Amanda Jiménez

GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery

OBJECTIVE Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP. RESEARCH DESIGN AND METHODS Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9–39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. RESULTS Infusion of exendin-(9–39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9–39) 116.5 ± 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9–39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses. CONCLUSIONS The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.

GLP-1 and Glucose Tolerance After Sleeve Gastrectomy in Morbidly Obese Subjects with Type 2 Diabetes

Although GLP-1 has been suggested as a major factor for the marked improvement of glucose tolerance commonly seen after sleeve gastrectomy (SG), several observations challenge this hypothesis. To better understand the role of GLP-1 in the remission of type 2 diabetes mellitus (T2DM) long term after SG in humans, we conducted two separate cross-sectional studies: 1) the GLP-1 response to a standardized mixed liquid meal (SMLM) was compared in subjects with T2DM antedating SG but with different long-term (>2 years) T2DM outcomes (remission, relapse, or lack of remission) (study 1) and 2) the effect of GLP-1 receptor blockade with exendin (9-39) on glucose tolerance was examined in subjects with T2DM antedating surgery, who had undergone SG and presented with long-term T2DM remission (study 2). In study 1, we observed a comparable GLP-1 response to the SMLM regardless of the post-SG outcome of T2DM. In study 2, the blockade of GLP-1 action resulted in impaired insulin secretion but limited deterioration of glucose tolerance. Thus, our data suggest the enhanced GLP-1 secretion observed long term after SG is neither sufficient nor critical to maintain normal glucose tolerance in subjects with T2DM antedating the surgery.

GLP-1 and the long-term outcome of type 2 diabetes mellitus after Roux-en-Y gastric bypass surgery in morbidly obese subjects.

Objective:To evaluate the association between glucagon-like peptide 1 (GLP-1) secretion and the long-term (>2 years) outcome of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGBP). Methods:Cross-sectional study in 18 T2DM morbidly obese subjects who underwent RYGBP but differed in the long-term outcome of T2DM (remission: G1, n = 6; relapse: G2, n = 6; lack of remission: G3: n = 6). Groups were matched for their sex, age, and body mass index. The GLP-1, glucose, C-peptide, and glucagon responses to a standardized test meal (STM) were evaluated. Insulin secretion and insulin sensitivity were estimated from the STM and by frequently sampling intravenous glucose tolerance test (FSIVGTT). Dual-energy X-ray absorptiometry was used to assess body composition. Results:Patients in G1 presented a lower area under the curve (AUC0–120) of glucose in response to the STM as compared with G2, and G3 (P < 0.01). In contrast, the AUC0–120 of GLP-1 (P = 0.884) and glucagon (P = 0.630) did not differ significantly among the 3 groups. Indices of insulin secretion adjusted by the prevailing insulin sensitivity derived from STM and FSIVGTT, demonstrated larger &bgr;-cell function in subjects in G1 as compared with G2 or G3 (Disposition Index-STM, P = 0.005; DI-FSIVGTT, P = 0.006). Body composition and inflammatory markers did not differ significantly among the 3 study groups. Conclusions:Our data show that in subjects with T2DM an enhanced GLP-1 response to meal intake is not sufficient to maintain normal glucose tolerance in the long term after RYGBP. Our data suggest that &bgr;-cell function is a key determinant of the long-term remission of T2DM after this bariatric surgery technique.

Remission of type 2 diabetes after Roux-en-Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile.

