Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced β-cell damage and diabetes in mice.
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.


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.
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, United States.
Makiko
M
Fukaya
Yoshiaki
Y
Tamura
Yuko
Y
Chiba
Toshihiro
T
Tanioka
Ji
J
Mao
Yoko
Y
Inoue
Marina
M
Yamada
Christian
C
Waeber
Yukari
Y
Ido-Kitamura
Tadahiro
T
Kitamura
Masao
M
Kaneki
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D059305:Diet, High-Fat / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000008:administration & dosage*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D013311:Streptozocin / Q000008:administration & dosage
D007004:Hypoglycemic Agents; D009536:Niacinamide; C027681:isonicotinamide; D013311:Streptozocin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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