Regulation of endogenous glucose production after a mixed meal in type 2 diabetes

Singhal, Parag; Caumo, Andrea; Carey, Peter; Cobelli, Claudio; Taylor, Roy

doi:10.1152/ajpendo.00424.2001

Cited by 67 publications

(60 citation statements)

References 70 publications

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“…An intravenous infusion of [6-3 H]glucose was started at the same time and infused in a pattern that minimized the change in the ratio of plasma tracer (i.e., [6-3 H]glucose) to plasma meal tracee (i.e., [1-13 C]glucose). In addition, the [6,6-2 H 2 ]glucose infusion was varied in a manner mimicking the anticipated pattern of change of EGP, thereby also minimizing the change in the ratio of plasma tracer (i.e., [6,6-2 H 2 ]glucose) to plasma tracee (i.e., concentration of endogenous plasma glucose), as previously described (18,27). Analytical techniques.…”

Section: Methodsmentioning

confidence: 99%

Pathogenesis of Pre-Diabetes

et al. 2006

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Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R d ) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S i ) and insulin-stimulated glucose disposal (S i *) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R d since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG. Diabetes 55: 3536 -3549, 2006

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Section: Methodsmentioning

confidence: 99%

Pathogenesis of Pre-Diabetes

et al. 2006

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“…The response is proportionate to the prevailing glucose concentration and does not appear to be influenced by the antecedent pattern of change in glucose. These data emphasize that alterations in EGP in various disease states such as diabetes need to be interpreted in light of the prevailing glucose concentrations, and suppression of EGP by glucose can compensate, in part or in whole, for a defect in insulin availability or action (4,13,19,20,22,29).…”

Section: Discussionmentioning

confidence: 82%

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

Vella¹,

Reed²,

Charkoudian³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Glucoseinduced suppression of endogenous glucose production: dynamic response to differing glucose profiles. Am J Physiol Endocrinol Metab 285: E25-E30, 2003. First published March 11, 2003 10.1152/ajpendo.00530.2002To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon (ϳ130 ng/l) and insulin (ϳ65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at ϳ5.3 mM (euglycemia), ϳ7.0 mM (sustained hyperglycemia; n ϭ 10), or varied to create a "postprandial" profile (profile; n ϭ 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 Ϯ 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 Ϯ 1.21 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 . On the profile study day, glucose increased to a peak of 11.2 Ϯ 0.5 mmol/l, and EGP decreased to a nadir of 6.79 Ϯ 2.54 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 Ϯ 2.45 vs. 12.11 Ϯ 3.21 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (Ϫ1,952 Ϯ 204 vs. Ϫ1,922 Ϯ 246 mmol ⅐ kg Ϫ1 ⅐ 6 h Ϫ1 ). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP. glucose effectiveness; glucose turnover ENDOGENOUS GLUCOSE PRODUCTION (EGP) is regulated by plasma glucose and insulin concentrations (2,11,12,22,25,27). In the presence of a constant glucose concentration, insulin suppresses glucose production by both direct and indirect mechanisms (11). The direct effects are mediated by activation of hepatic insulin receptors (33). The indirect effects are mediated by multiple factors, including inhibition of glucagon secretion, inhibition of lipolysis, and reduction in the concentration of gluconeogenic precursors (11). Although a change in plasma insulin concentration is accompanied by a reciprocal change in EGP, the effects of insulin are delayed, with suppression lagging behind an increase in plasma insulin and rises in EGP lagging behind a fall in plasma insulin (10). This presumably occurs because of the time required for insulin to activate its receptor and because of the slow rate of equilibration between plasma and muscle/adipose interstitial insulin concentrations (1).The kinetic response of EGP to a change in glucose concentration is less well defined. In the presence of constant insulin concentrations, clamping glucose at a progressively higher concentration results in a progressive decrease in steady-state rates of EGP (2,20,22). Furthermore, EGP decreases when glucose concentration is increased in a pattern mimicking that commonly o...

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“…Using a similar dynamic tracer methodology, we have previously reported similar initial postprandial suppression of EGP in subjects with type 2 diabetes compared with matched controls (43). The conventional dual tracer approach with fixed priming and fixed-rate tracer infusion has been extensively used to measure EGP and documents subnormal suppression of EGP in type 2 diabetes (44,45).…”

Section: Pioglitazone and Egpmentioning

confidence: 82%

Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

et al. 2008

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OBJECTIVE-Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes.RESEARCH DESIGN AND METHODS-Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by 1 H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging.RESULTS-Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 Ϯ 1.0 vs. 12.2 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 Ϯ 0.25 vs. 1.26 Ϯ 0.30 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001). Hepatic triglyceride content decreased by ϳ50% (P ϭ 0.03), and muscle (anterior tibialis) triglyceride content decreased by ϳ55% (P ϭ 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r ϭ 0.64, P ϭ 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r ϭ Ϫ0.63, P ϭ 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. H epatic triglyceride has been shown to be strongly associated with hepatic insulin resistance in type 2 diabetes (1-3). The exact mechanism by which hepatic triglyceride induces hepatic insulin resistance is unknown but is thought to relate to accumulation of intracellular fatty acid metabolites and consequent activation of a serine kinase cascade and induction of cellular insulin resistance (4). Reduction in hepatic triglyceride content by moderate weight reduction normalizes rates of basal endogenous glucose production (EGP) in patients with type 2 diabetes (2). Hepatic insulin resistance is also associated with impaired postprandial suppression of EGP in type 2 diabetes, but the effect of reduction of hepatic triglyceride content on postprandial suppression of EGP in type 2 diabetes is unknown. CONCLUSIONS-ReductionThiazolidinediones, such as pioglitazone, possess insulin-sensitizing properties and have been shown to decrease hepatic triglyceride content in type 2 diabetes (5). Because thiazolidinediones have been shown to reduce both fasting and postprandial glucose levels (6,7), we hypothesized that pioglitazone treatment in type 2 diabetes would reduce hepatic triglyceride content and consequently reduce basal and postprandial EGP. In addition, visceral fat has also been implicated in hepatic insulin resistance, and pioglitazone has been reported to decrease visceral fat content (8). The effect of this on EGP requires definition.To test our hypothesis, we used noninvasive 1 H magnetic resonance spectrosc...

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Regulation of endogenous glucose production after a mixed meal in type 2 diabetes

Cited by 67 publications

References 70 publications

Pathogenesis of Pre-Diabetes

Pathogenesis of Pre-Diabetes

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

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