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AIM: To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. RESULTS: Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. CONCLUSIONS: Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.
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Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown. We investigated the effects of ghrelin infusion on appetite and glucose tolerance in individuals with obesity before and three months after SG. Twelve participants scheduled for SG were included. Before and three months after surgery, a mixed-meal test followed by an ad libitum meal test was performed with concomitant infusions of acyl-ghrelin (1 pmol/kg/min) or placebo. Infusions began 60 minutes prior to meal intake to reach a steady state before the mixed-meal and were continued throughout the study day. Two additional experimental days with 0.25 pmol/kg/min and 10 pmol/kg/min of acyl-ghrelin infusions were conducted three months after surgery. Both before and after SG, postprandial glucose concentrations increased dose-dependently during ghrelin infusions compared with placebo. Ghrelin infusions inhibited basal and postprandial insulin secretion rates, resulting in lowered measures of ß-cell function, but no effect on insulin sensitivity was seen. Ad libitum meal intake was unaffected by the administration of ghrelin. Ghrelin infusion increases postprandial plasma glucose concentrations and impairs ß-cell function before and after SG, but has no effect on ad libitum meal intake. The improved glycemic control after SG may in part be due to the permanently lower concentration of ghrelin following this procedure.
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An intravenous glucose-infusion of 0.3 g glucose per Kg body weight was administered over 1 min in nine healthy males with simultaneous blood sampling from the hepatic vein, femoral artery and a peripheral vein. Insulin secretion rates (ISR) were determined by the Eaton method and the ISEC method using C-peptide concentrations from arterial and peripheral venous blood. First phase (0-10 min), second phase (10-60 min), and total insulin secretion (0-60 min) were calculated as the incremental areas (iAUC) above baseline. The primary endpoint was first phase insulin response. The first phase insulin response in artery and venous blood did not differ with the Eaton method (p = 0.25), but was significantly greater with the ISEC method in arterial compared with venous blood (p < 0.05). The first phase insulin responses did not differ between methods in artery (p = 0.73) or venous blood (p = 0.73). The first phase responses of insulin and C-peptide were significant higher in the hepatic vein compared with those in the artery (p < 0.05) and peripheral vein (p < 0.05) but did not differ significantly between the artery compared with the peripheral vein for insulin (p = 0.09) or C-peptide (p = 0.26). Prehepatic insulin secretion rates did not differ between the Eaton and ISEC methods, but with the ISEC method the first phase insulin response was significantly greater in arterial compared with venous blood. The first phase insulin response differs when calculated from plasma insulin or C-peptide and depends on sample sites.
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Glucosa , Insulina , Masculino , Humanos , Secreción de Insulina , Glucosa/farmacología , Péptido C , Prueba de Tolerancia a la Glucosa , Arterias/metabolismo , Glucemia , CinéticaRESUMEN
CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.
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Remodelación Ósea , Estudios Cruzados , Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Péptido 2 Similar al Glucagón , Humanos , Polipéptido Inhibidor Gástrico/sangre , Masculino , Péptido 2 Similar al Glucagón/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangre , Remodelación Ósea/efectos de los fármacos , Persona de Mediana Edad , Anciano , Adulto , Densidad Ósea/efectos de los fármacosRESUMEN
Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
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Postprandial hypoglycemia is a complication of Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and 10 age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI = 93) or low GI (LGI, GI = 54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 min at 70% of maximum oxygen uptake (VÌo2max). Blood was collected for 4 h. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7 ± 0.5 vs. HGI/Ex 4.1 ± 0.4 mmol/L, P = 0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1 ± 0.5 mmol/L, P = 0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95% CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide 1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Postexercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, whereas adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower postexercise glucagon responses compared with controls.NEW & NOTEWORTHY We investigate the effect of moderate exercise after a high or a low glycemic index meal on nadir glucose and glucoregulatory hormones in gastric bypass-operated individuals and in matched unoperated controls. Cycling shortly after meal intake did not increase the risk of hypoglycemia in operated individuals. The low glycemic index meal increased glucose nadir and reduced excursions compared with the high glycemic index meal. Operated individuals had lower postexercise glucagon responses compared with controls.
