RESUMO
Bariatric surgery is an important weight loss tool in individuals with severe obesity. It is currently the most effective long-term weight loss treatment that lowers obesity-related comorbidities. It also has significant physiological and nutritional consequences that can result in gastrointestinal complications and micronutrient deficiencies. After gastric bypass, clinical events that negatively affect nutritional status include malabsorption, dumping syndrome, kidney stones, altered intestinal bile acid availability, bowel obstruction, ulcers, gastroesophageal reflux, and bacterial overgrowth. Risk factors for poor nutritional status and excessive loss of lean body mass and bone include reduced dietary quality and inadequate intake, altered nutrient absorption, and poor patient compliance with nutrient supplementation. There are unique concerns in adolescents, older individuals, and individuals who become pregnant postoperatively. With careful management, health-care professionals can assist with long-term weight loss success and minimize the risk of acute and long-term nutrition complications after bariatric surgery.
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Cirurgia Bariátrica , Humanos , Cirurgia Bariátrica/efeitos adversos , Estado Nutricional , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Feminino , Obesidade Mórbida/cirurgia , Redução de Peso , Gravidez , Fatores de Risco , Obesidade/cirurgiaRESUMO
The concept of type 2 diabetes remission is evolving rapidly, and gaining wide public and professional interest, following demonstration that with substantial intentional weight loss almost nine in ten people with type 2 diabetes can reduce their HbA1c level below the diagnostic criterion (48 mmol/mol [6.5%]) without glucose-lowering medications, and improve all features of the metabolic syndrome. Pursuing nomoglycaemia with older drugs was dangerous because of the risk of side effects and hypoglycaemia, so the conventional treatment target was an HbA1c concentration of 53 mmol/mol (7%), meaning that diabetes was still present and allowing disease progression. Newer agents may achieve a normal HbA1c safely and, by analogy with treatments that send cancers or inflammatory diseases into remission, this might also be considered remission. However, although modern glucagon-like peptide-1 receptor agonists and related medications are highly effective for weight loss and glycaemic improvement, and generally safe, many people do not want to take drugs indefinitely, and their cost means that they are not available across much of the world. Therefore, there are strong reasons to explore and research dietary approaches for the treatment of type 2 diabetes. All interventions that achieve sustained weight loss of >10-15 kg improve HbA1c, potentially resulting in remission if sufficient beta cell capacity can be preserved or restored, which occurs with loss of the ectopic fat in liver and pancreas that is found with type 2 diabetes. Remission is most likely with type 2 diabetes of short duration, lower HbA1c and a low requirement for glucose-lowering medications. Relapse is likely with weight regain and among those with a poor beta cell reserve. On current evidence, effective weight management should be provided to all people with type 2 diabetes as soon as possible after diagnosis (or even earlier, at the stage of prediabetes, defined in Europe, Australasia, Canada [and most of the world] as ≥42 and <48 mmol/mol [≥6.0 and <6.5%], and in the USA as HbA1c ≥39 and <48 mmol/mol [≥5.7 and <6.5%]). Raising awareness among people with type 2 diabetes and their healthcare providers that remission is possible will enable earlier intervention. Weight loss of >10 kg and remission lasting 1-2 years may also delay vascular complications, although more evidence is needed. The greatest challenge for research is to improve long-term weight loss maintenance, defining cost-effective approaches tailored to the preferences and needs of people living with type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Estado Pré-Diabético , Humanos , Diabetes Mellitus Tipo 2/complicações , Hipoglicemia/complicações , Estado Pré-Diabético/complicações , Glucose , Redução de PesoRESUMO
AIMS: The contribution of endogenous glucagon-like peptide (GLP)-1 to ß-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 ß-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB. MATERIALS AND METHODS: Glucose, insulin secretion rates, ß-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 exendin9-39 (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 ß-cell glucose sensitivity at 3 months (-44.1%, p < .001) and 12 months (-43.3%, p < .001), but not at 24 months (-12.4%, 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 ß-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.
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Diabetes Mellitus Tipo 2 , Derivação Gástrica , Intolerância à Glucose , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose , Humanos , Insulina , Estudos RetrospectivosRESUMO
The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss.NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.
