A decreased acute insulin response to glucose in islet cell antibody positive humans predicts diabetes. Because the dominant mechanism leading to decreased in vivo acute insulin response to glucose remains unclear, perifused islets were examined before and after diabetes onset in BB rats to assess the role of glucose sensitivity on insulin secretion in individual islets. Islets from normal WF rats, diabetes-prone rats without inflamed islets, diabetes-prone rats with inflamed islets, and diabetic rats were studied at 2.0, 8.3, and 16.7 mM glucose. Immunoreactive insulin from WF islets at 16.7 mM glucose was 0.15 ± 0.02 ng · 0–7 min−1 · islet−1 for the first phase and 1.00 ± 0.05 ng · 7–20 min−1 · islet−1 for the second phase of biphasic secretion, compared with basal secretion of 0.10 ± 0.03 ng · 20 min−1 · islet−1 at 2 mM glucose. Diabetes-prone noninflamed islets showed a 0.20 ± 0.03 ng first-phase secretion, a 1.32 ± 0.13 ng second-phase secretion after 16.7 mM glucose, and 0.093 ± 0.02 ng · 20 min−1 · islet−1 at 2 mM glucose, indicating no intrinsic BB rat strain secretion abnormality. Diabetes-prone inflamed islets had secretions of 0.35 ± 0.02 ng during the first phase (P < 0.05 vs. WF) and 1.78 ± 0.29 ng during the second phase (P < 0.05 vs. WF) after 16.7 mM glucose, with 0.24 ± 0.08 ng · 20 min−1 · islet−1 at 2 mM glucose. Islets derived from diabetic rats had a first-phase secretion of 0.63 ± 0.14 ng (P < 0.05 vs. diabetes-prone noninf lamed and WF) and a second phase of 1.48 ± 0.28 ng (P < 0.05 vs. WF) with 0.30 ng · 20 min−1 · islet−1 at 2 mM glucose. Dose-response studies showed enhanced insulin secretion to each concentration of glucose when compared with controls (WF or diabetes-prone noninf lamed). These data indicate that 1) BB inflamed islets can be isolated for dynamic insulin secretion studies in nondiabetic and diabetic rats; 2) β-cell glucose sensitivity appears enhanced in islets derived from nondiabetic rats with inflamed islets or rats soon after diabetes onset; and 3) the reported impairment of in vivo acute insulin response to glucose in the BB rat model does not result primarily from a decrease in residually functioning β-cell sensitivity to glucose, but rather the data suggest a more important role for decreased residual β-cell mass.

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