Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes

At the time of diagnosis of type 2 diabetes (T2D), patients already have varying degrees of beta-cell dysfunction and insulin resistance and the defects continue to deteriorate despite treatment. We examined insulin secretion impairment and insulin resistance in overweight patients with T2D who had metformin failure, with elevated HbA1c at maximal metformin dose. Patients (N = 1,039) were examined at entry to the European Exenatide (EUREXA) clinical trial of add-on exenatide versus sulphonylurea. Mean (±SD) age was 57 ± 10 years, and BMI was 32.4 ± 4.1 kg/m². All patients underwent an oral glucose tolerance test; HOMA-IR, HOMA-B, ∆I ₃₀/∆G ₃₀, disposition index and pro-insulin/insulin ratio were evaluated in relation to stratified HbA1c levels (≤7.3, >7.3–8.2, >8.2%) and duration of diabetes (<3, ≥3–<6, ≥6 years) using non-parametric analysis of variance. Patients overall had a wide range of impaired insulin secretion (HOMA-B: median 50.4, interquartile range 32.8–78.8) and insulin resistance (HOMA-IR: 4.8, 3.0–7.4). With increasing HbA1c levels, there was a statistically significant decrease in HOMA-B (P < 0.001), ∆I ₃₀/∆G ₃₀ (P = 0.003) and disposition index (P < 0.001), and increase in pro-insulin/insulin (P < 0.001) and HOMA-IR (P < 0.001). With increasing duration since diabetes diagnosis, there was a significant decrease in HOMA-B (P < 0.001), but no significant trend in HOMA-IR, ∆I ₃₀/∆G ₃₀, disposition index or pro-insulin/insulin. Metformin failure in these patients was associated with beta-cell dysfunction to a greater extent than insulin resistance. Loss of the first-phase insulin release, indicated by a low ∆I ₃₀/∆G ₃₀, would indicate that this patient cohort requires add-on therapy that can maintain beta-cell function.