Insulin Secretory Effect of Sitagliptin: Assessment with a Hyperglycemic Clamp Combined with a Meal Challenge.

American Journal of Physiology - Endocrinology and Metabolism

5 years ago

Insulin Secretory Effect of Sitagliptin: Assessment with a Hyperglycemic Clamp Combined with a Meal Challenge.

Helmut O Steinberg, Sudha S Shankar, David E Kelley, Deborah L Miller, Chan R Beals, R Ravi Shankar, Lori A Mixson

Sitagliptin,a dipeptidylpeptidase-IVinhibitor(DPP-4),sustains activity of the incretin hormones GLP-1andGIP and improves hyperglycemia inT2DM.It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion(ISR) during a prandial challenge.The tight feedback governance ofISR by plasma glucose means that in the face of treatment-related lowering of postprandialglycemia,corresponding stimulation ofISR is lessened.We postulated that sustaining a stable level of moderate hyperglycemia prior to and during a mealchallenge(MC)would be a platform that enables greater clarity to assess the effect ofsitagliptin onISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemicclamp(HGC) at 160mg/dl was conducted in 12healthy volunteers (withoutdiabetes) for 6hours; 3hours into the HGC,MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3hours.Modeling of C-peptideresponse was used to calculateISR.In cross-overdesign of 3periods(sitagliptin twice and placebo once),the effect of sitagliptin versus placebo onISR and the reproducibility of the response to sitagliptin were assessed.Sitagliptin increased ISR compared to placebo by 50% and 20% during the HGC alone and theHGC-MCphases, respectively(p<0.001for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1.Robust reproducibility of the sitagliptin-mediatedISR response was observed;the intra-classcorrelationvalue was0.94.The findings delineate the effect of sitagliptin to stimulate insulin secretion and these benchmark data also demonstrate that anHGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulateISR via direct action on beta-cells as well as by augmenting release or action of incretins.

Publisher URL: http://doi.org/10.1152/ajpendo.00238.2017

DOI: 10.1152/ajpendo.00238.2017