Is the Diminished Incretin Effect in Type 2 Diabetes Just an Epi-Phenomenon of Impaired β-Cell Function?

Meier, Juris J.; Nauck, Michael A.

doi:10.2337/db09-1899

Cited by 204 publications

(154 citation statements)

References 68 publications

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“…Stimulation with the non-glucose beta cell stimulus arginine illustrates that a first-phase insulin response could still be produced if another intracellular beta cell pathway than that used by GLP-1 and GIP is stimulated. Importantly, the arginine response was unaffected by dexamethasone, indicating that the diminished incretin action of the two hormones is not related to a global dysfunction of the beta cells [12]. Rather, our results indicate that the impaired insulinotropic effects of GLP-1 and GIP represent a very early, specific beta cell defect, which can explain the impaired incretin effect in, for instance, obese individuals with insulin resistance [29].…”

Section: Discussionmentioning

confidence: 67%

“…It has recently been argued that the loss of incretin effect seen in type 2 diabetes is due to a globally reduced capacity of the beta cells to secrete insulin so that the release of incretin hormones during oral stimulation cannot further increase insulin secretion, leading to an 'apparent' loss of incretin effect [12]. We therefore also investigated whether the glucocorticoid-induced reduction in the incretin effect was associated with a reduced maximal secretory response of the beta cells to arginine, a non-glucose, non-incretin beta cell stimulus.…”

Section: Introductionmentioning

confidence: 99%

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Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

et al. 2015

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Aims/hypothesis We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoidinduced insulin resistance. Methods Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7 mmol/l and 15 mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. Results After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first-phase responses to 15 mmol/l glucose were reduced equally for both hormones.Conclusions/interpretation Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. Trial registration: Clinicaltrials.gov NCT02235584

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

et al. 2015

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“…18,19 Several lines of evidence support that the loss of incretin effect is secondary to development of diabetes. [19][20][21][22] However, more recent findings suggest that the loss of incretin effects in T2DM patients can only be explained by a specific loss of insulinotropic activity of the incretin hormones at physiological level. 19,2325 In overt T2DM, the consequence of the impaired incretin effect is that the ability of the patients to efficiently dispose of orally as opposed to intravenously administered glucose is completely lost.…”

Section: Discussionmentioning

confidence: 99%

Incretin Hormones and Insulin Responses During OGTT in Newly Diagnosed T2DM Patients

Jhuma

Giasuddin

Haque³

et al. 2018

Bangladesh Med Res Counc Bull

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Several research groups have reported variable results about incretin effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1) particularly, as well as cytokines balance in type 2 diabetes mellitus (T2DM). The present case-control prospective interventional study was conducted in 2014-2015 at Medical College for Women & Hospital, Dhaka, investigating responses of incretin hormones and insulin to oral glucose tolerance test (OGTT) in Bangladeshi subjects. Blood samples were collected from 36 OGTT positive adult T2DM patients (Pt) and 30 normal adults (NC) at '0' minute (fasting) and at 2 hours after OGTT. Routine laboratory investigations in blood were done and special parameters in serum, i.e. insulin, HGH, TSH, GIP and GLP-1 were analyzed using enzyme immunoassay kits. Pt had FBG and BG2Hr levels much higher than NC (p<0.001). In Pt, F-Insulin and Insulin2Hr were much lower than NC subjects (p<0.001), although Insulin2Hr level was higher than F-Insulin level in Pt. F-GIP (p=0.309) and F-GLP-1(p=0.984) levels were similar between Pt and NC. Interestingly, NC responded to OGTT by increasing GIP2Hr and GLP-1,2Hr levels about 3 times, whereas Pt responded by raising about 1.5 times only compared to F-GIP and F-GLP-1 (p< 0.001). Reduced insulin levels, both fasting and postprandial, were possibly due to decreased responses of GIP and GLP-1 to glucose load in T2DM patients. Further studies with a larger sample size including cytokines are warranted.

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“…Recently, it has been argued [45] that the maximal secretory capacity of the beta cells is reached during the IVGTT of isoglycaemic challenges for the study of incretin effect in type 2 diabetes, meaning that the incretin hormones cannot further increase insulin secretion on oral stimulation, which could explain the apparent loss of the incretin effect. However, in our participants with NGT, this is unlikely to be the cause of the reduced incretin effect, particularly as the beta cell response to the mixed meal was significantly greater than to i.v.…”

Section: Discussionmentioning

confidence: 99%

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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Is the Diminished Incretin Effect in Type 2 Diabetes Just an Epi-Phenomenon of Impaired β-Cell Function?

Cited by 204 publications

References 68 publications

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

Incretin Hormones and Insulin Responses During OGTT in Newly Diagnosed T2DM Patients

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

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