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Ácidos e Sais Biliares/metabolismo , Sistema Biliar/patologia , Ducto Colédoco/patologia , Derivação Gástrica/métodos , Glucose/metabolismo , Anastomose Cirúrgica/métodos , Animais , Ácidos e Sais Biliares/sangue , Sistema Biliar/metabolismo , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Glicemia/metabolismo , Ducto Colédoco/metabolismo , Ducto Colédoco/cirurgia , Feminino , Modelos Animais , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Período Pós-Prandial , Distribuição Aleatória , Suínos , Porco Miniatura , Redução de Peso/fisiologiaRESUMO
BACKGROUND/OBJECTIVES: Patients who receive Roux-en-Y gastric bypass (RYGB) lose more weight than those who receive vertical sleeve gastrectomy (VSG). RYGB and VSG alter hedonic responses to sweet flavor, but whether baseline differences in hedonic responses modulate weight loss after RYGB or VSG remains untested. PARTICIPANTS/METHODS: Male and female candidates (n = 66) for RYGB or VSG were recruited and tested for their subjective liking and wanting ratings of sucrose solutions and flavored beverages sweetened with aspartame. Participants were classified by unsupervised hierarchical clustering for their liking and wanting ratings of sucrose and aspartame. Participant liking ratings were also used in a supervised classification using pre-established categories of liking ratings (liker, disliker, and inverted u-shape). Effects of categories obtained from unsupervised or supervised classification on body weight loss and their interaction with surgery type were analyzed separately at 3 and 12 months after surgery using linear models corrected for sex and age. RESULTS: RYGB participants lost more body weight compared with VSG participants at 3 and 12 months after surgery (P < 0.001 for both time points). Unsupervised clustering analysis identified clusters corresponding to high and low wanting or liking ratings for sucrose or aspartame. RYGB participants in high-wanting clusters based on sucrose, but not aspartame, lost more weight than VSG at both 3 (P = 0.01) and 12 months (P = 0.03), yielding a significant cluster by surgery interaction. Categories based on supervised classification using liking ratings for sucrose or aspartame showed no significant effects on body weight loss between RYGB and VSG participants. CONCLUSIONS: Classification of patients into high/low-wanting ratings for sucrose before surgery can predict differential body weight loss after RYGB or VSG in adults and could be used to advise on surgery type.
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Bebidas , Gastrectomia , Derivação Gástrica , Obesidade Mórbida/cirurgia , Redução de Peso , Adulto , Aspartame , Sacarose Alimentar , Feminino , Preferências Alimentares , Humanos , Masculino , Período Pré-OperatórioRESUMO
In a previous study (Kissileff HR, Carretta JC, Geliebter A, Pi-Sunyer FX. Am J Physiol Regul Integr Comp Physiol 285: R992-R998, 2003), when subthreshold gastric distension (300 ml) and a low dose of cholecystokinin octapeptide (CCK-8) (112 ng/min for 21 min) were concurrently administered to human participants, intake of a test meal was significantly reduced. However, the supra-additive interaction of CCK-8 and gastric distension was not significant. The purpose of the present study was to determine whether a significant interaction would be obtained when CCK-8 and gastric distension were each increased by 50% above levels used in the previous study. Twelve normal-weight, healthy participants were tested four times each with either CCK-8 (168 ng/min for 30 min) or saline infusion crossed with gastric distension (450 ml) or no distension. The combination of CCK-8 and gastric distension reduced food intake by a mean of 405 ± 86 g (SE) in comparison with the saline nondistension condition (P < 0.001), which is a 51% reduction. Although there were some differences in the protocols, the combined effect was double that seen in the previous study. Although the interactive effect was larger [118 ± 109 g (SE)] than it was previously [73 ± 86 (SE)], it was not significant (P = 0.29). There were also reports of a short-lived sick feeling after CCK-8, with and without distension, that was not observed in the previous study. Thus the combination of CCK-8 at 1.5 times threshold and gastric distension at 450 ml (increased from 300 ml) resulted in a combined effect to reduce food intake, which was also 1.5 times its previous value, and thus appears linear.
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Colecistocinina/farmacologia , Esvaziamento Gástrico , Fragmentos de Peptídeos/farmacologia , Resposta de Saciedade/efeitos dos fármacos , Adolescente , Adulto , Ingestão de Alimentos , Feminino , Humanos , Masculino , Estômago/efeitos dos fármacos , Estômago/fisiologia , Adulto JovemRESUMO
The present study was a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self-monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon-like peptide-1 and ß-cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m2 ), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and ß-cell function did not differ between the placebo and sitagliptin groups at pre-intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on ß-cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose-lowering effect, with no identified improvement in ß-cell function.
