Glucose-lowering in Type 2 Diabetes may be mediated by improved Proinsulin Processing without better Beta-cell Compensation

In type 2 diabetes (T2DM), glucose-lowering is typically achieved by enhancing the capacity of the pancreatic beta-cells to compensate for ambient insulin resistance. Impaired processing of proinsulin, as reflected by an elevated ratio of fasting serum proinsulin to C-peptide (PI:C), is a marker of beta-cell stress but not compensation. Indeed, it is unclear whether enhancing proinsulin processing alone can improve glycemic control in T2DM. We thus sought to evaluate the impact of proinsulin processing on glucose-lowering in a recently-reported clinical trialin which 90 adults with T2DM (mean A1c 6.5%±0.7%) were randomized to 8-weeks treatment with (i) basal insulin glargine (Glar), (ii) glargine plus thrice-daily meal insulin lispro (Glar/Lispro), or (iii) glargine plus twice-daily administration of the glucagon-like peptide-1 receptor agonist exenatide (Glar/Exe). At baseline, after 8-weeks treatment and again after subsequent 12-weeks washout, participants underwent assessment of insulin sensitivity/resistance (Matsuda index; HOMA-IR), beta-cell compensation (Insulin Secretion-Sensitivity Index-2; insulinogenic index/HOMA-IR; ΔCpeptide0-120/Δglucose0-120×Matsuda; ΔISR0-120/Δgluc0-120×Matsuda), and proinsulin processing (fasting PI:C). At 8-weeks, both A1c (6.2%±0.4% vs 5.9%±0.5% vs 5.8%±0.4%, p=0.007) and fasting PI:C (0.013±0.011 vs 0.009±0.006 vs 0.008±0.005, p=0.01) progressively decreased from Glar to Glar/Lispro to Glar/Exe, with no differences between the groups in Matsuda index, HOMA-IR or any of the 4 measures of beta-cell compensation. On mediation analyses, fasting PI:Cemerged as the sole biologic mediator of the respective A1c treatment effects of Glar/Lispro (p=0.03) and Glar/Exe (p=0.01) versus Glar. In conclusion, it thus emerges that glucose-lowering in T2DM may be achieved through improved proinsulin processing without better beta-cell compensation.