Measurements of insulin responses as predictive markers of pancreatic beta-cell mass in normal and beta-cell-reduced lean and obese Göttingen minipigs in vivo.
At present, the best available estimators of beta-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 beta-cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and beta-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. Beta-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 beta-cell mass was determined histologically. AIR to 0.3 (r(2) = 0.4502, P < 0.0001) or 0.6 g/kg glucose (r(2) = 0.6806, P < 0.0001), 67 mg/kg arginine (r(2) = 0.5730, P < 0.001), and maximum insulin concentration (r(2) = 0.7726, P < 0.0001) were all correlated to beta-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 beta-cell mass across the study groups (r(2) = 0.1036, NS), whereas entrained pulse mass did show a correlation across groups (r(2) = 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate beta-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 beta-cell mass.
Larsen
Marianne O
MO
Department of Pharmacology Research I, Novo Nordisk A/S, Maaloev, Denmark. mmla@novonordisk.com
Rolin
Bidda
B
Sturis
Jeppe
J
Wilken
Michael
M
Carr
Richard D
RD
Pørksen
Niels
N
Gotfredsen
Carsten F
CF
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009536:Niacinamide / Q000494:pharmacology; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D013311:Streptozocin / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature
D001786:Blood Glucose; D007328:Insulin; D009536:Niacinamide; D013311:Streptozocin; D001120:Arginine