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Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Derivação Gástrica , Fosfato de Sitagliptina/farmacologia , Adulto , Idoso , Glicemia/metabolismo , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fosfato de Sitagliptina/uso terapêuticoRESUMO
OBJECTIVE: Insufficient sleep is associated with type 2 diabetes, yet the causal impact of chronic insufficient sleep on glucose metabolism in women is unknown. We investigated whether prolonged mild sleep restriction (SR), resembling real-world short sleep, impairs glucose metabolism in women. RESEARCH DESIGN AND METHODS: Women (aged 20-75 years) without cardiometabolic diseases and with actigraphy-confirmed habitual total sleep time (TST) of 7-9 h/night were recruited to participate in this randomized, crossover study with two 6-week phases: maintenance of adequate sleep (AS) and 1.5 h/night SR. Outcomes included plasma glucose and insulin levels, HOMA of insulin resistance (HOMA-IR) values based on fasting blood samples, as well as total area under the curve for glucose and insulin, the Matsuda index, and the disposition index from an oral glucose tolerance test. RESULTS: Our sample included 38 women (n = 11 postmenopausal women). Values are reported with ±SEM. Linear models adjusted for baseline outcome values demonstrated that TST was reduced by 1.34 ± 0.04 h/night with SR versus AS (P < 0.0001). Fasting insulin (ß = 6.8 ± 2.8 pmol/L; P = 0.016) and HOMA-IR (ß = 0.30 ± 0.12; P = 0.016) values were increased with SR versus AS, with effects on HOMA-IR more pronounced in postmenopausal women compared with premenopausal women (ß = 0.45 ± 0.25 vs. ß = 0.27 ± 0.13, respectively; P for interaction = 0.042). Change in adiposity did not mediate the effects of SR on glucose metabolism or change results in the full sample when included as a covariate. CONCLUSIONS: Curtailing sleep duration to 6.2 h/night, reflecting the median sleep duration of U.S. adults with short sleep, for 6 weeks impairs insulin sensitivity, independent of adiposity. Findings highlight insufficient sleep as a modifiable risk factor for insulin resistance in women to be targeted in diabetes prevention efforts.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Transtornos do Sono-Vigília , Adulto , Humanos , Feminino , Privação do Sono/complicações , Diabetes Mellitus Tipo 2/complicações , Adiposidade , Estudos Cross-Over , Obesidade/complicações , Insulina , Glucose/metabolismo , Insulina Regular Humana , Transtornos do Sono-Vigília/complicações , Glicemia/metabolismoRESUMO
OBJECTIVE: The objective of the study was to test whether there are sustained effects of the Look AHEAD intensive lifestyle intervention (ILI), versus diabetes support and education (DSE), on weight and body composition 12 to 16 years after randomization. METHODS: Participants were a subset of enrollees in the Look AHEAD dual-energy x-ray absorptiometry substudy who completed the final visit, composed of men (DSE = 99; ILI = 94) and women (DSE = 134; ILI = 135) with type 2 diabetes and mean (SD) age 57.2 (6.4) years and BMI 34.9 (5.1) kg/m2 at randomization. Dual-energy x-ray absorptiometry measured total and regional fat and lean masses at randomization, at Years 1, 4, and 8, and at the final visit. Linear mixed-effects regressions were applied with adjustment for group, clinic, sex, age, race/ethnicity, and baseline body composition. RESULTS: Weight and most body compartments were reduced by 2% to 8% (and BMI 4%) in ILI versus DSE in men but not women. ILI-induced loss of lean tissue did not show a lower percent lean mass versus DSE at 16 years after randomization. CONCLUSION: ILI-related changes in weight, fat, and lean mass were detectable 12 to 16 years after randomization in men but, for unknown reasons, not in women. There was no evidence that the intervention led to a disproportionate loss of lean mass by the end of the study.
