Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes.

Abstract

CONTEXT:

Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known.

OBJECTIVE:

The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors.

DESIGN, SETTING, AND PATIENTS:

We administered a mixed meal with glucose tracers ([6,6-(2)H(2)]-glucose infused, [1-(2)H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion.

INTERVENTION:

We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22).

RESULTS:

Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = -353 ± 915 vs. +146 ± 601 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min(-1) · m(-2) · mm(-1); median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml(-1) · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test.

CONCLUSIONS:

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.

• Authors: Elza Muscelli, Arturo Casolaro, Amalia Gastaldelli, Andrea Mari, Giuseppe Seghieri, Brenno Astiarraga, Yu Chen, Maria Alba, Jens Holst, Ele Ferrannini
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 8 Pg. 2818-26 (Aug 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22685234 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Pyrazines
• Triazoles
• Glucagon-Like Peptide 1
• Glucagon
• Sitagliptin Phosphate

Topics

• Adult
• Aged
• Blood Glucose (analysis)
• Diabetes Mellitus, Type 2 (blood, drug therapy, physiopathology)
• Double-Blind Method
• Female
• Glucagon (blood)
• Glucagon-Like Peptide 1 (blood)
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Insulin-Secreting Cells (drug effects, physiology)
• Male
• Middle Aged
• Pyrazines (pharmacology, therapeutic use)
• Sitagliptin Phosphate
• Triazoles (pharmacology, therapeutic use)