Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog.

Pagliassotti, Michael J.; Holste, Linda; Moore, Mary Courtney; Neal, Doss W.; Cherrington, Alan D.

doi:10.1172/jci118410

Cited by 123 publications

(200 citation statements)

References 46 publications

(63 reference statements)

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“…The mechanism of the preservation of normal glucose tolerance by the early insulin response probably involves insulin's regulation of liver glucose metabolism, as recently proposed by Teff (3). Maximal postprandial hepatic glucose uptake has been shown to be achieved at 15 min after meal ingestion in dogs (47); if portal insulin delivery is retarded during the initial minutes after meal intake, impairment of hepatic glucose uptake with exaggerated glycemia at 25-45 min after meal intake would be expected, as observed in the present study. However, the time course of the changes in hepatic glucose flux after meal ingestion in humans has not been established.…”

Section: Discussionsupporting

confidence: 71%

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Åhrén

Holst²

2001

Diabetes

254

176

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We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 ؎ 0.4 years; BMI 27.7 ؎ 1.7 kg/m 2 ). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 ؎ 11% by trimethaphan (P ‫؍‬ 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (⌬glucose ‫؍‬ -1.27 ؎ 0.5 [with saline] vs. 0.1 ؎ 0.4 mmol/l [with trimethaphan]; P ‫؍‬ 0.008). This reduction at 25-60 min in glucose levels correlated significantly to the 10-min insulin response (r ‫؍‬ 0.65, P ‫؍‬ 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 ؎ 9% (P ‫؍‬ 0.045), which was lower than the reduction with trimethaphan (P ‫؍‬ 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.

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Section: Discussionsupporting

confidence: 71%

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Åhrén

Holst²

2001

Diabetes

254

176

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“…In contrast to the action of insulin, the effect of portal glucose delivery (the "portal" signal) on net hepatic glucose uptake was rapid, reaching a peak net hepatic glucose uptake (2.4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) within 15 min. Perhaps in the presence of the portal signal, insulin's action is more rapid, as suggested by our data (19). The inability of insulin alone to rapidly activate glucose uptake by the liver suggests that first-phase insulin might not have a significant impact on the liver's ability to store glucose.…”

Section: Figmentioning

confidence: 69%

“…In that regard, we carried out a study (19) in which we created hyperglycemia (ϳ220 mg/dl) in the conscious dog in the presence of basal insulin and glucagon levels (maintained with a pancreatic clamp). After 2 h of selective hyperglycemia, which suppressed net hepatic glucose output to zero, the insulin level was increased fourfold or left at a basal value.…”

mentioning

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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“…In our study we can assume that the U 13 C 6 glucose appears in the systemic circulation slightly later than any appearance of glucose in the portal system, indicating a positive portal arterial glucose concentration gradient at the time of inducing hypoglycaemia as the tracer levels in the circulation are increasing. Portal-arterial glucose gradients have been implicated in the control of net hepatic glucose uptake [38,39,40], food intake [41], and recently tissue glucose utilisation [42]. Alternatively, any effects we observed could have been a direct result of changes in stimulus to the portal vein glucose sensors themselves.…”

Section: Discussionmentioning

confidence: 91%

The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man

et al. 2002

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Aims/hypothesis. The role of glucose sensing cells in the human hepatic portal system in the initiation of the neuroendocrine responses to acute hypoglycaemia is not known. We investigated the effect of raising blood glucose concentrations in the hepatic-portal vein on neurohumoral responses during induction of systemic hypoglycaemia in nine healthy male volunteers. Methods. Each subject received an insulin infusion (3 mU·kg -1 ·min -1 ) on two occasions, in random order. Variable rate glucose infusion was used to maintain plasma glucose at 5 mmol/l for 60 min, then 3.2 mmol/l for 60 min. At 20 min prior to hypoglycaemia, subjects drank 20 g of glucose in water or water sweetened with saccharin. In five of the volunteers, the oral glucose was labelled with U-13C6 glucose, which showed peak systemic glucose absorption between 90 and 110 min. Five volunteers also repeated the study with a euglycaemic clamp.Results. Oral glucose was associated with a reduction in the early adrenaline response to hypoglycaemia, the area under the curve from 90 to 110 min falling from 24.02±20.84 (means ± SD) to 15. vere hypoglycaemia during the pharmacological treatment of diabetes mellitus. The inability to generate or detect the warning symptoms of early hypoglycaemia puts diabetic patients at high risk of episodes of severe hypoglycaemia [1] and often the fear of hypoglycaemia limits the optimisation of glycaemic control [2]. Associated with loss of subjective awareness of hypoglycaemia is a lowering of the glucose concentration required to initiate the counterregulatory response to hypoglycaemia, as well as a reduction in the magnitude and intensity of the counterregulatory response at any given blood glucose concentration [3,4,5]. The speculation that these defects are principally the result of defective glucose sensing gains support from data showing similar changes in the neuroendocrine rePerception of a minor decrease in plasma glucose concentration and initiation of a counterregulatory response are essential factors in the defence against se-

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Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog.

Cited by 123 publications

References 46 publications

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Physiological Consequences of Phasic Insulin Release in the Normal Animal

The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man

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