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Derivación Gástrica , Hipoglucemia , Humanos , Femenino , Índice Glucémico , Glucemia , Glucagón/metabolismo , Consumo de Oxígeno , Oxígeno , Insulina , Comidas , Glucosa , Periodo PosprandialRESUMEN
Follistatin is secreted from the liver and may regulate muscle growth and insulin sensitivity. Protein intake stimulates follistatin secretion, which may be mediated by increased glucagon in the context of low insulin concentrations. We investigated circulating follistatin after mixed-meals in two cohorts of patients who were part of previously published studies and had undergone bariatric surgery with either simultaneous assessment of amino acid absorption or administration of the GLP-1 receptor antagonist exendin-(9-39), which increased glucagon concentrations and impaired insulin secretion. Study 1 comprised obese matched subjects with previous Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated controls who underwent 6-hour mixed-meal tests with intravenous and oral tracers including intrinsically labelled caseinate in the meal. Study 2 comprised obese subjects with previous RYGB who underwent two 5-hour mixed-meal tests with concomitant exendin-(9-39) or saline infusion. In study 1, the secretion of follistatin as well as the amino acid absorption was accelerated after RYGB compared with SG and controls, but the glucagon-to-C-peptide ratios did not differ between the groups. In study 2, exendin-(9-39) administration increased postprandial glucagon concentrations and lowered insulin secretion, whereas the concentration of follistatin was unchanged. In conclusion, postprandial follistatin secretion is accelerated in patients after RYGB which might be explained by an accelerated protein absorption rate rather than the glucagon-to-insulin ratio.
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Derivación Gástrica , Glucagón , Humanos , Glucagón/metabolismo , Glucemia/metabolismo , Folistatina , Insulina/metabolismo , Obesidad/cirugía , Obesidad/metabolismo , Gastrectomía , AminoácidosRESUMEN
Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial ß-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.
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Derivación Gástrica , Péptido 1 Similar al Glucagón , Humanos , Derivación Gástrica/métodos , Incretinas , Insulina , Glucemia , Polipéptido Inhibidor Gástrico , Glucosa , Gastrectomía/métodosRESUMEN
We investigated the effect of pharmacologically induced weight loss on markers of glucagon resistance in individuals with overweight during treatment with the glucagon-like peptide-1 receptor agonist liraglutide. We performed an open-label study in 14 men with overweight (age 38 ± 11 years, BMI 32 ± 4 kg/m2) without simultaneously diabetes. Subjects were treated with liraglutide, initiated and titrated with 0.6 mg/day/week to reach the final dose of 3.0 mg/day. Subjects were examined at baseline, during titration (Week 4), after 2 weeks of steady state (Week 6) of final dosing of liraglutide and 3 weeks after discontinuation of liraglutide (follow-up). Study participants lost 3.3 ± 1.9 kg (3%) total body weight during the first 4 weeks of treatment with liraglutide. Simultaneously, liver fat content decreased from 12.4 ± 11.6% to 10.2 ± 11.1%, p = 0.025, whereas fat content in the spleen and subcutaneous tissue was unaltered. Markers of glucagon resistance, including plasma glucagon and the glucagon-alanine-index, also decreased significantly during treatment, but total and individual plasma amino acid concentrations did not. Insulin resistance (HOMA-IR) was unchanged during treatment, whereas insulin clearance increased. Treatment with the GLP-1 receptor analogue liraglutide decreased liver fat content, and simultaneously attenuated glucagon concentrations and the glucagon-alanine index in individuals with overweight without diabetes.
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Diabetes Mellitus Tipo 2 , Liraglutida , Humanos , Masculino , Adulto , Persona de Mediana Edad , Liraglutida/farmacología , Liraglutida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Glucagón , Sobrepeso/tratamiento farmacológico , Sobrepeso/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Hígado/metabolismo , Alanina/uso terapéutico , AminoácidosRESUMEN
Background and aims: The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients' everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture. Methods: Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components. Results: Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal (p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups. Conclusion: A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated individuals. Small differences were observed for the postprandial peaks of C-peptide, GLP-1, and GIP concentrations. Overall, a liquid meal is suitable for evaluating glucose tolerance, ß-cell function, and gut hormones responses, both after RYGB and SG and in unoperated individuals. Clinical Trial Registration: [www.clinicaltrials.gov], identifier [NCT04082923].
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OBJECTIVE: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions. METHODS: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively. RESULTS: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9). CONCLUSION: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.
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Gastrectomía , Derivación Gástrica , Neurotensina/sangre , Obesidad/cirugía , Vagotomía Troncal , Glucemia , Péptido 1 Similar al Glucagón/sangre , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Liraglutida/administración & dosificación , Liraglutida/uso terapéutico , Obesidad/sangre , Obesidad/tratamiento farmacológico , Periodo PosprandialRESUMEN
Background: Altered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus. Methods: Two single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions. Results: In study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones. Conclusion: In RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.
