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 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 was studied in long -term (19-20 months) obese (n=5) and ob ese beta-cell reduced (nicotinamide+streptozotocin (STZ), n=5) minipigs and normal controls , representing different stages in the development towards 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±61pM in control and 67 mg/kg arginine: AIR=230±124 vs. 214±85pM in control), but reduced in obese-STZ animals (0.3 g/kg glucose: AIR=22±36, p<0.01 and arginine: AIR=87±92pM, 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 weight) was normal in obese and reduced in obese-STZ animals with pancreatic fat infiltration in both groups. In conclusion, o besity and insulin resistance are not linked with a general reduction of beta-cell function, but dyn amics 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.