BACKGROUND Roux-en-Y gastric bypass (RYGBP) and sleeve gastrectomy (SG) have been associated with a high remission rate of type 2 diabetes mellitus (T2DM). However, whether such remission is associated with full restoration of postprandial glucose profile and/or the potentially nonrestored glycemic profile is associated with altered beta cell function, and relapse of T2DM over time is unknown. METHODS Cross-sectional studies comparing (1) glucose and proinsulin/insulin response to a standardized liquid mixed meal (SLMM) challenge (n = 31), (2) glucose response in normal living conditions assessed using continuous glucose monitoring (CGM) (n = 16), and prospective observational study comparing (3) rates of relapse of T2DM after surgery (n = 232) in subjects with remission of T2DM ensuing RYGBP or SG. RESULTS In RYGB individuals, SLMM elicited faster and sharper rise in plasma glucose compared with SG, with 88.2% and 42.9% of the study subjects presenting respectively a peak glucose more than 180 mg/dL (all, P < 0.05). During CGM, average percent time in hyperglycemic and hypoglycemic range was larger in RYGBP (respectively, 4.6% and 12.7%) compared with SG subjects (respectively, 0.4% and 3.2%; both P < 0.05). However, (1) no differences were found in fasting or stimulated proinsulin/insulin ratio, and (2) higher rates of T2DM relapse were observed after SG (hazard ratio: 2.339; P = 0.034). CONCLUSIONS Remission of T2DM after RYGBP and SG is associated with distinct glycemic profiles. However, longer time spent in hyperglycemia and in hypoglycemia after RYGBP compared with SG is not associated with persistence of altered beta cell function or higher rates of relapse of T2DM over time.

Prediction of Whole-Body and Segmental Body Composition by Bioelectrical Impedance in Morbidly Obese Subjects

BackgroundValidated equations for body composition analysis using bioelectrical impedance (BIA) in morbidly obese (MO) subjects are scarce. Thus, our aim was to develop new equations from physical and BIA parameters to estimate whole-body and segmental body composition in MO subjects, with dual-energy X-ray absorptiometry (DXA) as the reference method.MethodsA cross-sectional study on 159 Caucasian MO subjects (female 78%, age 43.5 ± 11.8 years, BMI 45.6 ± 4.9 kg/m2) divided in two groups was conducted: model building cohort (n = 110) and model validation cohort (n = 49). Stepwise regression analysis was used to develop specific fat free mass (FFM) and fat mass (FM) equations.ResultsGender, body weight, and height2/impedance accounted, respectively, for 89.4% (p < 0.001) and 89.3% (p < 0.001) of the variability of DXA-total FFM in the two cohorts. Using the new equation, the mean difference between the DXA-FFM and BIA-FFM estimates was +0.180 kg (95% CI: -0.34 to +0.7 kg, p = NS), and the resulting limits of agreement were +6.76 and −6.40 kg. Similarly, good estimates of DXA truncal-, android-, and gynoid-FM from anthropometric and BIA parameters could be obtained from weight, height2/impedance, and waist and hip circumferences (respectively, R2 adjusted: 0.657, 0.776, and 0.770; p < 0.001).ConclusionsThe new equations derived from physical and BIA parameters provide accurate estimates of body composition in MO subjects.

Individualized Metabolic Surgery Score: Procedure Selection Based on Diabetes Severity

Objective: To construct and validate a scoring system for evidence-based selection of bariatric and metabolic surgery procedures according to severity of type 2 diabetes (T2DM). Background: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for >95% of bariatric procedures in United States in patients with T2DM. To date, there is no validated model to guide procedure selection based on long-term glucose control in patients with T2DM. Methods: A total of 659 patients with T2DM who underwent RYGB and SG at an academic center in the United States and had a minimum 5-year follow-up (2005–2011) were analyzed to generate the model. The validation dataset consisted of 241 patients from an academic center in Spain where similar criteria were applied. Results: At median postoperative follow-up of 7 years (range 5–12), diabetes remission (HbA1C <6.5% off medications) was observed in 49% after RYGB and 28% after SG (P < 0.001). Four independent predictors of long-term remission including preoperative duration of T2DM (P < 0.0001), preoperative number of diabetes medications (P < 0.0001), insulin use (P = 0.002), and glycemic control (HbA1C < 7%) (P = 0.002) were used to develop the Individualized Metabolic Surgery (IMS) score using a nomogram. Patients were then categorized into 3 stages of diabetes severity. In mild T2DM (IMS score ⩽25), both procedures significantly improved T2DM. In severe T2DM (IMS score >95), when clinical features suggest limited functional &bgr;-cell reserve, both procedures had similarly low efficacy for diabetes remission. There was an intermediate group, however, in which RYGB was significantly more effective than SG, likely related to its more pronounced neurohormonal effects. Findings were externally validated and procedure recommendations for each severity stage were provided. Conclusions: This is the largest reported cohort (n = 900) with long-term postoperative glycemic follow-up, which, for the first time, categorizes T2DM into 3 validated severity stages for evidence-based procedure selection.

