Different roles of insulin receptor a and b in maintaining blood glucose homeostasis in zebrafish

Abstract An inability of insulin to signal glycolysis and gluconeogenesis would largely result in type 2 diabetes. In this study, the physiological roles of zebrafish insulin receptor a and b in maintaining blood glucose homeostasis were characterized. We observed that, though blood glucose in insra −/− fish and insrb −/− fish were comparable with the control siblings at 0 h postprandium (hpp), the most evident hyperglycemia have been observed in insra −/− fish from 1 hpp to 3 hpp. A mild increase of blood glucose in insrb −/− fish has been seen only at 1.5 hpp. The down-regulated expressions of glycolytic enzymes were observed in insra −/− fish and insrb −/− fish liver and muscle, together with the significantly decreased activities or concentrations of glycolytic enzymes. These results suggest that both Insra and Insrb were critical in glycolysis. Intriguingly, the up-regulated expressions of gluconeogenic enzymes, pck1 and g6pca.1 , along with the elevated enzyme activities, were observed in insra −/− fish liver at 1 hpp and 1.5 hpp. Compared with the control fish, the elevated plasma insulin and lowered phosphorylated AKT were observed in insra −/− fish and insrb −/− fish, suggesting that there is an insulin resistance in insra −/− fish and insrb −/− fish. The increased levels of both transcriptions of foxo1a and Foxo1a protein abundance in the insra −/− fish liver have been found. When insra −/− fish treated with the Foxo1 inhibitor, the postprandial blood glucose levels could be normalized, accompanied with the normalized expression levels and enzyme activities of both pck1 and g6pca.1 . Therefore, Insra and Insrb demonstrate a similar role in promoting glycolysis, but Insra is involved in inhibiting gluconeogenesis via down-regulating the expression of foxo1a . Our results indicate that Insra and Insrb exhibit diversified functions in maintaining glucose homeostasis in zebrafish.