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


METHODS
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.


METHODS
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.
Department of Internal Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy.
Elza
E
Muscelli
Arturo
A
Casolaro
Amalia
A
Gastaldelli
Andrea
A
Mari
Giuseppe
G
Seghieri
Brenno
B
Astiarraga
Yu
Y
Chen
Maria
M
Alba
Jens
J
Holst
Ele
E
Ferrannini
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000068900:Sitagliptin Phosphate