The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose

• Published in: Clinical endocrinology (Oxford) Vol. 73; no. 2; pp. 189 - 196
• Main Authors: Bock, Gerlies, Man, Chiara Dalla, Micheletto, Francesco, Basu, Rita, Giesler, Paula D., Laugen, Jeanette, Deacon, Carolyn F., Holst, Jens J., Toffolo, Gianna, Cobelli, Claudio, Rizza, Robert A., Vella, Adrian
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2010; Blackwell; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting - blood; Fasting - metabolism; Female; Fundamental and applied biological sciences. Psychology; Glucose Intolerance - blood; Glucose Intolerance - metabolism; Humans; Incretins - blood; Incretins - metabolism; Male; Medical sciences; Middle Aged; Placebos; Postprandial Period - physiology; Pyrazines - pharmacology; Sitagliptin Phosphate; Triazoles - pharmacology; Vertebrates: endocrinology; Dipeptidyl-peptidase IV; Endocrinopathy; Human; Incretin; Enzyme; Secretion; Enzyme inhibitor; Sitagliptin; Glucose; Peptidases; Hypoglycemic agent; Gliptine derivatives; Hydrolases; Dipeptidyl-peptidase IV inhibitor; Inhibition; Fast; Impaired glucose tolerance; Endocrinology; Glycemia
• ISSN: 0300-0664; 1365-2265; 1365-2265
• DOI: 10.1111/j.1365-2265.2009.03764.x

Summary 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. Research design and methods  We studied 22 subjects with IFG using a double‐blinded, placebo‐controlled, parallel‐group design. At the time of enrolment, subjects ate a standardized meal labelled with [1‐13C]‐glucose. Infused [6‐3H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6‐2H2] 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 μmol/kg per min, P = 0·53), Rd (55·6 ± 4·3 vs 58·9 ± 3·3 μmol/kg per min, P = 0·47) and MRa (6639 ± 377 vs 6581 ± 316 μmol/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.