Genetic evidence of causal relation between intestinal glucose absorption and early postprandial glucose response: a Mendelian randomization study.

The post-prandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose-co-transporter-1 (SGLT1). This study utilizes Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1547 subjects with class II/III obesity from the ABOS cohort, the study employs SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype served as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-minute post-load glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results showed that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study linked a one standard deviation decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mM/L. MR analysis paralleled these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decreases of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early post-load glucose response. This finding has a potential translational impact on managing early glucose response in type 2 diabetes.

The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update.

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.

A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism-Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers.

BACKGROUND AND AIMS: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. METHODS: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. RESULTS: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. CONCLUSION: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).

State-of-the-art Medical Therapy Versus Roux-en-Y Gastric Bypass Alone for Treatment of Early Diabetic Kidney Disease.

OBJECTIVE: Type 2 diabetic kidney disease (DKD) is the most common global cause of kidney disease and failure. Obesity is a major risk factor for DKD due to its causal relationship with diabetes, hypertension, and other factors promoting kidney disease. We therefore investigated whether metabolic surgery such as Roux-en-Y gastric bypass is more effective than state-of-the-art medical therapy (i.e., renin-angiotensin-aldosterone system, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists) in treating DKD. DESIGN AND METHODS: In a post hoc analysis of the Microvascular Outcomes after Metabolic Surgery trial, we compared the likelihood of regression of microalbuminuria as the primary endpoint and other renal and metabolic secondary endpoints in a population of patients with obesity, type 2 diabetes, microalbuminuria, and early chronic kidney disease followed for 24 months. Nine patients underwent Roux-en-Y gastric bypass, and 24 patients were on state-of-the-art medical therapy. RESULTS: The gastric bypass arm had a significantly higher rate of regression of microalbuminuria (P < .001), borderline significant reduction in mean urine albumin-to-creatinine ratio (P = .055), and much greater weight loss (P = .001). There were no statistically significant differences between arms in estimated glomerular filtration rate, risk of developing estimated glomerular filtration rate <60 mL/min/1.73 m2 over 5 years, mean hemoglobin A1c, systolic blood pressure, low-density lipoprotein cholesterol, or the American Diabetes Association triple endpoint. CONCLUSION: We found that metabolic surgery offers more kidney protection than state-of-the-art triple therapy for DKD at 24 months. Prospective studies in this area are necessary to better define the benefits and risks of medical versus surgical treatment of DKD.

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study.

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.

Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study.

OBJECTIVE: To prospectively characterize changes in body weight, satiety, and postprandial gut hormone profiles following esophagectomy. BACKGROUND: With improved oncologic outcomes in esophageal cancer, there is an increasing focus on functional status and health-related quality of life in survivorship. Early satiety and weight loss are common after esophagectomy, but the pathophysiology of these phenomena remains poorly understood. METHODS: In this prospective study, consecutive patients undergoing esophagectomy with gastric conduit reconstruction were studied preoperatively and at 10 days, 6 weeks, and 3 months postoperatively. Glucagon-like peptide 1 (GLP-1) immunoreactivity of plasma collected immediately before and at 15, 30, 60, 90, 120, 150, and 180 minutes after a standardized 400-kcal mixed meal was determined. Gastrointestinal symptom scores were computed using European Organization for Research and Treatment of Cancer questionnaires. RESULTS: Body weight loss at 6 weeks and 3 months postoperatively among 13 patients undergoing esophagectomy was 11.1 ±â€Š2.3% (P < 0.001) and 16.3 ±â€Š2.2% (P < 0.0001), respectively. Early satiety (P = 0.043), gastrointestinal pain and discomfort (P = 0.01), altered taste (P= 0.006), and diarrhea (P= 0.038) scores increased at 3 months postoperatively. Area under the curve for the satiety gut hormone GLP-1 was significantly increased from 10 days postoperatively (2.4 ±â€Š0.2-fold increase, P < 0.01), and GLP-1 peak increased 3.8 ±â€Š0.6-, 4.7 ±â€Š0.8-, and 4.4 ±â€Š0.5-fold at 10 days, 6 weeks, and 3 months postoperatively (all P < 0.0001). Three months postoperatively, GLP-1 area under the curve was associated with early satiety (P = 0.0002, R = 0.74), eating symptoms (P = 0.007, R = 0.54), and trouble enjoying meals (P = 0.0004, R = 0.73). CONCLUSIONS: After esophagectomy, patients demonstrate an exaggerated postprandial satiety gut hormone response, which may mediate postoperative changes in satiety, body weight, and gastrointestinal quality of life.

