Physiologic action of glucagon on liver glucose metabolism - PubMed (original) (raw)

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Physiologic action of glucagon on liver glucose metabolism

C J Ramnanan et al. Diabetes Obes Metab. 2011 Oct.

Abstract

Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion.

© 2011 Blackwell Publishing Ltd.

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Conflict of interest statement

Conflict of Interests

The authors declare no conflicts of interests.

Figures

Figure 1

Figure 1

The effect of a selective rise in plasma glucagon brought about in conscious overnight fasted dogs maintained with a pancreatic clamp (somatostatin infusion, basal portal vein insulin replacement). This group was compared to control animals (somatostatin infusion, basal portal vein insulin and glucagon infusion) that were infused peripherally with glucose to match the glycemic level of the ‘high glucagon’ group. Net GLY = net hepatic glycogenolytic flux; GNG flux = gluconeogenic flux. Filled symbols refer to the response to a rise in glucagon infusion. Open symbols refer to the hyperglycaemic control studies. Adapted with permission from Ref. [1].

Figure 2

Figure 2

The effect of a selective fall in plasma glucagon brought about in conscious overnight fasted dogs maintained with a pancreatic clamp (somatostatin infusion, basal portal vein insulin infusion). The control group (open symbols) was maintained on basal infusion of insulin and glucagon intraportally. In the test group (filled symbols), glucagon infusion was stopped at 0 min and peripheral glucose infusion was required to maintain euglycemia. Net GLY = net hepatic glycogenolytic flux; GNG flux = gluconeogenic flux. Adapted with permission from Ref. [1].

Figure 3

Figure 3

Dose response relationship between the hepatic sinusoidal glucagon level and the initial (15 min) increase in glucose production in humans and dogs with insulin clamped at a basal value. Hepatic sinusoidal glucagon concentrations in the dog were calculated from measured arterial and portal vein glucagon concentrations and the measured rates of blood flow in these vessels. In humans the concentrations were extrapolated from arterial plasma glucagon levels. Adapted with permission from Ref. [1].

Figure 4

Figure 4

The impact of plasma glucagon on net hepatic glucose uptake under hyperglycemic-hyperinsulinemic conditions in conscious 42 h fasted dogs. At 0 min, a pancreatic clamp was initiated (infusion of somatostatin and basal amounts of insulin and glucagon into the portal vein). Hyperglycemia was brought about using peripheral vein glucose infusion beginning at 0 min. At 90 min (hormone manipulation period), the portal vein infusion of insulin was increased (~fourfold) and glucose was infused intraportally (22 μmol/kg/min) to mimic a meal response. At the same time, the portal vein glucagon infusion was altered to create either an elevated or low glucagon level. Adapted with permission from Ref. [16].

Figure 5

Figure 5

The role of glucagon in defense of a low blood sugar. Pancreatic clamps (somatostatin + portal vein insulin infusion at a 20-fold basal rate) were used in two groups of conscious overnight fasted dogs. In one group the normal glucagon response to hypoglycemia was reproduced using a variable portal vein glucagon infusion. In the other glucagon was kept basal. Adapted with permission from Ref. [22].

Figure 6

Figure 6

The role of glucagon in support of an exercise-induced increase in glucose utilization. Pancreatic clamps were used in two groups of conscious overnight fasted dogs (somatostatin infusion + replacement of insulin and glucagon via the portal vein). After a basal period (−40 to 0 min), treadmill exercise was initiated and the insulin infusion was decreased (to mimic the insulin level that would normally occur during exercise). Glucagon infusion was either increased (to mimic the glucagon level that would normally occur in response to exercise) or kept basal. Adapted with permission from Ref. [24].

Figure 7

Figure 7

The impact of normalizing plasma insulin and glucagon in pancreatectomized dogs withdrawn from insulin and fasted overnight. Adapted with permission from Ref. [29].

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