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

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

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