Effects of Sitagliptin and Metformin Treatment on Incretin Hormone and Insulin Secretory Responses to Oral and “Isoglycemic” Intravenous Glucose

Vardarli, İrfan; Arndt, E; Deacon, Carolyn F.; Holst, Jens J.; Nauck, Michael A.

doi:10.2337/db13-0805

Cited by 85 publications

(80 citation statements)

References 40 publications

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“…Insulin, C-peptide, glucagon, and total and intact GLP-1 and GIP were determined by specific immunoassays as previously described (18,19). Exendin cross-reacted in the glucagon assay (by ;0.014%), thus not allowing interpretation of glucagon measurements.…”

Section: Laboratory Determinationsmentioning

confidence: 99%

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Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist

Nauck

Kind²,

Köthe

et al. 2016

Diabetes

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We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age-and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin . The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUC ISR ) and glucose (total AUC glucose ) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUC ISR / AUC glucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 6 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

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Section: Laboratory Determinationsmentioning

confidence: 99%

“…Blood was drawn from an indwelling Teflon cannula inserted into a forearm vein and processed as previously described (18).…”

Section: Blood Specimensmentioning

confidence: 99%

Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist

Nauck

Kind²,

Köthe

et al. 2016

Diabetes

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“…Several of the DPP-4 inhibitors have also been demonstrated to increase levels of (intact) GLP-1 after meal ingestion (8)(9)(10)(11). For vildagliptin and sitagliptin, it has in addition been demonstrated that intact GLP-1 levels are increased not only after meal ingestion, but also throughout the entire 24-h period with elevated fasting levels (12,13).…”

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confidence: 99%

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

2014

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DPP-4 is an enzyme that is widely expressed throughout the body and abundantly expressed in endothelial cells. It is attached to the intravascular portion of vascular endothelial cells and also exists in a soluble circulating form (4). It is a serine protease that cleaves peptides between the amino acid 2 and 3 from the N-terminal end, particularly if the second amino acid is alanine or proline. GLP-1 has alanine as the second amino acid and is therefore a substrate for DPP-4, which cleaves the intact GLP-1 7-36 to GLP-1 9-36 , which is largely inactive. The

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“…The effects of the two hormones with respect to insulin secretion have been shown to be additive in humans (3), but, nevertheless, the role of the ratio between active hormones and their inactivated metabolites for the incretin effect remains to be established in healthy humans. Interestingly, several studies have evaluated the impact of DPP4 inhibition (using the DPP4 inhibitors sitagliptin or vildagliptin) on the incretin effect in type 2 diabetic subjects (4,5,6) and found that the incretin effect did not change numerically (because insulin secretion increased, not only during oral glucose load but also after isoglycaemic intravenous (i.v.) glucose infusion (IIGI)) despite greater DPP4 inhibitor-mediated potentiation of active levels of incretin hormones during the oral glucose stimulus compared with the IIGI.…”

Section: Introductionmentioning

confidence: 99%

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

Rhee

Østoft

Holst

et al. 2014

European Journal of Endocrinology

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Objective: Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects. Design: A randomised, controlled and open-labelled study. Methods: Ten healthy subjects (six women; age, 40G5 years (meanGS.E.M.); BMI, 24G3 kg/m 2 ; fasting plasma glucose, 5.1G0.2 mmol/l and HbA1c, 34G1 mmol/mol (5.3G0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A 1 CB 1 ) and without (A 2 CB 2 ) preceding administration of the DPP4 inhibitor sitagliptin. Results: Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1G0.1 vs 4.9G0.1 mmol/l, PZ0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151G35 vs 137G26 mmol/l!min, PZ0.7) or peak plasma glucose during OGTT (8.5G0.4 vs 8.1G0.3 mmol/l, PZ0.3) was observed. Neither incretin effect (40G9% (without DPP4 inhibitor) vs 40G7% (with DPP4 inhibitor), PZ1.0), glucagon responses (1395G165 vs 1223G195 pmol/l!min, PZ0.41), GIGD (52G4 vs 56G5%, PZ0.40) nor gastric emptying (T max for plasma paracetamol: 86G9 vs 80G12 min, PZ0.60) changed following DPP4 inhibition. Conclusions: These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.

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Effects of Sitagliptin and Metformin Treatment on Incretin Hormone and Insulin Secretory Responses to Oral and “Isoglycemic” Intravenous Glucose

Cited by 85 publications

References 40 publications

Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist

Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

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

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