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Absorciometria de Fóton , Composição Corporal , Diabetes Mellitus Tipo 2 , Estilo de Vida , Humanos , Diabetes Mellitus Tipo 2/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Índice de Massa CorporalRESUMO
OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fasting plasma samples from individuals undergoing bariatric surgery (n = 71 Roux-en-Y gastric bypass [RYGB], n = 22 gastric banding), lifestyle intervention (n = 66), or usual care (n = 14) were profiled for 139 metabolites before and 2 years after weight loss. Principal component analysis grouped correlated metabolites into factors. Association of preintervention metabolites was tested with preintervention clinical features and changes in T2D markers. Association between change in metabolites/metabolite factors and change in T2D remission markers, homeostasis model assessment of ß-cell function, homeostasis model assessment of insulin resistance, and glycated hemoglobin (HbA1c) was assessed. RESULTS: Branched-chain amino acids (BCAAs) were associated with preintervention adiposity. Changes in BCAAs (valine, leucine/isoleucine) and branched-chain ketoacids were positively associated with change in HbA1c (false discovery rate q value ≤ 0.001) that persisted after adjustment for percentage weight change and RYGB (p ≤ 0.02). In analyses stratified by RYGB or other weight loss method, some metabolites showed association with non-RYGB weight loss. CONCLUSIONS: This study confirmed known metabolite associations with obesity/T2D and showed an association of BCAAs with HbA1c change after weight loss, independent of the method or magnitude of weight loss.
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Diabetes Mellitus Tipo 2 , Derivação Gástrica , Obesidade Mórbida , Humanos , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas , Obesidade/cirurgia , Obesidade/complicações , Aminoácidos de Cadeia Ramificada , Redução de Peso/fisiologia , Obesidade Mórbida/cirurgia , Obesidade Mórbida/complicaçõesRESUMO
This observational pilot study examined the association between diet, meal pattern and glucose over a 2-week period under free-living conditions in 26 adults with dysglycemia (D-GLYC) and 14 with normoglycemia (N-GLYC). We hypothesized that a prolonged eating window and late eating occasions (EOs), along with a higher dietary carbohydrate intake, would result in higher glucose levels and glucose variability (GV). General linear models were run with meal timing with time-stamped photographs in real time, and diet composition by dietary recalls, and their variability (SD), as predictors and glucose variables (mean glucose, mean amplitude of glucose excursions [MAGE], largest amplitude of glucose excursions [LAGE] and GV) as dependent variables. After adjusting for calories and nutrients, a later eating midpoint predicted a lower GV (ß = -2.3, SE = 1.0, p = 0.03) in D-GLYC, while a later last EO predicted a higher GV (ß = 1.5, SE = 0.6, p = 0.04) in N-GLYC. A higher carbohydrate intake predicted a higher MAGE (ß = 0.9, SE = 0.4, p = 0.02) and GV (ß = 0.4, SE = 0.2, p = 0.04) in N-GLYC, but not D-GLYC. In summary, our data suggest that meal patterns interact with dietary composition and should be evaluated as potential modifiable determinants of glucose in adults with and without dysglycemia. Future research should evaluate causality with controlled diets.
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Glicemia , Diabetes Mellitus Tipo 2 , Dieta , Refeições , Estado Pré-Diabético , Humanos , Projetos Piloto , Masculino , Feminino , Estado Pré-Diabético/sangue , Diabetes Mellitus Tipo 2/sangue , Glicemia/metabolismo , Adulto , Pessoa de Meia-Idade , Comportamento Alimentar , Carboidratos da Dieta/administração & dosagem , IdosoAssuntos
Infertilidade Feminina , Obesidade , Cuidado Pré-Concepcional/métodos , Saúde Reprodutiva , Técnicas de Reprodução Assistida , Adulto , Terapia Comportamental , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Obesidade/complicações , Estudos Observacionais como Assunto , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Programas de Redução de PesoRESUMO
Importance: Poor access to care and lack of health insurance are important contributors to disparities in glycemic control. However expanding health insurance coverage may not be enough to fully address the high burden of poor glycemic control for some groups. Objective: To characterize racial and ethnic disparities in glycemic control among adults with private and public insurance in the US over a 15-year timeframe and to evaluate whether social, health care, and behavioral or health status factors attenuate estimates of disparities. Design, Setting, and Participants: This cross-sectional study used data from the National Health and Nutrition Examination Survey from 2003 to 2018. Participants included Hispanic or Latino, non-Hispanic Black, and non-Hispanic White adults aged 25 to 80 years with self-reported diabetes and health insurance. Data were analyzed from January 15 to August 23, 2023. Exposure: Participants self-identified as Hispanic or Latino, non-Hispanic Black, or non-Hispanic White. Main Outcomes and Measures: The main outcome, poor glycemic control, was defined as glycated hemoglobin A1c (HbA1c) of 7.0% or greater. Information about social (education, food security, and