title: Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus.
abstract: Aberrant regulation of glucose production makes a critical contribution to the impaired glycemic control that is observed in type 2 diabetes. Although isotopic tracer methods have proven to be informative in quantifying the magnitude of such alterations, it is presumed that one must rely on venous access to administer glucose tracers which therein presents obstacles for the routine application of tracer methods in rodent models. Since intraperitoneal injections are readily used to deliver glucose challenges and/or dose potential therapeutics, we hypothesized that this route could also be used to administer a glucose tracer. The ability to then reliably estimate glucose flux would require attention toward setting a schedule for collecting samples and choosing a distribution volume. For example, glucose production can be calculated by multiplying the fractional turnover rate by the pool size. We have taken a step-wise approach to examine the potential of using an intraperitoneal tracer administration in rat and mouse models. First, we compared the kinetics of [U-13C]glucose following either an intravenous or an intraperitoneal injection. Second, we tested whether the intraperitoneal method could detect a pharmacological manipulation of glucose production. Finally, we contrasted a potential application of the intraperitoneal method against the glucose-insulin clamp. We conclude that it is possible to 1) quantify glucose production using an intraperitoneal injection of tracer and 2) derive a "glucose production index" by coupling estimates of basal glucose production with measurements of fasting insulin concentration; this yields a proxy for clamp-derived assessments of insulin sensitivity of endogenous production.
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Zuliang
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Daurio
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Wu
authors.initials: W
authors.lastname: Yin
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Nawrocki
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Craig
authors.initials: C
authors.lastname: Fancourt
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Corin
authors.initials: C
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Deborah
authors.initials: D
authors.lastname: Slipetz
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey stephen_previs@merck.com.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: David E
authors.initials: DE
authors.lastname: Kelley
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes; D059305:Diet, High-Fat; D005260:Female; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010865:Pilot Projects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002247:Carbon Isotopes; D007004:Hypoglycemic Agents; D007202:Indicators and Reagents; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: animal models; insulin resistance; stable isotopes; tracer kinetics; type 2 diabetes