Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.

Basu, Ananda; Alzaid, Aus; Dinneen, Seán F.; Caumo, Andrea; Cobelli, Claudio; Rizza, Robert A.

doi:10.1172/jci118678

Cited by 84 publications

(68 citation statements)

References 54 publications

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“…However, it took longer for glucose to return to preprandial concentrations, resulting in higher glucose concentrations at 2 h in subjects with NFG/IGT. Since insulin secretion was relatively intact in these individuals, whereas insulin action was markedly decreased, this postprandial pattern of change in glucose concentrations (and the OGTT pattern, since that is why subjects in this group were classified as having IGT) is consistent with previous reports indicating that a delay and decrease in early insulin secretion results in a higher peak glucose concentration, whereas a defect in insulin action results in an increased duration of hyperglycemia (38,39). Of interest, subjects …”

Section: Pathogenesis Of Pre-diabetessupporting

confidence: 88%

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: Pathogenesis Of Pre-diabetessupporting

confidence: 88%

Pathogenesis of Pre-Diabetes

et al. 2006

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“…The increase in energy expenditure could suggest that restoration of early phase insulin secretion is of importance in activating the membrane bound Na + -K + -ATPase and/or by stimulating the sympathetic nervous system. By using a more sophisticated technique, similar results were found [15]. Non-diabetic subjects were studied during somatostatin inhibition of endogenous insulin secre-M4 S. Del Prato: Loss of early insulin secretion leads to postprandial hyperglycaemia tion, while exogenous insulin was infused so as to mimic postprandial insulin profiles of a typical healthy or diabetic subject.…”

Section: Early-phase Insulin Secretion and Glucose Homeostasismentioning

confidence: 64%

Loss of early insulin secretion leads to postprandial hyperglycaemia

2003

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Aims/Hypothesis. A loss of early-phase insulin response is common in Type 2 diabetic patients and in people with impaired glucose metabolism. It is hypothesized that this alteration is not simply a marker for the risk of developing diabetes, rather it is a an important pathogenetic mechanism causing excessive postprandial hyperglycaemia. Methods. Relevant literature on the epidemiology, physiopathology, and therapeutic intervention related to loss of early insulin secretion and postprandial hyperglycaemia has been analysed. Results. In response to intravenous glucose, insulin secretion is biphasic. This behaviour translates as a rapid release of insulin into the blood stream in response to the ingestion of carbohydrates or a mixed meal. The rapid increase in portal insulin concentration and the avid binding of the hormone to its receptor on liver cell membranes, account for a prompt suppression of endogenous glucose production and reduction of the rate of increase in plasma glucose concentrations. This has been supported by experimental studies carried out in both animals and humans: the selective abolition of early insulin secretion in healthy subjects results in impaired glucose tolerance, excessive glucose excursions, and possible hampering of the thermic effects of ingested carbohydrates. In nondiabetic subjects, the loss of early insulin secretion is a determinant for developing diabetes. The critical role of the early-phase insulin response in determining postprandial hyperglycaemia, is supported by an amelioration of glucose tolerance by restoring the acute rise in plasma insulin concentrations after the ingestion of both glucose and a mixed meal. This amelioration in plasma glucose profile can prevent late hyperglycaemia and hyperinsulinaemia. Conclusion/interpretation. Therapeutic approaches aimed at restoring a physiological pattern of insulin secretion could prove effective in reducing postprandial glucose excursions particularly in the early stage of Type 2 diabetes. [Diabetologia (2003)

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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: 80%

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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Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.

Cited by 84 publications

References 54 publications

Pathogenesis of Pre-Diabetes

Pathogenesis of Pre-Diabetes

Loss of early insulin secretion leads to postprandial hyperglycaemia

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

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