Gastrointestinal hormones and weight loss response after Roux-en-Y gastric bypass

BACKGROUND Mechanisms underlying variable weight loss (WL) response after Roux-en-Y gastric bypass (RYGB) are poorly understood. The objective of this study was to compare gastrointestinal hormonal responses to meal intake, and fasting plasma concentrations of surrogate markers of enterocyte mass and bile acid effect between patients with failed (F-WL) or successful WL (S-WL) after RYGB. METHODS Cross-sectional study including 30 nondiabetic patients, evaluated at≥24 months after RYGB. Cases (F-WL; n = 10) and controls (S-WL; n = 20) were selected based on percent of excess WL (%EWL)<50% or≥50% from 12 months onwards after surgery. Groups were matched for gender, age, presurgical BMI, and length of follow up. Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), GLP-2, and ghrelin responses to a meal challenge, and fasting plasma concentrations of citrulline and serum fibroblast growth factor 19 (FGF-19) were compared. RESULTS F-WL patients presented lesser suppression of ghrelin (incremental area under the curve [iAUC]: F-WL -12490±6530 versus S-WL -31196±4536 pg×mL(-1)×min; P<.01), and lesser increase in the GLP-1 (iAUC: F-WL 3354±737 versus S-WL 5629±542 pmol×L(-1)×min; P = .02) but not in the PYY and GLP-2, response to meal intake. Citrulline concentrations were significantly correlated with time after surgery (rho = .537; P<.01). However, citrulline was higher in S-WL compared to F-WL patients (P<.05). Serum FGF-19 concentration was similar between groups. CONCLUSION Although limited by the cross-sectional design, our data suggest a role of some gastrointestinal hormones as mediators of successful weight loss but argues against larger enterocyte mass after BS as determinant of failed weight loss after RYGB.

Relevance of beta-cell function for improved glycemic control after gastric bypass surgery

BACKGROUND Residual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (>.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups. METHODS Percent excess weight loss (%EWL), HbA1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0-120 minutes) after a mixed meal at last follow-up visit were also compared. RESULTS At 24-months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean±standard error, 82.6% ± 11.3% and 87.4% ± 30.5%, respectively; P = .722]. In women with T1 DM, HbA1c (4 months, P<.05) and DID improved transiently (P<.05, up to 8 months) but were comparable to baseline thereafter (HbA1c: baseline, 8.3 ± 1.2 and 24 months, 8.2 ± .9, P = 1.00; DID: baseline, .61 ± .17 and 24 months .62 ± .12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA1c decreased significantly throughout follow-up, with 2 patients presenting diabetes remission and all but one an HbA1c<7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake. CONCLUSIONS In the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake.

Diabetes Remission Following Metabolic Surgery: Is GLP-1 the Culprit?

The parallel occurrence of improved glucose tolerance and increased glucagon-like peptide 1 (GLP-1) response to meal intake following metabolic surgery (MS) demonstrated in several studies has led to the notion that GLP-1 is the culprit for the impressive rates of remission of type 2 diabetes mellitus (T2DM) following MS. In this article, we critically review current evidence supporting this view. Recent studies specifically designed to elucidate a causative role of GLP-1 in the antidiabetic effects of MS call into question GLP-1 as a key player for T2DM outcome following MS procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy in morbidly obese subjects. Whether GLP-1 plays a more prominent role in the remission of T2DM following MS in subjects with moderate obesity warrants further studies. Appraisal of the mechanisms involved in the amelioration of hyperglycemia following MS is a priority, as it could help in the battle against the current combined epidemics of obesity and T2DM.

Pancreas and kidney transplantation: long-term endocrine function

Mora M, Ricart MJ, Casamitjana R, Astudillo E, López I, Jiménez A, Fernández‐Cruz L, Esmatjes E. Pancreas and kidney transplantation: long‐term endocrine function. 
Clin Transplant 2010: 24: E236–E240.