ABSTRACT
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.
ABSTRACT
BACKGROUND/OBJECTIVES: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure. SUBJECTS/METHODS: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting. RESULTS: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]). CONCLUSIONS: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.
Subject(s)
Gastric Bypass , Gastrointestinal Hormones , Humans , Female , Ghrelin , Octreotide/pharmacology , Peptide YY , Glucagon-Like Peptide 1 , Cholecystokinin , Eating , Weight Loss/physiologyABSTRACT
INTRODUCTION: Roux-en-Y gastric bypass (RYGB) surgery markedly increases the rate of intestinal nutrient exposure after food intake, accelerates intestinal absorption of dietary glucose and protein, and alters the postprandial gut hormone response. However, our understanding of postprandial fat absorption and metabolism after RYGB is incomplete. METHODS: Stable palmitate tracers were administered intravenously (K-[2,2-2H2]palmitate) and orally with a mixed meal ([U-13C16]palmitate) to study fatty acid absorption and metabolism before and 3 months after RYGB in 10 participants with obesity and normal glucose tolerance. RESULTS: There was a tendency toward reduced fasting plasma nonesterified palmitate concentrations after RYGB, but neither fasting palmitate kinetics nor fasting triacylglycerol (TAG) concentrations changed compared with before surgery. Postprandial TAG concentrations were numerically, but nonsignificantly, reduced 3-4 h after meal intake after compared with before RYGB. However, the postprandial appearance of the oral palmitate tracer in the plasma TAG pool and overflow into the nonesterified palmitate pool were initially faster but overall reduced after RYGB by 50% (median, IQR: [47;64], P = 0.004) and 46% (median, IQR: [33;70], P = 0.041), respectively. The maximal postprandial suppression of plasma nonesterified palmitate concentrations was slightly greater but shorter lasting after RYGB ('time × visit' interaction: P < 0.001), without detectable effects of surgery on the rate of appearance and disappearance of plasma palmitate. CONCLUSION: RYGB resulted in an initially accelerated but overall ~50% reduced 4-h postprandial systemic appearance of dietary palmitate in participants with obesity and normal glucose tolerance. This is likely a result of faster but incomplete intestinal fat absorption combined with enhanced chylomicron-TAG clearance, but it needs further investigation in studies specifically designed to investigate these mechanisms.
Subject(s)
Gastric Bypass , Obesity, Morbid , Blood Glucose/metabolism , Fatty Acids , Gastric Bypass/methods , Glucose/metabolism , Humans , Obesity/surgery , Obesity, Morbid/surgery , Palmitates , Postprandial Period/physiology , TriglyceridesABSTRACT
The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.
Subject(s)
Bone Remodeling/drug effects , Gastric Inhibitory Polypeptide/pharmacology , Glucagon-Like Peptide 2/pharmacology , Glucagon-Like Peptide-2 Receptor/agonists , Receptors, Gastrointestinal Hormone/agonists , Adult , Animals , COS Cells , Chlorocebus aethiops , Cross-Over Studies , Female , Gastric Inhibitory Polypeptide/blood , Gastric Inhibitory Polypeptide/pharmacokinetics , Glucagon-Like Peptide 2/blood , Glucagon-Like Peptide 2/pharmacokinetics , Glucagon-Like Peptide-2 Receptor/genetics , Humans , Male , Mice, Inbred C57BL , Osteoporosis/drug therapy , Receptors, Gastrointestinal Hormone/genetics , Single-Blind Method , Young AdultABSTRACT
BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is a therapeutic intervention for morbid obesity and type 2 diabetes (T2D) that improves metabolic regulation. Follistatin (Fst) could be implicated in improved glycemia as it is highly regulated by RYGB. However, it is unknown if metabolic status, such as T2D, alters the Fst response to RYGB. In addition, the effect of RYGB on the Fst target, activin A, is unknown in individuals with obesity and T2D, but is needed to interpret the functional effects of altering Fst. Finally, whether Fst-regulated intracellular signaling contributes to beneficial effects of RYGB is undetermined. METHODS: Circulating Fst and activin A were measured before, 1 week, and 1 year after RYGB surgery in a total of 20 individuals with obesity, 10 with normoglycemia (NGT) and 10 with preoperative T2D. Intracellular signaling downstream of the Activin receptor type IIB (ActRIIB) signaling pathway was analyzed in skeletal muscle and adipose tissue. RESULTS: The doubling in circulating Fst observed in subjects with NGT 1-week and 1-year post surgery was absent in T2D. After 1 week, RYGB reduced activin A by 27% (p < 0.001) and 20% (p < 0.01) in subjects with NGT and T2D, respectively; a reduction that tended to be maintained in the subjects with T2D at 1-year post-RYGB (-15%; p = 0.0592). RYGB had no effects on skeletal muscle ActRIIB signaling. In contrast, adipose tissue phosphorylation of SMAD2Ser465/467, p70S6KThr389, S6RPSer235/236, and 4E-BP1Thr37/49 was highly regulated, particularly 1-year post-RYGB (p < 0.05). CONCLUSIONS: In subjects with preoperative T2D, RYGB did not increase circulating Fst contrasting subjects with NGT, while the reduction in activin A was maintained. ActRIIB signaling was upregulated in adipose tissue, but not skeletal muscle, following RYGB in both individuals with NGT and T2D. Our results suggest a role of adipose tissue ActRIIB signaling for the beneficial effects of RYGB surgery.
