Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man

Abstract

The present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220-240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7-12 ~tU/ml. Glucagon (1.5ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148 _+ 37 to 228 + 25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132 + 21 to 74 _+ 15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143 + 31 to-72.5 + 39 rag/ rain (p < 0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137 +_ 20 vs 151 + 60 rag/rain) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.

The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans.

“…This insulin concentration range is close to the half-maximally effective concentration for suppression of hepatic glucose production (22)(23)(24). Since hepatic accumulation of glycogen might be expected to reflect glucose uptake by the liver (1), the present results are supported by reports on stimulation of net splanchnic glucose uptake during hypoglucagonemia at low plasma insulin concentrations in dogs (25) and healthy humans (26), but even at increased insulin levels in dogs (27).…”

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

“…Not only is the liver very sensitive to changes in plasma glucagon, it also responds rapidly, with a half-maximal activation time of only 8 minutes (27). Human studies, although less well controlled, confirmed that the observations made in the dog extend to man (22)(23)(24)(25)(28)(29)(30). Thus, it is evident that after an overnight fast, basal levels of glucagon drive resting glucose production, thereby allowing insulin to link hepatic glucose output to the body's need for glucose.…”

“…Glucagon also modulates hepatic glucose uptake (HGU) (28,31,32) and hepatic glycogen synthesis (33). A decrease in plasma glucagon has little effect on HGU in the presence of elevated insulin (31), but the effect can be quite marked when insulin is deficient (32), which has obvious implications for diabetes.…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…These beneficial effects of SST on glucose control were attributed to the ability of SST to suppress glucagon secretion (Liljenquist et al, 1979). Although it has not been directly studied, SST treatment may also improve insulin sensitivity by lowering elevated GH levels, which are known to impair insulin signaling (Takano et al, 2001;Hansen et al, 1986).…”