Physiological Consequences of Phasic Insulin Release in the Normal Animal

Abstract

The dose-response relationship between the hepatic sinusoidal insulin level and glucose production by the liver is such that a half-maximally effective concentration is at or slightly below the hormone levels seen basally after an overnight fast. In the normal individual, the direct effect of the hormone on the hepatocyte is far more important in restraining glucose production than its indirect effect mediated via a suppression of lipolysis. Because insulin regulates the liver in a direct fashion, its effect occurs within several minutes. Thus, the speed with which insulin works and the sensitivity of the liver to it predict that first-phase insulin release should have a significant effect in quickly suppressing hepatic glucose production. On the other hand, nonhepatic tissues are much less sensitive to insulin and respond slowly as a result of the need for insulin to cross the endothelial barrier. As a result, first-phase insulin is unlikely to significantly alter peripheral glucose disposal. Simulation studies in humans and dogs in which the effects of first-phase insulin were simulated confirmed the aforementioned predictions. In addition, they confirmed the ability of second-phase insulin release to have significant effects on both glucose production and utilization. Diabetes 51 (Suppl. 1):S103-S108, 2002 I nsulin plays a key role in glucose homeostasis by virtue of its actions on liver, muscle, and fat. In the liver, it has a sensitive inhibitory effect on glucose production. If one examines data from experiments in the human (1) and the dog (2), it is evident that the half-maximally effective liver sinusoidal insulin concentration is slightly below the insulin level evident within the sinusoids after an overnight fast (Fig. 1). Likewise, it is clear that a threefold increase in insulin above the basal level can almost completely inhibit hepatic glucose release. Thus, the dose-response curve relating insulin to glucose production by the liver is such that small changes in the plasma insulin level up or down can have marked effects on hepatic glucose output. This would predict that first-phase insulin release should have a significant impact on glucose production by the liver.The question of whether insulin inhibits glucose produc- The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris. FIG. 1. A:Relationship between the liver sinusoidal insulin level and net hepatic glucose output (NHGO) in overnight fasted conscious dogs maintained on a pancreatic clamp. The sinusoidal insulin level existing in blood as it enters the sinusoids was calculated knowing the arterial and portal vein insulin levels and hepatic arterial and portal vein blood flows. Euglycemia existed for all but the 0 insulin point. That value represents NHGO at 15 min after insulin deficiency when hyperglycemia was mild (ϳ25 mg/dl). Glucagon was clamped at a basal value in all studies. A is reprinted with permission from Cherrington (2). B: The relationship between the e...

Suppression of Hepatic Glucose Production by Human Neutrophil α-Defensins through a Signaling Pathway Distinct from Insulin

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First-phase insulin secretion: does it exist in real life? Considerations on shape and function

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