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Ácidos y Sales Biliares/sangre , Derivación Gástrica , Péptido 1 Similar al Glucagón/sangre , Glucosa/metabolismo , Obesidad Mórbida/cirugía , Adulto , Glucemia , Péptido C/sangre , Clorhidrato de Colesevelam/uso terapéutico , Femenino , Glucagón/sangre , Humanos , Masculino , Persona de Mediana Edad , Neurotensina/sangre , Obesidad Mórbida/sangre , Obesidad Mórbida/tratamiento farmacológico , Periodo Posprandial , Método Simple CiegoRESUMEN
BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. RESULTS: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. CONCLUSIONS: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).
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Fármacos Antiobesidad/uso terapéutico , Terapia por Ejercicio , Liraglutida/uso terapéutico , Obesidad/terapia , Pérdida de Peso , Tejido Adiposo , Adulto , Fármacos Antiobesidad/efectos adversos , Tamaño Corporal , Restricción Calórica , Terapia Combinada , Femenino , Humanos , Liraglutida/efectos adversos , Masculino , Persona de Mediana Edad , Obesidad/dietoterapia , Obesidad/tratamiento farmacológico , Pérdida de Peso/efectos de los fármacosRESUMEN
The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss-independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a â¼10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial ß-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Derivación Gástrica , Glucemia , Gastrectomía , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Humanos , InsulinaRESUMEN
Follistatin is secreted from the liver and is involved in the regulation of muscle mass and insulin sensitivity via inhibition of activin A in humans. The secretion of follistatin seems to be stimulated by glucagon and inhibited by insulin, but only limited knowledge on the postprandial regulation of follistatin exists. Moreover, results on postoperative changes after Roux-en-Y gastric bypass (RYGB) are conflicting with reports of increased, unaltered, and lowered fasting concentrations of follistatin. In this study, we investigated postprandial follistatin and activin A concentrations after intake of isocaloric amounts of protein, fat, or glucose in subjects with obesity with and without previous RYGB to explore the regulation of follistatin by the individual macronutrients. Protein intake enhanced follistatin concentrations similarly in the two groups, whereas glucose and fat ingestion did not change postprandial follistatin concentrations. Concentrations of activin A were lower after protein intake compared with glucose intake in RYGB. Glucagon concentrations were also particularly enhanced by protein intake and tended to correlate with follistatin in RYGB. In conclusion, we demonstrated that protein intake, but not glucose or fat, is a strong stimulus for follistatin secretion in subjects with obesity and that this regulation is maintained after RYGB surgery.NEW & NOTEWORTHY Circulating follistatin and activin A were studied after intake of isocaloric protein, fat, or glucose drinks in subjects with obesity with and without previous Roux-en-Y gastric bypass (RYGB). Protein intake enhanced follistatin similarly in both groups, whereas glucose and fat ingestion did not change follistatin. Activin A was lower after protein compared with glucose in RYGB. The novel finding is that protein intake, but neither glucose nor fat, stimulates follistatin secretion independently of previous RYGB.
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Grasas de la Dieta , Proteínas en la Dieta , Folistatina/sangre , Derivación Gástrica , Glucosa , Obesidad/cirugía , Activinas/sangre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Periodo PosprandialRESUMEN
AIM: To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans. MATERIALS AND METHODS: We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes. RESULTS: Plasma amylase (+7 U/L [95% confidence intervals 3-11], P < .01) and lipase (+19 U/L [7-30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm3 [-8-8], P = .96) and no change in pancreatic cellular infiltration was found (P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17], P = .0507). CONCLUSIONS: Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Edema/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/tratamiento farmacológicoRESUMEN
BACKGROUND/OBJECTIVES: Bile acids in plasma are elevated after bariatric surgery and may contribute to metabolic improvements, but underlying changes in bile flow are poorly understood. We assessed bilio-enteric flow of bile and plasma bile concentrations in individuals with Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with matched non-surgical controls (CON). SUBJECTS/METHODS: Fifteen RYGB, 10 SG and 15 CON underwent 99Tc-mebrofenin cholescintigraphy combined with intake of a high-fat 111In-DTPA-labelled meal and frequent blood sampling. A 75Se-HCAT test was used to assess bile acid retention. RESULTS: After RYGB, gallbladder filling was decreased (p = 0.045 versus CON), basal flow of bile into the small intestine increased (p = 0.005), bile acid retention augmented (p = 0.021) and basal bile acid plasma concentrations elevated (p = 0.009). During the meal, foods passed unimpeded through the gastric pouch resulting in almost instant postprandial mixing of bile and foods, but the postprandial rise in plasma bile acids was brief and associated with decreased overall release of fibroblast growth factor-19 (FGF-19) compared with CON (p = 0.033). After SG, bile flow and retention were largely unaltered (p > 0.05 versus CON), but gastric emptying was accelerated (p < 0.001) causing earlier mixture of bile and foods also in this group. Neither basal nor postprandial bile acid concentrations differed between SG and CON. CONCLUSIONS: Bilio-enteric bile flow is markedly altered after RYGB resulting in changes in plasma concentrations of bile acids and FGF-19, whereas bile flow and plasma concentrations are largely unaltered after SG.
