Characterization Of Metabolic Phenotypes Of Pancreatic Islet Specific TP53-induced Glycolysis And Apoptosis Regulator(TIGAR)Knockout Mice

BACGROUND Tp53-induced glycolysis and apoptosis regulator(TIGAR)functions as a fructose-2,6-bisphosphatase(Fru-2,6-BPase),decreasing glycolytic flux and promoting pentose phosphate pathway to increase NADPH production against reactive oxygen species(ROS),thus plays an important role in redox homeostasis and glucose metabolism.Pancreatic β-cells are sensitive to the change of glucose levels,and exert insulin secretion function under the control of intracellular glucose metabolism.We thus hypothesized that pancreatic TIGAR may exert important roles in pancreatic β-cell function and survival via regulating glucose metabolism and redox homeostasis.OBJECTIVE To investigate the role of TIGAR in regulating mouse metabolic phenotypes under physiological and pathological conditions,thus to clarify its roles in pancreatic islet function and survival.MARERIALS AND METHODS Pancreatic islet-specific TIGAR conditional knockout mice were generated using Cre-LoxP strategy.Diabetic model was induced by single high dose streptozotocin(STZ)injection.Obese model was induced by high-fat diet feeding.Body weight and random blood glucose was monitored weekly.Insulin tolerance,glucose tolerance test was conducted.Oxygen consumption,carbondioxide production,activity,food intake,energy expenditure and heat production were detected by CLAMS.Results Random blood glucose,body weight,glucose tolerance and Insulin tolerance were of no difference between pancreatic islet-specific TIGAR conditional knockout mice and control mice under physiological conditions.In STZ induced diabetes model,the blood glucose and diabetic morbidity of both female mice and male mice were significantly lower in pancreatic islet-specific TIGAR conditional knockout mice compared to that of the control group.In high-fat diet induced obese model,compared to the control mice,pancreatic islet-specific TIGAR conditional knockout mice resulted in a decreased body weight against high fat diet induce obesity in both female and male mice.In male but not female mice,blood glucose in pancreatic islet-specific TIGAR conditional knockout mice was lower than that in control mice.Compared to the control mice,pancreatic islet-specific TIGAR conditional knockout mice had improved insulin resistance and glucose tolerance.For energy metabolic measurements,oxygen consumption,carbon dioxide production,activity and energy expenditure of pancreatic islet-specific TIGAR conditional knockout mice were increased.No significant difference in food intake was detected.Conclusions Pancreatic islet-specific TIGAR conditional knockout reduced the high blood glucose and diabetic morbidity induced by STZ.Pancreatic islet-specific TIGAR conditional knockout ameliorated body weight gain induced by high fat diet,improved the energy metabolism rate,as well as the glucose tolerance and insulin resistance.Pancreatic islet-specific TIGAR conditional knockout protects islet cells and increases energy metabolism,and may plays an important role in the treatment of obesity and diabetes.