Markedly Reduced β-Cell Function Does Not Result in Insulin Resistance in Islet Autografted Dogs

Autotransplantation of islets of Langerhans has resulted in long-term normoglycemia in pancreatectomized dogs. This canine model is useful in evaluating both the progress of islet transplantation and the effect of a reduced islet mass upon the determinants of glucose tolerance: i.e., insulin secretion, insulin sensitivity, and glucose effectiveness. To determine the effect of a reduced islet mass on these factors, we measured the acuteinsulin response to arginine (AIR_a) and glucose (AIR_g), the slope of glycemic potentiation of AIR_a (SP), insulin sensitivity (S₁), and glucose effectiveness (S_G) in control (CN), diabetic (DM), and pancreatectomized dogs rendered normoglycemic with transplanted autografts of islets of Langerhans (TX). Normal fasting plasma glucose (FPG) (TX 4.7 ± 0.2 mM; CN 4.9 ± 0.1 mM; P > 0.05) was maintained despite a markedly reduced insulin secretion in TX (AIR_a 24%, AIR_g 15%, and SP 11% of CN). All measures of insulin secretion were significantly correlated (SP vs. AIR_g r = 0.80, P < 0.0001; AIR_a vs. AIR_g r = 0.92, P < 0.0001) across all animals, but none of the measures of secretion were significantly correlated with either the number of islets transplanted or time posttransplant (P > 0.10). Insulin sensitivity was normal in islet autografted dogs (TX: 136 ±12 min⁻¹/(nmol/ml); CN: 101 ±11 min⁻¹/(nmol/ml), P > 0.05) but S_G was reduced (TX:±1.93 ± 0.28 × 100 min⁻¹; CN: 3.53 ± 0.35 × 100 min⁻¹ P < 0.05), as determined by the minimal-model method. In diabetic animals (FPG = 16.1 ±1.3 mM), insulin secretion was negligible by all measures (P > 0.05), and was associated with insulin resistance (S₁ = 28 ± 8 min⁻¹/(nmol/ml)) and reduced S_G (1.72 ±0.11 × 100 min⁻¹). These studies indicate that across a range of insulin secretion in dogs, thesecretagogues arginine and glucose provide similar estimates of β-cell function. This markedly reduced β-cell function does not result in insulin resistance when fasting normoglycemia is maintained, but is associated with a decrease in glucose action at basal insulin.