Biphasic insulin secretion during intravenous glucose tolerance test promotes optimal interstitial insulin profile.

Getty, Lisa; Hamilton-Wessler, Marianthe; Ader, Marilyn; Dea, Melvin K.; Bergman, Richard N.

doi:10.2337/diabetes.47.12.1941

Cited by 41 publications

(34 citation statements)

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“…This prime was calculated to raise the insulin concentration to a theoretical peak of ϳ1,600 U/ml. Previous studies have shown that R d is maximal at plasma insulin of ϳ200 -300 U/ml in dogs and humans (43)(44)(45). This may explain the rapid stabilization of GIR in studies using the 300-compared with the 16-mU/kg prime in 18-h-fasted mice (Fig.…”

Section: Discussionmentioning

confidence: 63%

Considerations in the Design of Hyperinsulinemic-Euglycemic Clamps in the Conscious Mouse

et al. 2006

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Despite increased use of the hyperinsulinemic-euglycemic clamp to study insulin action in mice, the effects of experimental parameters on the results obtained have not been addressed. In our studies, we determined the influences of sampling sites, fasting duration, and insulin delivery on results obtained from clamps in conscious mice. Carotid artery and jugular vein catheters were implanted in C57BL/6J mice (n ‫؍‬ 6 -10/group) fed a normal diet for sampling and infusions. After a 5-day recovery period, mice underwent a 120-min clamp (2.5-mU ⅐ kg ؊1 ⅐ min ؊1 insulin infusion; ϳ120 -130 mg/dl glucose) while receiving T he hyperinsulinemic-euglycemic clamp, or insulin clamp, has been referred to as the "gold standard" for measuring insulin sensitivity in vivo. In this procedure, insulin is administered to raise the insulin concentration while glucose is infused to maintain euglycemia. The glucose infusion rate (GIR) needed to maintain euglycemia is a reflection of insulin action. When radioisotopes, such as [ 3 H]glucose, are infused in conjunction with an insulin clamp, endogenous glucose appearance (endoR a ) and glucose disappearance (R d ) can be measured, allowing for the differentiation between hepatic and peripheral insulin sensitivity. Given the prominent role of insulin resistance in the development of various metabolic disorders, the insulin clamp is a useful tool in basic and clinical research.With the development of transgenic technologies in the mouse, the miniaturization of the insulin clamp for use in this animal has been an important advancement. It is thus surprising that in the Ͼ10 years since its first use in the mouse, there has been no assessment of the insulin clamp methodology in this animal. A literature search for the period 2003-2004 found 25 publications using the insulin clamp in conscious mice (1-25). In these studies, the various protocols that were used differed in blood sampling sites, insulin and tracer infusion methods, and fasting duration. For example, 44% of these studies described the sampling site as the cut tail, whereas 12% used an arterial catheter. The remaining 44% did not indicate or reference a study indicating a sampling site. In a similar finding, 48% of these studies used mice fasted overnight (for 16 -18 h), 40% used mice fasted for 5-6 h, and 12% used other fasting durations. Finally, 40% of these clamp studies were performed without a priming dose of insulin, whereas 48% administered a prime equal to the total insulin infused at a constant rate. The remaining 12% used priming doses ranging between these two extremes. Given this diversity of approaches, it is crucial to determine how experimental parameters influence clamp studies in the mouse to better compare results obtained by different investigators. Using common clamp protocols as guidelines (18,26 -28), three parameters were compared: blood sampling sites, fasting duration, and insulin infusion (prime and constant rate) methods. RESEARCH DESIGN AND METHODSAll procedures were approved by the Vanderbilt Anima...

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Section: Discussionmentioning

confidence: 63%

Considerations in the Design of Hyperinsulinemic-Euglycemic Clamps in the Conscious Mouse

et al. 2006

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“…A8). A quick but short first-phase insulin pattern obviates the usual delay in insulin action (seen during glucose clamp experiments, for example), resulting in a rapid and profound increase in glucose disposal (68). It is tempting to hypothesize that the first phase of insulin release was naturally selected to accord the most rapid glucose disposal after nutrient ingestion and to limit the postprandial glycemia.…”

Section: Branch #2: Transendothelial Transport and Insulin Resistancementioning

confidence: 99%

Orchestration of Glucose Homeostasis

Bergman

2007

Diabetes

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“…First-phase insulin release can serve an important function in muscle and fat, but only when it is large and when its contribution to the overall increase in insulin is of the order of Ն50% (16). Getty et al (16) have shown that a large first-phase insulin release allows the interstitial insulin level to rise more rapidly than would otherwise be the case. Therefore, even though insulin must first cross the endothelial barrier to act, muscle can be called upon more quickly to deal with the metabolic challenge at hand.…”

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confidence: 99%

Physiological Consequences of Phasic Insulin Release in the Normal Animal

et al. 2002

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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...

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Biphasic insulin secretion during intravenous glucose tolerance test promotes optimal interstitial insulin profile.

Cited by 41 publications

References 0 publications

Considerations in the Design of Hyperinsulinemic-Euglycemic Clamps in the Conscious Mouse

Considerations in the Design of Hyperinsulinemic-Euglycemic Clamps in the Conscious Mouse

Orchestration of Glucose Homeostasis

Physiological Consequences of Phasic Insulin Release in the Normal Animal

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