The physiological reasons why salmonids show glucose intolerance are unclear. In mammals, rapid clearance of a glucose load is mainly achieved through insulin-mediated inhibition of hepatic glucose production ( Ra) and stimulation of glucose disposal ( Rd), but the effects of insulin on Ra and Rd glucose have never been measured in fish. The goal of this study was to characterize the impact of insulin on the glucose kinetics of rainbow trout in vivo. Glucose fluxes were measured by continuous infusion of [6-3H]glucose before and during 4 h of insulin administration. The phosphorylated form of the key signaling proteins Akt and S6 in the insulin cascade were also examined, confirming activation of this pathway in muscle but not liver. Results show that insulin inhibits trout Rd glucose from 8.6 ± 0.6 to 5.4 ± 0.5 µmol kg−1 min−1: the opposite effect than classically seen in mammals. Such a different response may be explained by the contrasting effects of insulin on gluco/hexokinases of trout versus mammals. Insulin also reduced trout Ra from 8.5 ± 0.7 to 4.8 ± 0.6 µmol·kg−1·min−1, whereas it can almost completely suppresses Ra in mammals. The partial inhibition of Ra glucose may be because insulin only affects gluconeogenesis but not glycogen breakdown in trout. The small mismatch between the responses to insulin for Rd (−37%) and Ra glucose (−43%) gives trout a very limited capacity to decrease glycemia. We conclude that the glucose intolerance of rainbow trout can be explained by the inhibiting effect of insulin on glucose disposal.

Glucagon increases fish glycemia, but how it affects glucose fluxes in vivo has never been characterized. The goal of this study was to test the hypothesis that glucagon stimulates hepatic glucose production (Ra) and inhibits disposal (Rd) of rainbow trout. Changes in the mRNA abundance of key proteins involved in glycolysis, gluconeogenesis, and glycogen breakdown were also monitored. Results show that glucagon increases glycemia (+38%) by causing a temporary mismatch between Ra and Rd before both fluxes converge below baseline (-17%). A novel aspect of the regulation of trout gluconeogenesis is also demonstrated: the completely different effects of glucagon on the expression of three Pepck isoforms (stimulation of pck1, inhibition of pck2a, and no response of pck2b). Glycogen phosphorylase was modulated differently among tissues, and muscle upregulated pygb and downregulated pygm. Glucagon failed to activate the cAMP-dependent protein kinase or FoxO1 signalling cascades. We conclude that trout hyperglycemia results from the combination of two responses: (i) an increase in Ra glucose induced by the stimulation of gluconeogenesis through transcriptional activation of pck1 (and possibly glycogen phosphorylase), and (ii) a decrease in Rd glucose via inhibition of glycogen synthase and glycolysis. The observed decrease in glucose fluxes after 4 h of glucagon administration may be caused by a counterregulatory response of insulin, potentially linked to the decrease in pygm transcript abundance. Overall, however, these integrated effects of glucagon only lead to modest changes in glucose fluxes that partly explain why trout seem to be unable to control glycemia very tightly.

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