Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes

Højberg, Patricia V.; Zander, Mette; Vilsbøll, Tina; Knop, Filip K.; Krarup, Thure; Vølund, Aage; Holst, Jens J.; Madsbad, Sten

doi:10.1007/s00125-008-0943-x

Cited by 83 publications

(46 citation statements)

References 33 publications

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“…Note that in the present study insulin treatment and near-normalisation of blood glucose did not improve beta cell responsiveness to glucose alone. This result is in agreement with our previous study, and indicates that the absence of responsiveness to intravenous glucose is a fundamental beta cell defect in type 2 diabetic patients with diabetes of several years' duration [42].…”

Section: Discussionsupporting

confidence: 93%

“…In the participants with type 2 diabetes, a positive correlation between HbA 1c and DPP-IV was demonstrated [45]. Nevertheless, in a previous study the intact GLP-1 level did not differ before and after near-normalisation of blood glucose using aggressive insulin treatment when the same amount of GLP-1 was infused intravenously [42]. In another study we have demonstrated similar elimination rates of GLP-1 and GIP in obese type 2 diabetic patients and healthy subjects [14,15], indicating that higher intact GLP-1 and GIP levels after insulin treatment cannot explain the present results.…”

Section: Discussionmentioning

confidence: 85%

“…Given that the loss of incretin action is likely to be secondary to the development of diabetes, it might be expected that improvement of metabolic control could result in at least a partial restoration of incretin action, and this is the hypothesis that we investigated in the present study. A beneficial effect of insulin treatment and strict glycaemic control of beta cell function has been documented in several studies [18,20,[22][23][24][42][43][44]. For instance, Turner and co-workers demonstrated in people with mild diabetes that 3 days of normoglycaemia enhanced the first-phase insulin responses to intravenous glucose [23], while Garvey and colleagues found that 3 weeks of continued subcutaneous insulin infusion in patients with type 2 diabetes and a long duration of diabetes improved insulin secretion in response to mixed meals and to intravenous glucagon administration, whereas the first-phase insulin response was unchanged [18].…”

Section: Discussionmentioning

confidence: 99%

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Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

et al. 2008

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Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods Eight obese patients with type 2 diabetes with poor glycaemic control (HbA 1c 8.6±1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4±1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0±8.5 to 103.9±24.2 (nmol/l)×(110 min)

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

et al. 2008

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“…As the increase in insulin resistance in the two groups was identical, our results suggest that insulin resistance and glucose intolerance contribute as separate factors to the reduced incretin effect in patients with type 2 diabetes. Even though our study design per se does not allow us to conclude that the reduced incretin effect observed is a consequence and not a cause of the declining glucose tolerance, previous studies [11,35] from our group have addressed this question, and together the evidence supports the former. The mechanistic explanation for the impaired incretin effect in our study does not involve a reduced secretion of the two incretin hormones GLP-1 and GIP (measured as total hormones to capture all changes in secretion, independent of possible variations in dipeptidyl peptidase-4 (DPP-4) activity [36]) as neither GLP-1 nor GIP secretion decreased during OGTT after dexamethasone.…”

Section: Discussionmentioning

confidence: 79%

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

et al. 2012

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Aims/hypothesis The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect. Methods Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function.Results After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71±3.2% and 67±4.6% (p00.4) before treatment, but decreased significantly in both groups to 58±5.2% and 32±8.8% (p<0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio. Conclusion/interpretation Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT.Trial registration: ClinicalTrials.gov NCT00784745.

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“…This is important because chronic exposure of human islets to hyperglycaemia induces inflammation (increased IL-1β expression), impairs glucose-stimulated insulin secretion, and augments beta cell apoptosis [25]. Normalising plasma glucose in diabetic patients using intensive insulin treatment increases both glucose-stimulated insulin secretion (GSIS) [26] and GLP-1-induced potentiation of GSIS [27]. Similarly, prolonged lipid infusion has been associated with a reduction in insulin secretion in both animal models and healthy humans [28,29].…”

Section: Search Strategymentioning

confidence: 99%

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

et al. 2014

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Type 1 diabetes is characterised by immunemediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes.

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Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes

Abstract: Aims/hypothesis The ability of glucagon-like peptide-1

Cited by 83 publications

References 33 publications

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

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