Management of patients with type 2 diabetes before and after bariatric surgery: evolution and microvascular complications / Manejo de pacientes con diabetes tipo 2 antes y después de la cirugía bariátrica: evolución y complicaciones microvasculares

Bariatric surgery is increasingly seen as a treatment option for patient with type 2 diabetes (T2DM) and severe complex obesity (SCO). There is however no consensus on how to manage this cohort preoperatively and postoperatively. Patients with T2DM having cardiac surgery benefit from glycaemic optimisation prior to surgery. National Health Service Diabetes in the United Kingdom recommends that glucose is optimised prior to all elective surgery. However, bariatric surgery such as gastric bypass (RYGB) is distinct from general surgery. Glycaemic control improves immediately after RYGB and thus all T2DM patients need a review of their glucose lowering medications postoperatively. Preoperatively most bariatric centres use a low calorie diet (LCD) which improved glycaemic control and may predisposed patients using insulin or sulphonylureas to risks of hypoglycaemia. There are no protocols and consensus among bariatric centres on how best to manage patients with T2DM preoperatively and postoperatively. Moreover patients with difficult to control T2DM are at risk of microvascular complications of diabetes. So far, there is little evidence on the impact of bariatric surgery on diabetes nephropathy, retinopathy and neuropathy. In conclusion, bariatric surgery improves glycaemic control; however, there are limited studies, and no guidelines on how to manage patients with T2DM pre and postoperatively. Given the increasing proportion of T2DM patients referred for bariatric surgery, there is a need to review current practice on how to manage these patients in the short term and long term with a specific focus on improving end organ damage such as retinopathy, neuropathy and nephropathy (AU)

La cirugía bariátrica se considera cada vez más como una opción de tratamiento para los pacientes con diabetes tipo 2 (DM2) y obesidad severa compleja (SCO). Sin embargo, no hay consenso sobre cómo manejar este grupo de pacientes ni preoperatoria ni postoperatoriamente. Los pacientes con diabetes tipo 2 se benefician de los conocimientos procedentes de la cirugía cardiaca en la optimización de la glucemia antes de la cirugía. Por otra parte, el Servicio Nacional de Salud para la diabetes del Reino Unido recomienda que la glucosa haya sido optimizada antes de toda cirugía electiva. Sin embargo, la cirugía bariátrica como el bypass gástrico (BPG) es diferente de la cirugía general. El control glucémico del paciente intervenido mejora inmediatamente después de la cirugía (BGYR) y por lo tanto, todos los pacientes con DM2 necesita una revisión de sus medicamentos para el control de la glucosa durante el postoperatorio. Antes de la operación, la mayoría de los centros bariátricos utilizan una dieta baja en calorías (LCD) que mejora el control glucémico y si algunos de estos pacientes continúan usando sus fármacos antidiabéticos como insulina o sulfonilureas existe un alto riesgo de hipoglucemia. Hasta el momento no existen protocolos y no hay consenso entre los centros bariátricos sobre la mejor manera de tratar a los pacientes con diabetes tipo 2 antes de la cirugía y durante el postoperatorio. Además los pacientes con difícil control de la DMT2 se encuentran en riesgo de padecer complicaciones microvasculares debidas a la diabetes. Hasta el momento, hay pocas evidencias acerca del impacto de la cirugía bariátrica sobre la nefropatía diabética, retinopatía y neuropatía. En conclusión, la cirugía bariátrica mejora el control glucémico, sin embargo, hay pocos estudios, y no hay directrices sobre la manera de tratar a los pacientes con diabetes tipo 2 antes y después de la operación. Dado el creciente número de pacientes con DM2 que se someten a cirugía bariátrica, hay una necesidad de revisar las prácticas actuales sobre la forma de tratar a estos pacientes tanto a corto como a largo plazo con un enfoque específico en la mejora de daños tales como retinopatía, neuropatía y nefropatía (AU)

Influence of diabetes surgery on gut hormones and incretins / Influencia de cirugía diabetes sobre hormonas intestinales e incretinas

The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) has become a major global public health issue. There is increasing evidence that metabolic surgery is more effective than diet and exercise for diabetes remission and weight loss. Moreover, the rapid time course and disproportional degree of T2DM improvement after metabolic procedures compared with equivalent weight loss with conservative treatment, suggest surgery-specific, weight-independent effects on glucose homeostasis. Gut hormones has been proposed as one of the potential mechanisms for the weight-independent diabetes remission and long-term weight loss after these procedures. In this review we discuss the available current metabolic procedures and we review the current human data on changes in gut hormones after each metabolic procedure (AU)

El espectacular aumento de la prevalencia de la obesidad y la diabetes mellitus tipo 2 (DMT2) se ha convertido en un importante problema de salud pública mundial. Hay evidencias crecientes de que la cirugía metabólica es más eficaz que la dieta y el ejercicio para remisión de la diabetes y la pérdida de peso. Por otra parte, el inmediato y elevado grado de mejora de la DM2 tras los procedimientos metabólicos en comparación con la equivalente pérdida de peso mediante el tratamiento conservador, sugieren efectos específicos de la cirugía, peso-independientes en la homeostasis de la glucosa. Se han propuesto a las hormonas intestinales como uno de los posibles mecanismos para la remisión de la diabetes peso-independiente y la pérdida de peso a largo plazo la después de estos procedimientos. En esta revisión se discuten los procedimientos metabólicos actuales disponibles y se revisan los datos humanos actuales sobre los cambios en las hormonas intestinales después de cada procedimiento metabólico (AU)