Proinsulin Associates With Poor Beta‐Cell Function, Glucose‐Dependent Insulinotropic Peptide and Insulin Resistance in Persistent Type 2 Diabetes After Roux‐en‐Y Gastric Bypass in Humans

BACKGROUND: The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized beta- and alpha-cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non-remitters) diabetes remission after RYGB. METHODS: This is a cross-sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent-either an oral glucose (remitters) or a mixed meal (non-remitters) test; glucose, proinsulin, insulin, C-peptide, glucagon, incretins and leptin were measured. RESULTS: Compared to remitters (n = 23), non-remitters (n = 31) were older (mean [+/-SD] age 56.1 +/- 8.2 vs. 46.0 +/- 8.9 years, P < 0.001), had longer diabetes duration (13.1 +/- 10.1 vs. 2.2 +/- 2.4 years, P < 0.001), were further out from the surgery (5.6 +/- 3.3 vs. 3.5 +/- 1.7 years, P < 0.01), were more insulin resistant (HOMA-IR 4.01 +/- 3.65 vs. 2.08 +/- 1.22, P < 0.001), but did not differ for body weight. As predicted, remitters had higher beta-cell glucose sensitivity (1.95 +/- 1.23 vs. 0.86 +/- 0.55 pmol/kg/min/mmol, P < 0.001) and disposition index (1.55 +/- 1.75 vs 0.33 +/- 0.27, P = 0.003), compared to non-remitters, who showed non-suppressibility of glucagon during the oral challenge (time x group P = 0.001). Higher proinsulin (16.55 +/- 10.45 vs. 6.62 +/- 3.50 PM, P < 0.0001), and proinsulin: C-peptide (40.83 +/- 29.43 vs. 17.13 +/- 7.16, P < 0.001) were strongly associated with non-remission status, while differences in incretins between remitters and non-remitters were minimal. CONCLUSIONS: Individual without diabetes remission after gastric bypass have poorer beta-cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status.