The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

Rhee, Nicolai; Østoft, Signe Harring; Holst, Jens J.; Deacon, Carolyn F.; Vilsbøll, Tina; Knop, Filip K.

doi:10.1530/eje-14-0314

Cited by 30 publications

(18 citation statements)

References 36 publications

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“…Administration of sitagliptin increased the concentrations of endogenously secreted intact GLP-1 and GIP ϳ2.5-fold, which is in line with previous findings (2), but surprisingly, this did not affect postprandial glucose excursions, insulin secretion, or indices of ␤-cell function. In other studies with glucose-tolerant subjects, acute DPP-4 inhibition has also failed to affect postprandial glucose excursions or enhance the incretin effect (12,42). An explanation might be that responses corresponding to the maximal ␤-cell secretory capacity were achieved on the placebo day in the present study.…”

Section: E509 Incretins and Glucose Tolerance After Roux-en-y Gastricmentioning

confidence: 46%

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Svane

Bojsen‐Møller

Nielsen

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and ␤-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9 -39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated ␤-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two-to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or ␤-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.Roux-en-Y gastric bypass; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; exendin-(9 -39); dipeptidyl peptidase-4 inhibition ROUX-EN-Y GASTRIC BYPASS (RYGB) is an effective treatment of severe obesity and induces large and sustainable weight loss, which is superior to diet, intensive lifestyle, or pharmaceutical interventions (47, 51). Moreover, RYGB improves glycemic control within days after surgery, before major weight loss (24), and induces remission of type 2 diabetes in the majority of patients (5, 47). Patients with preoperative normal glucose tolerance (NGT) also display changed postprandial glycemic profile after RYGB with increased peak plasma glucose, followed by a lower nadir (24,45). A combination of improved hepatic insulin sensitivity induced by hypocaloric postoperative diet (18), rapid glucose absorption (19), and exaggerated postprandial insulin secretion seems to be responsible for the early changes in glucose metabolism after RYGB in patients with NGT and type 2 diabetes (3).The postprandial gastrointestinally induced stimulation of insulin secretion, the incretin effect, is due to the insulinotropic effects of the two hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (38,56). In glucose-tolerant subjects, GLP-1 and GIP contribute nearly equally to the incretin effect, which explains up to 70% of the postprandial insulin secretion (36,38,56). The incretin effect is severely impaired in type 2 diabetes (35) but is also reduced in obese people with NGT ...

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Section: E509 Incretins and Glucose Tolerance After Roux-en-y Gastricmentioning

confidence: 46%

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Svane

Bojsen‐Møller

Nielsen

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Thus, the incretins GLP1 and GIP are secreted by distal small intestine in response to its stimulation bind receptors in the endocrine pancreas so eliciting insulin secretion and lowering postprandial blood glucose . ROS are important regulator of this phenomenon by activating DPP‐4, which rapidly inactivates incretin activity so impairing insulin secretion . Supplementation of a meal with 10 g EVOO had positive effects on postprandial glycaemic profile as it was associated with an increase of incretins coincidentally with a decrease of DPP‐4 activity; this led to the suggestion that EVOO behaves as a DPP‐4 inhibitor and that EVOO was responsible for improved postprandial glycaemia via an oxidative stress‐mediated mechanism and eventually incretin upregulation .…”

Section: Discussionmentioning

confidence: 99%

Oleuropein, a component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects

Carnevale

Silvestri

Loffredo

et al. 2018

Brit J Clinical Pharma

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“…The incretin effect most likely constitutes an important contributor to GIGD, but other factors affecting plasma glucose concentrations differently during OGTT and IIGI, including differences in glucagon secretion, activation of afferent nerves in the intestinal mucosa, first-pass hepatic glucose uptake, differences in portal and venous blood glucose concentrations and/or at the present unknown factors are also taken into account when calculating GIGD. In healthy subjects, GIGD typically amounts to ~60% (31,56,65,67,68,69,70), whereas patients with diabetes exhibit a severely reduced GIGD in the range of ~10-30% (31,56,57,58,64). As mentioned earlier, Hare et al performed OGTT and IIGI in C-peptide-negative patients with type 1 diabetes and were, thus, able to describe GIGD in the context of abrogated incretin effect (59).…”

Section: Implications Of Gastrointestinal-stimulated Glucagon Secretionmentioning

confidence: 98%

EJE PRIZE 2018: A gut feeling about glucagon

Knop

2018

European Journal of Endocrinology

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Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues - most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.

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The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

Cited by 30 publications

References 36 publications

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Oleuropein, a component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects

EJE PRIZE 2018: A gut feeling about glucagon

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