The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose.
OBJECTIVE
Low glucagon-like peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain whether these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG.


METHODS
We studied 22 subjects with IFG using a double-blinded, placebo-controlled, parallel-group design. At the time of enrollment, subjects ate a standardized meal labelled with [1-(13)C]-glucose. Infused [6-(3)H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-(2)H(2)] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to 100 mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated.


RESULTS
As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1 +/- 0.7 vs 17.6 +/- 0.8 micromol/kg per min, P = 0.53), Rd (55.6 +/- 4.3 vs 58.9 +/- 3.3 micromol/kg per min, P = 0.47) and MRa (6639 +/- 377 vs 6581 +/- 316 micromol/kg per 6 h, P = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion.


CONCLUSIONS
DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.
Bock
Gerlies
G
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Dalla Man
Chiara
C
Micheletto
Francesco
F
Basu
Rita
R
Giesler
Paula D
PD
Laugen
Jeanette
J
Deacon
Carolyn F
CF
Holst
Jens J
JJ
Toffolo
Gianna
G
Cobelli
Claudio
C
Rizza
Robert A
RA
Vella
Adrian
A
D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004311:Double-Blind Method; D005215:Fasting / Q000097:blood / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D019518:Postprandial Period / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D010919:Placebos; D011719:Pyrazines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate