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.