Glucose metabolism during exercise in man: the role of insulin and glucagon in the regulation of hepatic glucose production and gluconeogenesis

Abstract

This study was designed to further characterize the role of insulin and glucagon in the regulation of glucose production and gluconeogenesis during a 2-h mild intensity exercise (40% VO2max) in 14 h fasted healthy male subjects. Endogenous insulin and glucagon secretions were suppressed by the infusion of somatostatin. The pancreatic hormones were replaced singly or in combination to match the hormonal concentrations observed during exercise in control subjects. Glucose turnover was determined by a tracer method using the stable isotope D-[2,3,4,6,6-2H]glucose. Gluconeogenesis was estimated by the simultaneous infusion of L-[1,2,3-13C]alanine to follow the conversion of alanine to glucose. Hepatic glucose production significantly increased from a resting rate of 12.1 +/- 0.2 to 27.6 +/- 1.4 mumol.kg-1.min-1 during exercise (p < 0.05). In the absence of glucagon, this increase in hepatic glucose production during exercise was totally abolished (p < 0.05). When insulin was made deficient, in the presence of glucagon, there was an overshoot in the increase in hepatic glucose production during exercise to 36.4 +/- 1.6 mumol.kg-1.min-1 (p < 0.05). The normal increase in hepatic glucose output during exercise was reproduced when both insulin and glucagon were replaced. Exercise increased gluconeogenesis by 47% above the resting level (p < 0.05). When glucagon was made deficient, in the absence or presence of insulin, this increase in gluconeogenesis was totally suppressed (p < 0.05). Furthermore, glucagon replacement during exercise in the absence of insulin resulted in a further increase in gluconeogenesis to 93% above resting value (p < 0.05). From these observations, it is concluded that during prolonged mild intensity exercise in healthy subjects, the rise in glucagon is essential for the increase in hepatic glucose production and the increase in gluconeogenesis. It is also suggested that the lower level of insulin during exercise still exerts a restraining effect on glucagon-stimulated glucose production and gluconeogenesis, thus preventing hyperglycemia.

Four grams of glucose

“…By combining isotopes and hepatic arterial-venous differences, glucagon was shown to be key to both the glycogenolytic and gluconeogenic responses to exercise (99). Studies (41,49,54,103) conducted in human subjects were consistent with those findings.…”

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

“…It could be argued that, despite the prevailing hyperinsulinaemic conditions, a preserved glucagon response to exercise could have accounted for the lack of differences in exercise-induced changes in liver glycogen content between groups. Indeed, a rise in glucagon is required during postabsorptive exercise for the full increment in hepatic glucose output [8,13]. On the contrary, it has been shown in patients with type 1 diabetes that, during exercise under fasting conditions, hepatic glucose output is comparable to that of controls, and this is despite higher circulating insulin concentrations and lower glucagon responses in the patient group [36].…”

“…Increases in both hepatic glycogenolysis and gluconeogenesis contribute to augmented hepatic glucose output during exercise, usually with a greater contribution from the former [5,7]. However, during prolonged exercise under fasting conditions a greater contribution of hepatic glucose output is derived from gluconeogenesis [8,9].…”

The physiological regulation of glucose flux into musclein vivo

“…The decline in insulin secretion potentiates the actions of glucagon (Lavoie et al, 1997;Lins et al, 1983;Wasserman et al, 1989c). Studies in animals (Wasserman et al, 1984;Wasserman et al, 1985;Wasserman et al, 1989b) and humans (Hirsch et al, 1991;Lavoie et al, 1997;Wolfe et al, 1986) demonstrate that the increase in glucagon is the primary stimulator of hepatic glucose production during exercise. The powerful effect of glucagon on hepatic glucose production was recently demonstrated by Berglund et al (Berglund et al, 2009).…”