Glucose-lowering in type 2 diabetes may be mediated by improved proinsulin processing without better β-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 trial in which 90 adults with T2DM (mean A1c 6.5% ± 0.7%) were randomized to 8-wk treatment with 1) basal insulin glargine (Glar), 2) glargine plus thrice-daily meal insulin lispro (Glar/Lispro), or 3) glargine plus twice-daily administration of the glucagon-like peptide-1 receptor agonist exenatide (Glar/Exe). At baseline, after 8-wk treatment and again after subsequent 12-wk washout, participants underwent assessment of insulin sensitivity/resistance [Matsuda index; Homeostasis Model of Assessment of Insulin Resistance (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-wk, 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 four measures of beta-cell compensation. In mediation analyses, fasting PI:C emerged as the sole biologic mediator of the respective A1c treatment effects of Glar/Lispro (P = 0.03) and Glar/Exe (P = 0.01) vs. Glar. In conclusion, it thus emerges that glucose-lowering in T2DM may be achieved through improved proinsulin processing without better beta-cell compensation.NEW & NOTEWORTHY In this report, mediation analyses identify the fasting proinsulin-to-C-peptide ratio as a biologic determinant of the A1c treatment effect observed in a recently reported clinical trial in which the study interventions had no differential effect on pancreatic beta-cell compensation. These findings suggest that glucose-lowering may be achieved through improved proinsulin processing without better beta-cell compensation, supporting consideration of proinsulin biology as a potential novel therapeutic target in the management of type 2 diabetes.