Insulin secretory effect of sitagliptin

Assessment with a hyperglycemic clamp combined with a meal challenge

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

Research output: Contribution to journalArticle

Abstract

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). 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 of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively (P < 0.001 for 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-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.

Original languageEnglish (US)
Pages (from-to)E406-E412
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume314
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

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Meals
Insulin
Incretins
Hyperglycemia
Glucagon-Like Peptide 1
Sitagliptin Phosphate
Placebos
Dipeptidyl-Peptidase IV Inhibitors
Benchmarking
Placebo Effect
C-Peptide
Cross-Over Studies
Type 2 Diabetes Mellitus
Healthy Volunteers
Therapeutics
Hormones
Glucose

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Insulin secretory effect of sitagliptin : Assessment with a hyperglycemic clamp combined with a meal challenge. / Shankar, Sudha S.; Ravi Shankar, R.; Mixson, Lori A.; Miller, Deborah L.; Steinberg, Helmut; Beals, Chan R.; Kelley, David E.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 314, No. 4, 01.04.2018, p. E406-E412.

Research output: Contribution to journalArticle

Shankar, Sudha S. ; Ravi Shankar, R. ; Mixson, Lori A. ; Miller, Deborah L. ; Steinberg, Helmut ; Beals, Chan R. ; Kelley, David E. / Insulin secretory effect of sitagliptin : Assessment with a hyperglycemic clamp combined with a meal challenge. In: American Journal of Physiology - Endocrinology and Metabolism. 2018 ; Vol. 314, No. 4. pp. E406-E412.
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