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Fukaya M, Tamura Y, Chiba Y, Tanioka T, Mao J, Inoue Y, Yamada M, Waeber C, Ido-Kitamura Y, Kitamura T, Kaneki M.
Biochem Biophys Res Commun
Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced β-cell damage and diabetes in mice
Scopus: 11 ()
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Diabetes, HD-STZ, Isonicotinamide, LD-STZ, MD-STZ, NAD(+), PARP, Pancreatic β-cells, STZ, Streptozotocin, TUNEL, TdT-mediated dUTP Nick-End Labeling, high-dose streptozotocin, low-dose streptozotocin, medium-dose streptozotocin, nicotinamide adenine dinucleotide, poly(ADP-ribose) polymerase, streptozotocin
OBJECTIVE: Nicotinamide rescues β-cell damage and diabetes in rodents, but a large-scale clinical trial failed to show the benefit of nicotinamide in the prevention of type 1 diabetes. Recent studies have shown that Sirt1 deacetylase, a putative protector of β-cells, is inhibited by nicotinamide. We investigated the effects of isonicotinamide, which is a derivative of nicotinamide and does not inhibit Sirt1, on streptozotocin (STZ)-induced diabetes in mice. RESEARCH DESIGN AND METHODS: Male C57BL/6 mice were administered with three different doses of STZ (65, 75, and 100 mg/kg BW) alone or in combination with subsequent high-fat feeding. The mice were treated with isonicotinamide (250 mg/kg BW/day) or phosphate-buffered saline for 10 days. The effects of isonicotinamide on STZ-induced diabetes were assessed by blood glucose levels, glucose tolerance test, and immunohistochemistry. RESULTS: Isonicotinamide effectively prevented hyperglycemia induced by higher doses of STZ (75 and 100mg/kg BW) alone and low-dose STZ (65 mg/kg BW) followed by 6-week high-fat diet in mice. The protective effects of isonicotinamide were associated with decreased apoptosis of β-cells and reductions in both insulin content and insulin-positive area in the pancreas of STZ-administered mice. In addition, isonicotinamide inhibited STZ-induced apoptosis in cultured isolated islets. CONCLUSIONS: These data clearly demonstrate that isonicotinamide exerts anti-diabetogenic effects by preventing β-cell damage after STZ administration. These findings warrant further investigations on the protective effects of isonicotinamide and related compounds against β-cell damage in diabetes.
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