scholarly journals Inhibition of DPP-4 with Vildagliptin Improved Insulin Secretion in Response to Oral as well as “Isoglycemic” Intravenous Glucose without Numerically Changing the Incretin Effect in Patients with Type 2 Diabetes

2011 ◽  
Vol 96 (4) ◽  
pp. 945-954 ◽  
Author(s):  
Irfan Vardarli ◽  
Michael A. Nauck ◽  
Lars D. Köthe ◽  
Carolyn F. Deacon ◽  
Jens J. Holst ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glycosylated Hemoglobin ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide 1 ◽  
D 12

Abstract Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 (“isoglycemic” iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUCISR oral, by 32.7%, P = 0.0006; AUCISR iv, by 33.1%, P = 0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans

2004 ◽  
Vol 287 (2) ◽  
pp. E199-E206 ◽  
Author(s):  
Jens Juul Holst ◽  
Jesper Gromada
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Response ◽  
Strong Support ◽  
Oral Glucose ◽  
Second Phase ◽  
Incretin Hormones ◽  
Incretin Effect ◽  
Glucagon Like Peptide 1

The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the β-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.

scholarly journals No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect

2020 ◽  
Vol 9 (12) ◽  
pp. 1221-1232
Author(s):  
David S Mathiesen ◽  
Jonatan I Bagger ◽  
Katrine B Hansen ◽  
Anders E Junker ◽  
Astrid Plamboeck ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Cell Function ◽  
Tolerance Test ◽  
Detectable Effect ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
Elevated Glucose

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes

2011 ◽  
Vol 300 (6) ◽  
pp. E1038-E1046 ◽  
Author(s):  
Asger Lund ◽  
Tina Vilsbøll ◽  
Jonatan I. Bagger ◽  
Jens J. Holst ◽  
Filip K. Knop
Keyword(s):  
Type 2 Diabetes ◽  
Glucagon Secretion ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Intestinal Hormones ◽  
Intravenous Glucose ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes mellitus (T2DM) is associated with reduced suppression of glucagon during oral glucose tolerance test (OGTT), whereas isoglycemic intravenous glucose infusion (IIGI) results in normal glucagon suppression in these patients. We examined the role of the intestinal hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) in this discrepancy. Glucagon responses were measured during a 3-h 50-g OGTT ( day A) and an IIGI ( day B) in 10 patients with T2DM [age (mean ± SE), 51 ± 3 yr; body mass index, 33 ± 2 kg/m2; HbA1c, 6.5 ± 0.2%]. During four additional IIGIs, GIP ( day C), GLP-1 ( day D), GLP-2 ( day E) and a combination of the three ( day F) were infused intravenously. Isoglycemia during all six study days was obtained. As expected, no suppression of glucagon occurred during the initial phase of the OGTT, whereas significantly ( P < 0.05) lower plasma levels of glucagon during the first 30 min of the IIGI ( day B) were observed. The glucagon response during the IIGI + GIP + GLP-1 + GLP-2 infusion ( day F) equaled the inappropriate glucagon response to OGTT ( P = not significant). The separate GIP infusion ( day C) elicited significant hypersecretion of glucagon, whereas GLP-1 infusion ( day D) resulted in enhancement of glucagon suppression during IIGI. IIGI + GLP-2 infusion ( day E) resulted in a glucagon response in the midrange between the glucagon responses to OGTT and IIGI. Our results indicate that the intestinal hormones, GIP, GLP-1, and GLP-2, may play a role in the inappropriate glucagon response to orally ingested glucose in T2DM with, especially, GIP, acting to increase glucagon secretion.

scholarly journals Incretin-based Therapies for Type 2 Diabetes—Comparisons Between Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors

2011 ◽  
Vol 07 (02) ◽  
pp. 82 ◽  
Author(s):  
Timothy Bailey ◽  
Keyword(s):  
Type 2 Diabetes ◽  
Glycosylated Hemoglobin ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Agonists ◽  
Increased Risk ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes exerts a huge toll on both morbidity and mortality, despite an expanding range of antiglycemic drugs and epidemiological evidence highlighting the benefits of effective glycemic control. Incretin-based agents offer important benefits, including a meal-dependent mode of action that may protect against hypoglycemia, and weight loss—in contrast to other antihyperglycemic drugs that cause weight gain. There are now two glucagon-like peptide-1 (GLP-1) receptor agonists and three dipeptidyl peptidase-4 (DPP-4) inhibitors approved for the management of type 2 diabetes in the US. Clinical trials have established the efficacy of incretin-based agents in controlling fasting and post-prandial blood glucose levels as well as glycosylated hemoglobin (HbA1c), both as monotherapy (including as first-line pharmacological treatment) and in combination with other antihyperglycemic treatments. GLP-1 receptor agonists and DPP-4 inhibitors have different mechanisms of action, which may explain their inconsistent efficacy results in direct comparator trials; for example, liraglutide has better efficacy than sitagliptin. However, GLP-1 receptor agonists can cause transient nausea in some patients. There is also evidence of different effects of individual agents within the same class; for example, liraglutide has shown superior efficacy to exenatide when added to metformin and/or sulfonylurea. Linagliptin is not cleared through renal mechanisms, unlike sitagliptin and saxagliptin. Isolated cases of pancreatitis led to concerns about a putative link with incretin-based therapies. However, the data currently available do not support a mechanistic or epidemiological link, although there does appear to be an increased risk of pancreatitis in people with diabetes that is independent of incretin-based treatment. Ongoing studies aim to extend our longer-term understanding of these agents, and hence, allow us to develop an optimal approach to patient management.

scholarly journals Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice

2015 ◽  
Vol 228 (3) ◽  
pp. 171-178 ◽  
Author(s):  
Linda Ahlkvist ◽  
Bilal Omar ◽  
Anders Valeur ◽  
Keld Fosgerau ◽  
Bo Ahrén
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Receptor Activation ◽  
Oral Glucose ◽  
Β Cell ◽  
Glucagon Receptor ◽  
Intravenous Glucose ◽  
Β Cell Function

Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.

scholarly journals Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2474-2482 ◽  
Author(s):  
Elena Sebokova ◽  
Andreas D. Christ ◽  
Haiyan Wang ◽  
Sabine Sewing ◽  
Jesse Z. Dong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Affinity Constant ◽  
Camp Production ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [125I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 ± 0.2 nm) to the natural ligand (affinity constant 1.5 ± 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC50 Taspo 0.06 nm and EC50 hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.

Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort

2021 ◽  
pp. 153537022110094
Author(s):  
Ibiye Owei ◽  
Nkiru Umekwe ◽  
Frankie Stentz ◽  
Jim Wan ◽  
Sam Dagogo-Jack
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Intravenous Glucose Tolerance Test ◽  
Cross Sectional ◽  
Parental History ◽  
Intravenous Glucose

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

scholarly journals Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

2022 ◽  
Author(s):  
Marta Garaulet ◽  
Jesus Lopez-Minguez ◽  
Hassan S Dashti ◽  
Céline Vetter ◽  
Antonio Miguel Hernández-Martínez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Postprandial Glucose ◽  
Oral Glucose ◽  
Elevated Concentration ◽  
Endogenous Melatonin

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P<sub>int</sub></i><sub> </sub>AUCgluc=0.009, <i>P<sub>int</sub></i><sub> </sub>CIR=0.022, <i>P<sub>int </sub></i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

Sign in / Sign up

Export Citation Format

Share Document