Beta-cell function and islet morphology in normal, obese, and obese beta-cell mass-reduced Göttingen minipigs.
Herein, we bridge beta-cell function and morphology in minipigs. We hypothesized that different aspects of beta-cell dysfunction are present in obesity and obesity with reduced beta-cell mass by using pulsatile insulin secretion as an early marker. Measures for beta-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 beta-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). Beta-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 beta-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of beta-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 beta-cell dysfunction.
Dept. of Pharmacology Research I, Pharmacology Research and Development, Novo Nordisk Park F6.1.30, Maaloev DK-2760, Denmark. mmla@novonordisk.com
M O
MO
Larsen
C B
CB
Juhl
N
N
Pørksen
C F
CF
Gotfredsen
R D
RD
Carr
U
U
Ribel
M
M
Wilken
B
B
Rolin
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D004041:Dietary Fats / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009536:Niacinamide; D009765:Obesity / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D012016:Reference Values; D013311:Streptozocin; D013552:Swine; D013556:Swine, Miniature
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D009536:Niacinamide; D013311:Streptozocin