB controls granule biogenesis Knock et al. Polypyrimidine tract-binding protine promotes insulin secretory granule biogenesis Nat Cell Biol : 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

A Pancreatic islet-specific microRNA regulates insulin secretion Poy et al Nature 432: , 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

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