Hepatic insulin clearance is a significant regulator of glucose homestasis. We hypothesized that the improvement in insulin clearance rates (ICRs) under fasting conditions and in response to oral and intravenous (IV) glucose would improve similarly after Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) as a function of weight loss; the difference in ICR after oral and IV glucose stimulation will be enhanced after RYGB compared with AGB, an effect mediated by glucagon-like peptide 1 (GLP-1). RESEARCH DESIGN AND METHODS In study 1, the ICR was calculated under fasting condition (F-ICR), after oral glucose (O-ICR), and after an isoglycemic IV glucose clamp (IV-ICR) in individuals from an established cohort with type 2 diabetes mellitus (T2DM) before, after 10% matched weight loss, and 1 year after either RYGB (n = 22) or AGB (n = 12). In study 2, O-ICR was studied in a separate cohort of individuals with T2DM (n = 22), before and 3 months after RYGB, with and without exendin(9-39) infusion. RESULTS In study 1, age, BMI, T2DM duration and control, and ICR did not differ between RYGB and AGB preintervention. Weight loss at 1 year was two times greater after RYGB than after AGB (31.6 6 5.9% vs. 16.6 6 9.8%; P < 0.05). RYGB and AGB both significantly increased F-ICR, O-ICR, and IV-ICR at 1 year. ICR was inversely associated with insulinemia. The difference between IV-ICR and O-ICR was significantly greater after RYGB versus AGB. GLP-1 antagonism with exendin(9-39) led to an increase in O-ICR in subjects post-RYGB. CONCLUSIONS Weight loss increased ICR, an effect more pronounced after RYGB compared with AGB. Our data support a potential role for endogenous GLP-1 in the control of postprandial ICR after RYGB. Hyperinsulinemia is a risk factor for cardiovascular disease (1). Circulating concentrations of insulin are dependent on b-cell insulin secretion capacity and insulin clearance from the blood (2). About 70% of secreted insulin is cleared by the liver prior to entering the systemic circulation (3). Hepatic insulin clearance rate (ICR) is decreased in many aspects of the metabolic syndrome, such as obesity (4), hypertension, hypertriglyceridemia, and glucose intolerance (5).
Aims:The contribution of endogenous glucagon-like peptide (GLP)-1 to β-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on β-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB.Materials and Methods: Glucose, insulin secretion rates, β-cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP-1 receptor blocker exendin 9À39 (EX9). The cohort was retrospectively classified based on T2D remission (REM) status at the latest study time point: REM (n = 5), persistent T2D (n = 8), or impaired glucose tolerance (n = 16).Results: EX9 blunted the increase in β-cell glucose sensitivity at 3 months (À44.1%, p < .001) and 12 months (À43.3%, p < .001), but not at 24 months (À12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p < .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months.Conclusions: GLP-1 blockade reversed the improvement in β-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.
<i>Objective</i>: The role of the gut in diabetes remission after gastric bypass (RYGB) is incompletely understood. We therefore assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. <p><i>Research Design and Methods:</i> Longitudinal, prospective measures of β-cell function after oral glucose and IV graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n=29), 12 (n=24) and 24 (n=20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center.</p> <p><i>Results</i>: The decreases in body weight, fat mass, waist circumference and insulin resistance after surgery (all p<0.001 at 12 and 24 months), did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose differed by remission status (p=0.04): greater (6.5 fold, p<0.01) and sustained in full remitters, moderate and not sustained past 12 months in partial remitters (3.3 fold, p<0.001), minimal in non-remitters (2.7 fold, p=ns). The improvement in β-cell function after IV glucose was not apparent until 12 months, significant only in full remitters, and only ~1/3 of that observed after oral glucose.</p> <p>Pre-intervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. </p> <p><i>Conclusion</i>: Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.</p>
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).
Supplemental Table 2: Change of β-cell function and insulin clearance during oral and GGI challenges by remission statusData are given as mean ± SD. Different letter superscripts indicate statistically significant differences between groups at each condition by one-way ANOVA post-hoc multiple comparison tests at p<0.05 level. *p<0.05; **p<0.01;***p<0.001 indicate within group differences from pre-surgery; Variables denoted by (¥) are not normally distributed and statistical analysis was done with log-transformed data.
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