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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/E670    most recent 00251.2005v2 00251.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Larsen, M. O. Articles by Gotfredsen, C. F. Search for Related Content PubMed PubMed Citation Articles by Larsen, M. O. Articles by Gotfredsen, C. F.

Measurements of insulin responses as predictive markers of pancreatic -cell mass in normal and -cell-reduced lean and obese Göttingen minipigs in vivo

¹Department of Pharmacology Research I and ²Department of Pharmacology Research III, Novo Nordisk A/S, Maaloev; ³Department of Assay and Cell Technology, Novo Nordisk A/S, Bagsvaerd; ⁴Discovery Management, Novo Nordisk A/S, Bagsvaerd; ⁵Medical Department C, Aarhus University Hospital, Aarhus; and ⁶Department of Pharmacology Research IV, Novo Nordisk A/S, Maaloev, Denmark

Submitted 6 June 2005 ; accepted in final form 1 November 2005

At present, the best available estimators of -cell mass in humans are those based on measurement of insulin levels or appearance rates in the circulation. In several animal models, these estimators have been validated against -cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and -cell mass must be evaluated over a range of body weights to include different levels of insulin sensitivity. For this purpose, obese (n = 10) and lean (n = 25) Göttingen minipigs were studied. -Cell mass had been reduced (n = 16 lean, n = 5 obese) with a combination of nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg), acute insulin response (AIR) to intravenous glucose and/or arginine was tested, pulsatile insulin secretion was evaluated by deconvolution (n = 30), and -cell mass was determined histologically. AIR to 0.3 (r² = 0.4502, P < 0.0001) or 0.6 g/kg glucose (r² = 0.6806, P < 0.0001), 67 mg/kg arginine (r² = 0.5730, P < 0.001), and maximum insulin concentration (r² = 0.7726, P < 0.0001) were all correlated to -cell mass when evaluated across study groups, and regression lines were not different between lean and obese groups except for AIR to 0.3 g/kg glucose. Baseline pulse mass was not significantly correlated to -cell mass across the study groups (r² = 0.1036, NS), whereas entrained pulse mass did show a correlation across groups (r² = 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate -cell mass over a range of body weights in the minipig. Extensive stimulation of insulin secretion by a combination of glucose and arginine seems to give the best correlation to -cell mass.

animal model; streptozotocin; arginine; pulsatile insulin secretion

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