Biliopancreatic diversion in patients with type 2 diabetes and moderate obesity: impact and mechanisms.

Context Diabetes remission is frequent after biliopancreatic diversion (BPD) in morbidly obese patients with type 2 diabetes (T2DM). Data, mechanisms, and clinical indications in nonobese T2DM patients are scanty. Objective To assess remission and investigate insulin sensitivity and ß-cell function after BPD in non-morbidly obese patients with long-standing T2DM. Design, setting and patients Clinical research study comparing 15 T2DM patients (age 551 years, duration 16±2 years, BMI=28.3±0.6 kg/m2, HbA1c=8.6±1.3%) with 15 gender-, age-, and BMI-matched nondiabetic controls. Before surgery, and 2 months and one year later, a 3-hour OGTT, a 5-hour mixed meal test, and a 3-hour euglycemic clamp were performed. Intervention BPD (gastric resection, distal jejunum anastomosed to remaining stomach, biliopancreatic tract anastomosed to ileum 75cm from the ileocecal valve). Results Glycemia improved in all patients, but remission (HbA1c<6.5% and normal OGTT) occurred in 6/15. Insulin resistance (19.8±0.8 µmol.min-1.kgffm-1, p<0.001 vs 40.9±5.3 of controls) resolved already at 2 months (34.2±2.8) and was sustained at one year (34.7±1.6), although insulin-mediated suppression of endogenous glucose production remained impaired. In contrast, ß-cell glucose sensitivity (19[12] pmol.min-1.m-2.mM-1 vs 96[73] of controls, p<0.0001) rose (p=0.02) only to 31[26] at one year, and was lower in non-remitters (16[18]) than remitters (46[33]). Conclusions In nonobese patients with long-standing T2DM, BPD improves metabolic control but induces remission in only ~30% of patients. Peripheral insulin sensitivity is restored early after surgery, and similarly in remitters and non-remitters, indicating a weight-independent effect of the operation. The initial extent of ß-cell incompetence is the main predictor of the metabolic outcome

Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery

Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. We related the histology of subcutaneous (SAT), visceral fat (VAT), and skeletal muscle to the metabolic abnormalities, and tested their mutual changes after bariatric surgery in type 2 diabetic (T2D) and weight-matched non-diabetic (ND) patients. We measured IR (insulin clamp), lipolysis ((2)H5-glycerol infusion), ß-cell glucose-sensitivity (ß-GS, mathematical modeling), and VAT, SAT, and rectus abdominis histology (light and electron microscopy). Presurgery, SAT and VAT showed signs of fibrosis/necrosis, small mitochondria, free interstitial lipids, thickened capillary basement membrane. Compared to ND, T2D had impaired ß-GS, intracapillary neutrophils and higher intramyocellular fat, adipocyte area in VAT, crown-like structures (CLS) in VAT and SAT with rare structures (cyst-like) ~10-fold larger than CLS. Fat expansion was associated with enhanced lipolysis and IR. VAT histology and intramyocellular fat were related to impaired ß-GS. Postsurgery, IR and lipolysis improved in all, ß-GS improved in T2D. Muscle fat infiltration was reduced, adipocytes were smaller and richer in mitochondria, and CLS density in SAT was reduced. In conclusion, IR improves proportionally to weight loss but remains subnormal, whilst SAT and muscle changes disappear. In T2D postsurgery, some VAT pathology persists and beta-cell dysfunction improves but is not normalized

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass

ObjectiveTo determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement.Materials and methodsProspective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota.ResultsThirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P&lt;0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P&lt;0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients.ConclusionsPatients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature

SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes

Pancreatic beta cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in beta cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone -like metabolite and stimulated insulin secretion via a SUCNR1-GqPKC-dependent mechanism in human beta cells. Mice with beta cell-specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high -fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet -induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition -related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states

Changes in glucagon‐like peptide 1 and 2 levels in people with obesity after a diet‐induced weight‐loss intervention are related to a specific microbiota signature: A prospective cohort study

The study was supported by grants from the Instituto de Salud Carlos III (PI14/00228, PI17/0153 and PI20/00338 to J.V.), Ministerio de Ciencia e Innovación (RTI2018- 093919-B-I00 to S.F.-V. and PID2019-105969GB-I00 to A.M) and Generalitat Valenciana (PROMETEO/2018/A/133 to A.M), co-financed by the European Regional Development Fund. The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. S.FV. acknowledges the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from Fondo de Investigación Sanitaria.Peer reviewe

Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD

[Objective]: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.[Methods]: We studied the phenotype of wild-type and Sucnr1−/− mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages.[Results]. Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm.[Conclusions]. We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.This study was supported by grants from MCIN/AEI/10.13039/501100011033 (SAF2015-65019-R, RTI2018-093919-B-100 and PID2021-122480OB-100 to S.F.-V.; PID2021-122766OB-100 to A.M.V; PID2021-124425OB-I00 to P.A.) co-financed by the European Regional Development Fund (ERDF) and Grupos consolidados Gobierno Vasco IT1476-22 to P.A. This research was funded by the Institute of Health “Carlos III” (ISCIII) and co-financed by ERDF (PI20/00095 to V.C.-M.; PI20/00338 to J.V. and PI20/00505 to B.R.-M.). This study was also supported by a grant from ISCIII and CIBERDEM, DEM19PI01/2019 to V.C.-M. and P.R. The project that gave rise to these results received funding from “La Caixa” Foundation (ID 100010434), under the grant agreement LCF/PR/HR20/52400013 (to S.F.-V.). This study was also supported by Rovira i Virgili University and Tarragona Provincial Council with the Talent Salut fellowship to A.R.-C. A.M.-B. is a recipient of an FPU grant (FPU20/05633) from MCIN/AEI/10.13039/501100011033. B.A. acknowledges support from the PERIS program 2016–2020 (LT017/20/000033), from Departament de Salut de la Generalitat de Catalunya. V.C.-M. acknowledges support from the Ramón y Cajal program (RYC2019-02649-I), from MCIN/AEI/10.13039/501100011033/ and the European Social Fund (ESF), “Investing in your future”. B.R.-M. acknowledges support from the Miguel Servet Type I program (CP19/00098) from the Fondo de Investigación Sanitaria, co-financed by the ERDF. SFV and JVO acknowledge support from the Agency for Management of University Research Grants of the Generalitat de Catalunya (2021 SGR 01409, 2021 SGR 0089). The study was also supported by CIBER–Consorcio Centro de Investigación Biomédica en Red (CB07708/0012), ISCIII, Ministerio de Ciencia e Innovación.Peer reviewe

Decreased expression of hepatic glucokinase in type 2 diabetes

Background/objectives: Increased endogenous glucose production is a hallmark of type 2 diabetes. Evidence from animal models has suggested that a likely cause of this is increased mRNA expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase (encoded by G6PC, PCK1 and PCK2). But another contributing factor may be decreased liver glucokinase (encoded by GCK). Methods: We examined expression of these enzymes in liver biopsies from 12 nondiabetic and 28 diabetic individuals. Diabetic patients were further separated into those with HbA1c lower or higher than 7.0. Results: In diabetic subjects with HbA1c > 7.0, we found that gluconeogenic enzymes were expressed normally, but GCK was suppressed more than 60%. Moreover, HbA1c and fasting glucose were negatively correlated with GCK, but showed no correlation with G6PC, PCK1, or PCK2. Conclusion: These findings suggest an underlying dysregulation of hepatic GCK expression during frank diabetes, which has implications for the therapeutic use of glucokinase activators in this population