Proinsulin associates with poor β‐cell function, glucose‐dependent insulinotropic peptide, and insulin resistance in persistent type 2 diabetes after Roux‐en‐Y gastric bypass in humans

Abstract

Background: The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized β-and α-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 under-wenteither 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 β-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 × 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 nonremitters were minimal. † This study is registered with Clinicaltrials.gov (ID: NCT01512797 and NCT01516320).

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes

“…For some individuals, reductions in metabolic demand may enable reversal of beta-cell dysfunction, as illustrated by improvements in proinsulin levels and proinsulin/insulin ratios. For example, T2D subjects who respond to bariatric surgery with diabetes remission are characterized by lower proinsulin levels and proinsulin/C-peptide ratios than nonremitters ( 20 ). In contrast, increased metabolic demand with experimental induction of insulin resistance and increased insulin secretion can increase proinsulin/insulin ratios in T2D subjects ( 21 ).…”

Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. Two Sculptors of the Pancreatic Islet

“…Like SG, the outcomes of RYGB published in relevant trials have shown a progressive worsening of diabetes-related parameters such as glycated hemoglobin, reaching a 50% relapse in diabetes at five years [ 2 ]. Patel et al proposed weak beta-cell function and peripheral insulin resistance as possible causes of relapse after RYGB [ 43 ]. An decrease in beta-cell mass and an increase in alpha-cell mass could explain this, but what is the mechanism that triggers trans-differentiation?…”

Glucagon‐like peptide‐1 effect on β‐cell function varies according to diabetes remission status after Roux‐en‐Y gastric bypass

“…The incretin hormone glucagon‐like peptide‐1 (GLP‐1), secreted in response to nutrient ingestion, is critical for postprandial glucose‐mediated insulin secretion 3 . After RYGB, postprandial circulating GLP‐1 concentrations increase 5‐10‐fold in response to accelerated nutrient entry and absorption 4 and the blunted incretin effect observed in T2D 5 is restored; these effects occur within days 4,6 and persist for years 7,8 …”

“…3 After RYGB, postprandial circulating GLP-1 concentrations increase 5-10-fold in response to accelerated nutrient entry and absorption 4 and the blunted incretin effect observed in T2D 5 is restored; these effects occur within days 4,6 and persist for years. 7,8 The contribution of endogenous GLP-1 to improved β-cell function and glycaemia after RYGB has been investigated by blocking the GLP-1 receptor with the peptide exendin 9À39 (EX9) during a mixed meal or oral glucose administration. Intravenous infusion of EX9 before an oral stimulus blunts insulin secretion by approximately half and reverses the improvement in β-cell glucose sensitivity (BCGS) observed after RYGB.…”