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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/E412    most recent 00352.2004v1 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 ISI Web of Science 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 (11) Citing Articles via Google Scholar Google Scholar Articles by Larsen, M. O. Articles by Rolin, B. Search for Related Content PubMed PubMed Citation Articles by Larsen, M. O. Articles by Rolin, B.

-Cell function and islet morphology in normal, obese, and obese -cell mass-reduced Göttingen minipigs

¹Department of Pharmacology Research I, ²Department of Pharmacology Research IV, and ³Department of Pharmacology Research III, Novo Nordisk A/S, Maaloev; ⁴Medical Department M and ⁵Medical Department C, Aarhus University Hospital, Aarhus; and ⁶Discovery Management and ⁷Department of Assay and Cell Technology, Novo Nordisk A/S, Bagsvaerd, Denmark

Submitted 2 August 2004 ; accepted in final form 2 October 2004

Herein, we bridge -cell function and morphology in minipigs. We hypothesized that different aspects of -cell dysfunction are present in obesity and obesity with reduced -cell mass by using pulsatile insulin secretion as an early marker. Measures for -cell function (glucose and arginine stimulation plus baseline and glucose-entrained pulsatile insulin secretion) and islet morphology were studied in long-term (19–20 mo) obese (n = 5) and obese -cell-reduced [nicotinamide + streptozotocin (STZ), n = 5] minipigs and normal controls, representing different stages in the development toward type 2 diabetes. Acute insulin response (AIR) to glucose and arginine were, surprisingly, normal in obese (0.3 g/kg glucose: AIR = 246 ± 119 vs. 255 ± 61 pM in control; 67 mg/kg arginine: AIR = 230 ± 124 vs. 214 ± 85 pM in control) but reduced in obese-STZ animals (0.3 g/kg glucose: AIR = 22 ± 36, P < 0.01; arginine: AIR = 87 ± 92 pM, P < 0.05 vs. control). Baseline pulsatile insulin secretion was reduced in obese (59 ± 16 vs. 76 ± 16% in control, P < 0.05) and more so in obese-STZ animals (43 ± 13%, P < 0.01), whereas regularity during entrainment was increased in obese animals (approximate entropy: 0.85 ± 0.14 vs. 1.13 ± 0.13 in control, P < 0.01). -Cell mass (mg/kg body wt) was normal in obese and reduced in obese-STZ animals, with pancreatic fat infiltration in both groups. In conclusion, obesity and insulin resistance are not linked with a general reduction of -cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of -cell dysfunction, with the three groups representing stages in the progression from normal physiology to diabetes, and assessment of pulsatility as the single most sensitive marker of -cell dysfunction.

-cell reduction; obesity; pulsatile insulin secretion; in vivo model

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