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

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Abstract
Herein, we bridge β-cell function and morphology in minipigs. We hypothesized that different aspects of β-cell dysfunction are present in obesity and obesity with reduced β-cell mass by using pulsatile insulin secretion as an early marker. Measures for β-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 β-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). β-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 β-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of β-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 β-cell dysfunction.

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