Fructose-1,6-bisphosphatase regulates glucose-stimulated insulin secretion of mouse pancreatic beta-cells.
Pancreatic β-cells can precisely sense glucose stimulation and accordingly adjust their insulin secretion. Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme, but its physiological significance in β-cells is not established. Here we determined its physiological role in regulating glucose sensing and insulin secretion of β-cells. Considerable FBPase mRNA was detected in normal mouse islets and β-cell lines, although their protein levels appeared to be quite low. Down-regulation of FBP1 in MIN6 cells by small interfering RNA could enhance the glucose-stimulated insulin secretion (GSIS), whereas FBP1-overexpressing MIN6 cells exhibited decreased GSIS. Inhibition of FBPase activity in islet β-cells by its specific inhibitor MB05032 led to significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro. Pretreatment of mice with the MB05032 prodrug MB06322 could potentiate GSIS in vivo and improve their glucose tolerance. Therefore, FBPase plays an important role in regulating glucose sensing and insulin secretion of β-cells and serves a promising target for diabetes treatment.
Zhang
Ye
Y
Center for Obesity & Diabetes Research and Innovation, Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Xie
Zhifang
Z
Zhou
Guangdi
G
Zhang
Hai
H
Lu
Jian
J
Zhang
Weiping J
WJ
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
C553230:(5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphonic acid; D004791:Enzyme Inhibitors; D007328:Insulin; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D034741:RNA, Small Interfering; D013844:Thiazoles; C502805:N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester; D006597:Fructose-Bisphosphatase; D005947:Glucose; D000409:Alanine