Increased Beta Cell Workload Modulates Proinsulin/Insulin Ratio in Humans

Increased proinsulin secretion, which characterizes type 2 diabetes and insulin resistance, may be due to an intrinsic, primitive defect in proinsulin processing, or be secondary to increased demand on β-cells (hyperinsulinemia secondary to insulin resistance). An alternative way to investigate the relation between relative hyperproinsulinemia and increased secretory demand is to study the dynamic changes in proinsulin to insulin ratio after partial pancreatectomy, a model of acute increased beta cell workload on the remaining pancreas. To pursue this aim, non-diabetic patients, scheduled for partial pancreatectomy, underwent 4-hour mixed meal tests and hyperinsulinemic euglycemic clamps before and after surgery. Following acute beta cell mass reduction, no changes were observed in fasting proinsulin to insulin ratio, while fold change in proinsulin to insulin ratio significantly increased over time after the meal. Further, our data demonstrate that whole-body insulin resistance is associated with underlying defects in proinsulin secretion, which become detectable only in the presence of increased insulin secretion demand.