Asunto(s)
Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Gastrectomía/estadística & datos numéricos , Derivación Gástrica/estadística & datos numéricos , Adulto , Conductos Biliares/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Periodo Posprandial/fisiologíaRESUMEN
Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3-O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol-1·L-1, P = 0.23), although peak GLP-1 concentrations were lowered (-28%, P = 0.03). Canagliflozin reduced GIP (iAUC -28%, P = 0.01; peak concentrations -57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L-1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.
Asunto(s)
Canagliflozina/farmacología , Derivación Gástrica , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Péptido C/efectos de los fármacos , Péptido C/metabolismo , Estudios Cruzados , Polipéptido Inhibidor Gástrico/efectos de los fármacos , Glucagón/efectos de los fármacos , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Persona de Mediana Edad , Polipéptido Pancreático/efectos de los fármacos , Polipéptido Pancreático/metabolismo , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidoresRESUMEN
Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, FGF-21, and C-peptide were increased after glucose compared with the other meals. The neurotensin and bile acids responses were greater after fat, while the glucagon and CCK responses were greater after protein ingestion. Furthermore, compared with control subjects, RYGB subjects had greater responses of total PYY after glucose, glucagon after glucose and fat, glicentin after glucose and protein, and GLP-1 and neurotensin after all meals, while GIP and CCK responses were lower after fat. Ghrelin responses did not differ between meals or between groups. Orlistat reduced all hormone responses to fat ingestion, except for ghrelin in the RYGB group. In conclusion, after RYGB glucose is a more potent stimulator of most gut hormones, especially for the marked increased secretion of GLP-1 compared with fat and protein.NEW & NOTEWORTHY We investigated the impact of glucose, protein, and fat meals on intestinal and pancreatic hormones, bile acid, and fibroblast growth factor 21 (FGF-21) secretion in gastric bypass-operated patients compared with matched nonoperated individuals. The fat meal was administered with and without a pancreas lipase inhibitor. We found that the impact of the different meals on gut hormones, bile, and FGF 21 secretion differ and was different from the responses observed in nonoperated control subjects.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Derivación Gástrica , Tracto Gastrointestinal/metabolismo , Glucosa/administración & dosificación , Páncreas/metabolismo , Acetaminofén/administración & dosificación , Acetaminofén/sangre , Acetaminofén/farmacocinética , Adolescente , Adulto , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/farmacocinética , Glucemia , Colecistoquinina/metabolismo , Grasas de la Dieta , Proteínas en la Dieta/administración & dosificación , Femenino , Polipéptido Inhibidor Gástrico/metabolismo , Ghrelina/metabolismo , Glicentina/metabolismo , Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neurotensina/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs). OBJECTIVE: We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals. METHODS: In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: olive oil (digested to 2-OG + LCFAs), C8-dietary oil (2-OG + MCFAs), and tricaprylin (MCFAs; negative control). Hormone responses were calculated as area under the curve (AUC). RESULTS: Independent of group status, olive oil had greater effects than C8-dietary oil on AUCs of plasma GLP-1 (+32%; 95% CI: 23%, 43%; P < 0.01), CCK (+53%, P < 0.01), and NT (+71%, P < 0.01), whereas the effect on GIP differed between groups (+90% in controls, P < 0.01; +24% in RYGB, P = 0.10). Independent of group status, C8-dietary oil had greater effects than tricaprylin on AUCs of plasma CCK (+40%, P < 0.01) and NT (+32%, P < 0.01), but not GLP-1 (+5%; 95% CI: -2.9%, 13%; P = 0.22), whereas the effect on GIP again differed between groups (+78% in controls, P < 0.01; +39% in RYGB, P = 0.01). Distal (GLP-1/PYY/NT), but not proximal (CCK/GIP), enteroendocrine responses were generally greater in RYGB patients than in controls. CONCLUSIONS: The combination of LCFAs plus 2-OG was substantially more effective than 2-OG plus MCFAs in stimulating enteroendocrine secretion in RYGB-operated and matched control individuals. Distal lipid-induced gut hormone release was greater after RYGB.This trial was registered at clinicaltrials.gov as NCT03223389.