title: Linearity of β-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series.
abstract: The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in β-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI. Insulin secretory response was measured as changes in insulin, C-peptide, insulin secretion rates (ISR), and ratio of ISR to prevailing glucose (ISR/G). The GGI correlated well with the HGC (r = 0.72 for ISR/G, P < 0.01). The insulin secretory response in type 2 diabetes (T2DM) was significantly blunted (P < 0.001), whereas it was significantly increased in obese nondiabetics compared with healthy nonobese (P < 0.001). Finally, robust (P < 0.001 over placebo) pharmacological effects were observed in T2DM and healthy nonobese volunteers. Collectively, the findings of this investigational series bolster confidence that the GGI has solid attributes for assessing insulin secretory response to glucose across populations and pharmacology. Notably, the coupling of insulin secretory response to glycemic changes was distinctly and uniformly linear across populations and in the context of insulin secretagogues. (Clinical Trial Registration Nos. NCT00782418, NCT01055340, NCT01373450).
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and sudhashankar@comcast.net.
authors.forename: Sudha S
authors.initials: SS
authors.lastname: Shankar
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: R Ravi
authors.initials: RR
authors.lastname: Shankar
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Mixson
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Miller
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chung
authors.affiliation: Merck Sharp & Dohme Corp. (Europe), Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cilissen
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: Chan R
authors.initials: CR
authors.lastname: Beals
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: Helmut O
authors.initials: HO
authors.lastname: Steinberg
authors.affiliation: Merck & Company, Inc., Kenilworth, New Jersey; and.
authors.forename: David E
authors.initials: DE
authors.lastname: Kelley
mesh_terms: D003920:Diabetes Mellitus / Q000378:metabolism*; D004311:Double-Blind Method; D005947:Glucose / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D016014:Linear Models; D008954:Models, Biological; D017711:Nonlinear Dynamics; D009765:Obesity / Q000097:blood*; D015990:Placebo Effect; D015996:Survival Rate
chemical_list: D007328:Insulin; D005947:Glucose
keywords: diabetes; exenatide; graded glucose infusion; hyperglycemic clamp; liraglutide; nonobese; obese