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
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.