Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes

Muscelli, Elza; Casolaro, A; Gastaldelli, Amalia; Mari, Andrea; Seghieri, Giuseppe; Astiarraga, Brenno; Chen, Yu; Alba, Maria; Holst, Jens J.; Ferrannini, Ele

doi:10.1210/jc.2012-1205

Cited by 97 publications

(95 citation statements)

References 37 publications

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“…Despite the plausibility of this hypothesis, our previous study using vildagliptin treatment did not show any change in the numerical contribution of the incretin effect to insulin secretory responses after oral glucose challenges (19). A similar study, using mixed-meal stimulation of insulin secretion, also came to a similar conclusion (20).…”

mentioning

confidence: 84%

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

et al. 2014

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Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition. The incretin effect denotes the phenomenon whereby oral glucose stimulation elicits a higher insulin secretory response compared with "isoglycemic" intravenous glucose and is explained by the actions of the intestinally derived incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). In patients with type 2 diabetes, this incretin effect is impaired (2), mainly because diabetic b-cells no longer respond to GIP (3,4). However, the effects of GLP-1 in type 2 diabetes are impaired (5)

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mentioning

confidence: 84%

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

et al. 2014

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“…A major determinant of the reduction of fasting glucose by DPP-4 inhibition is a reduction in hepatic glucose output (11,12). This effect is mainly caused by reduction of circulating glucagon through the GLP-1-induced inhibition of glucagon secretion since prevention of changes in glucagon secretion also prevents GLP-1 from inhibiting hepatic glucose output in humans (23).…”

Section: Effects Through Insulin-independent Mechanisms Of Glp-1mentioning

confidence: 99%

“…All of the DPP-4 inhibitors used in clinical practice have been shown to give robust and long-lasting inhibition of plasma DPP-4 activity (7). 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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“…Thirdly, GCs induce peripheral insulin resistance, resulting in increased hepatic glucose production, increased adipose tissue lipolysis, and impaired glucose disposal at the level of skeletal muscle (31). Although sitagliptin was shown by others to reduce hepatic glucose production in the postprandial state to some extent (32), by suppressing glucagon secretion, DPP-4 inhibitors, in general, fail to improve peripheral insulin sensitivity. These factors may explain why GC-induced glucose intolerance was not mitigated by sitagliptin, despite clamp-measured improvements in b-cell function.…”

Section: Clinical Study R E Van Genugten and Othersmentioning

confidence: 99%

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

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et al. 2014

European Journal of Endocrinology

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Objective: Anti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects. Design and methods: Men with the metabolic syndrome but without diabetes received prednisolone 30 mg once daily plus sitagliptin 100 mg once daily (nZ14), prednisolone (nZ12) or sitagliptin alone (nZ14) or placebo (nZ12) for 14 days in a double-blind 2!2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. b-cell function parameters were assessed both from a hyperglycemic-arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp. Results: Prednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P!0.001 vs placebo) and postprandial AUC-glucagon by 50% (P!0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated-and combined hyperglycemia-arginine-stimulated C-peptide secretion (all P%0.001). When sitagliptin was added, both clamp-measured b-cell function (PZNS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (PZNS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P!0.001 vs placebo). M-value was not altered by any treatment. Conclusion: Fourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment.

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Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes

Abstract: Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.

Cited by 97 publications

References 37 publications

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

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

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

Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

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