nativity), health care (insurance type, routine place for health care, insurance gap in past year, and use of diabetes medications), and behavioral or health status (years with diabetes, waist circumference, and smoking) factors were collected via questionnaires. Results: A total of 4070 individuals (weighted mean [SE] age, 61.4 [0.27] years; 1970 [weighted proportion, 49.3%] were women) were included, representing 16â¯337â¯362 US adults, including 1146 Hispanic or Latino individuals (weighted proportion, 13.2%), 1196 non-Hispanic Black individuals (weighted proportion, 15.7%), and 1728 non-Hispanic White individuals (weighted proportion, 71.1%). In models adjusted for age, sex, and survey year, Hispanic or Latino and non-Hispanic Black individuals had significantly higher odds of poor glycemic control than non-Hispanic White individuals (Hispanic or Latino: odds ratio [OR], 1.46; 95% CI, 1.16-1.83; Black: OR, 1.28; 95% CI, 1.04-1.57). There was some attenuation after adjustment for social factors, especially food security (Hispanic or Latino: OR, 1.39; 95% CI, 1.08-1.81); Black: OR, 1.39; 95% CI, 1.08-1.81). However, accounting for health care and behavioral or health status factors increased disparities, especially for Hispanic or Latino individuals (OR, 1.63; 95% CI, 1.24-2.16), with racial and ethnic disparities persisting even among those with private insurance (OR, 1.66; 95% CI, 1.10-2.52). Conclusions and Relevance: In this cross-sectional study of insured adults with diabetes in the US, disparities in poor glycemic control persisted despite adjustment for social, health care, and behavioral factors. Research is needed to identify the barriers contributing to poor control even in populations with access to care.
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Diabetes Mellitus , Hiperglicemia , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Inquéritos Nutricionais , Estudos Transversais , Controle Glicêmico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , BrancosRESUMO
Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with p-value of 3.6e-12 in the UK biobank cohort. Additionally, we identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity and report the clinical histories of these individuals with non-syndromic obesity with no history of neurobehavioral or cognitive disability. The BMI association was replicated in the All of Us whole genome sequencing data. Heterozygous pLoF BSN variants constitute a new etiology for obesity.
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Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(18F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.
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OBJECTIVE: The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Longitudinal, prospective measures of ß-cell function were assessed after oral glucose intake and 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. RESULTS: 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 ß-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P < 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P < 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in ß-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only â¼33% of that observed after oral glucose intake. Preintervention ß-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS: Our data show the time course of changes in ß-cell function after RYGB. The improvement in ß-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.
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Diabetes Mellitus Tipo 2 , Derivação Gástrica , Resistência à Insulina , Obesidade Mórbida , Glicemia , Diabetes Mellitus Tipo 2/cirurgia , Humanos , Insulina , Resistência à Insulina/fisiologia , Obesidade Mórbida/cirurgia , Estudos ProspectivosRESUMO
Time-restricted feeding (TRF, animal-based studies) and time-restricted eating (TRE, humans) are an emerging behavioral intervention approach based on the understanding of the role of circadian rhythms in physiology and metabolism. In this approach, all calorie intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories. This article will summarize the origin of TRF/TRE starting with concept of circadian rhythms and the role of chronic circadian rhythm disruption in increasing the risk for chronic metabolic diseases. Circadian rhythms are usually perceived as the sleep-wake cycle and dependent rhythms arising from the central nervous system. However, the recent discovery of circadian rhythms in peripheral organs and the plasticity of these rhythms in response to changes in nutrition availability raised the possibility that adopting a consistent daily short window of feeding can sustain robust circadian rhythm. Preclinical animal studies have demonstrated proof of concept and identified potential mechanisms driving TRF-related benefits. Pilot human intervention studies have reported promising results in reducing the risk for obesity, diabetes, and cardiovascular diseases. Epidemiological studies have indicated that maintaining a consistent long overnight fast, which is similar to TRE, can significantly reduce risks for chronic diseases. Despite these early successes, more clinical and mechanistic studies are needed to implement TRE alone or as adjuvant lifestyle intervention for the prevention and management of chronic metabolic diseases.