Zinc Finger Protein ZBTB20Regulates Insulin Secretion By Islet β Cells Through Fructose-1,6-Bisphosphatase1

Tightly controlled insulin secretion by pancreatic β-cells is critical to themaintenance of glucose homeostasis, the dysfunction of which is a central component ofthe pathogenesis of type2diabetes. However, the regulatory mechanism of β-cellsphysiological and pathological process of β-cell is still largely unknown.Fructose1,6-bisphosphatase (FBPase) is a highly regulated, rate-limiting enzymecatalyzing the third to last step in gluconeogenesis. It has liver and muscle, two distinctisoenzymes in mammals, namely fructose1,6-bisphosphate (FBP)-1and FBP2,respectively. Coupled with PFK, FBPase controls the futile recycling betweenfructose-6-phosphate and fructose-1,6-bisphosphate, and the glycolytic/gluconeogenicflux. Glucose is the major secretagogue for insulin secretion. Under normalcircumstances, β-cells can precisely sense glucose stimulation and accordingly adjustinsulin secretion using a metabolism-secretion coupling system. However, thephysiological significance of FBPase underlying this system is yet not established.In the first part of the paper，we studied the physiological role of FBPase in β-cells.We found that liver FBPase (FBP1) mRNA is expressed at considerable levels in mouseislets under physiological conditions. Down-expression of FBP1in β-cells leads toaugmented glucose-stimulated insulin secretion (GSIS), while over-expression of FBP1leads to the opposite results. Pharmacological inhibition of endogenouslyexpressed-F BPase inβ-cells can increase their glucose use and cellular ATP to ADPratios, leading to augmented GSIS in vitro. Administration of MB06322to selectivelyinhibit FBPase activity in vivo significantly potentiates GSIS and enhances glucosetolerance. Our researches demonstrate that FBP1is a critical regulator of β-cellscontrolling glucose sensing and insulin secretion.In our previous studies, we identified Zinc finger and BTB domain-containingprotein20(ZBTB20) plays an essential role in glucose homeostasis, ZBTB20whole-body deletion mice display serious hypoglycemia. Given the important role ofβ-cells in glucose metabolism, during the following part of the paper, we used the Cre-loxP system to generate β cell-specific ZBTB20knockout (β-ZB20KO) mice tofurther investigate the function of ZBTB20in regulating β-cells biology and theunderlying mechanism.Comparing to the control mice, the β-ZB20KO mice had normal development ofβ-cells but had hyperglycemia, hypoinsulinemia, glucose intolerance, and impairedglucose-stimulated insulin secretion. Islets isolated from these mice had impaired glucosemetabolism, adenosine triphosphate production, and insulin secretion after glucosestimulation in vitro, although insulin secretion returned to normal levels in the presenceof KCl. ZBTB20knockdown with small interfering RNAs impaired glucose-stimulatedinsulin secretion in the β cell line MIN6. Expression of Fbp1was up-regulated in β-cellswith ZBTB20knockout or knockdown; impairments to glucose-stimulated insulinsecretion were restored by inhibition of FBPase activity. ZBTB20was recruited to theFbp1promoter and repressed its transcription in β-cells.Taken together, our studies reveal that FBP1plays an important role in β-cellscontrolling glucose sensing and insulin secretion. Zinc finger protein ZBTB20regulatesthe insulin secretion through modulating the FBP1gene expression, which may representa novel target for the treatment of Diabetes.