Determinants of reversibility of β-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes

Short-term intensive insulin therapy (IIT) can improve pancreatic beta-cell function when administered early in the course of type 2 diabetes mellitus (T2DM). However, the degree of improvement in response to this therapy varies between patients. Thus, we sought to characterize the determinants of improvement in beta-cell function in response to short-term IIT in early T2DM. Sixty-three patients with mean 3.0 +/- 2.1 yr duration of T2DM and Hb A(1c) of 6.8 +/- 0.8% underwent 4 wk of IIT consisting of basal insulin detemir and premeal insulin aspart, with oral glucose tolerance test administered at baseline and 1 day post-IIT. beta-Cell function before and after IIT was assessed by Insulin Secretion Sensitivity Index-2 (ISSI-2). Reversibility of beta-cell dysfunction was defined as percentage change in ISSI-2 of >= 25%. Overall, the study population experienced an increase in ISSI-2 from baseline to post-IIT (P = 0.01), with one-third of participants achieving = 25% improvement in ISSI-2. Compared with their peers, those with increases in ISSI-2 of >= 25% had greater decrements in fasting glucose (P < 0.0001), Hb A(1c) (P = 0.001), ALT (P = 0.04), AST (P = 0.02), and HOMA-IR (P < 0.0001). On logistical regression analysis, baseline Hb A(1c) (OR = 2.83, 95% CI 1.16-6.88, P = 0.02) and change in HOMA-IR (OR = 0.008, 95% CI 0.0004-0.16, P = 0.001) emerged as independent predictors of reversibility of beta-cell dysfunction. Indeed, reversibility of beta-cell dysfunction was achieved in only those participants in whom IIT yielded an improvement in HOMA-IR. In conclusion, decline in HOMA-IR may be a key determinant of improvement of beta-cell function in response to short-term IIT, suggesting a fundamental contribution of insulin resistance to the reversible component of beta-cell dysfunction in early T2DM.