Subject(s)
Activin Receptors, Type II/analysis , Activins/blood , Activins/metabolism , Diabetes Mellitus, Type 2/complications , Follistatin/blood , Follistatin/metabolism , Obesity, Morbid , Adipose Tissue/metabolism , Adult , Biopsy , Blood Glucose , Female , Follow-Up Studies , Gastric Bypass , Glucose/metabolism , Glycemic Control , Humans , Inhibin-beta Subunits/metabolism , Male , Middle Aged , Muscles/metabolism , Obesity, Morbid/complications , Obesity, Morbid/metabolism , Obesity, Morbid/physiopathology , Obesity, Morbid/surgery , Signal Transduction , Time FactorsABSTRACT
INTRODUCTION: The increasing prevalence of obesity represents a huge threat to public health and the current pharmacological treatment options are limited. Bariatric surgery is by far the most effective treatment for severe obesity, highlighting the urgent need for new and improved drug therapies. Areas covered: Based on the physiological regulation of energy homeostasis, pharmacological strategies to treat obesity are evaluated with focus on drugs in phase 2 and 3 clinical development. The potential impact of these drugs on current treatment standards and the barriers for development are discussed and set in a historical perspective of previous antiobesity medications. Expert opinion: The radical effects of bariatric surgery have extended our understanding of the mechanisms controlling appetite and boosted the search for new drug targets in obesity treatment. Accordingly, several compounds targeting the central nervous system and/or periphery are in pipeline for obesity. These drugs should be evaluated over a wide array of end-points; in particular, long-term safety monitoring is necessary as serious adverse events may appear. Combination therapy targeting more than one pathway controlling energy balance might be necessary to achieve substantial weight loss while minimising side effects.
Subject(s)
Anti-Obesity Agents/therapeutic use , Appetite Depressants/therapeutic use , Obesity/drug therapy , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/adverse effects , Appetite Depressants/administration & dosage , Appetite Depressants/adverse effects , Drug Design , Drug Therapy, Combination , Humans , Molecular Targeted Therapy , Time Factors , Weight Loss/drug effectsABSTRACT
Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH2 terminally truncated metabolite, PYY3-36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY1-36 and PYY3-36 in eight young, healthy men. A metabolite, corresponding to PYY3-34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY3-34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY1-36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 ± 0.5 and 9.4 ± 0.8 min (means ± SE) and metabolic clearance rates of 15.7 ± 1.5 and 14.1 ± 1.1 ml·kg(-1)·min(-1) after infusion, whereas PYY3-36 was eliminated with a significantly longer half-life of 14.9 ± 1.3 min and a metabolic clearance rate of 9.4 ± 0.6 ml·kg(-1)·min(-1) We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOH-terminal amino acids. In healthy men, PYY3-36 has a longer half-life than PYY1-36.
Subject(s)
Peptide Fragments/metabolism , Peptide YY/metabolism , Animals , Blood Glucose , Blood Pressure , COS Cells , Chlorocebus aethiops , Humans , Male , Peptide Fragments/chemistry , Peptide YY/chemistry , Proteolysis , Single-Blind Method , Young AdultABSTRACT
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
Subject(s)
Gastrectomy , Gastric Bypass , Glucagon-Like Peptide 1 , Peptide YY , Weight Loss , Humans , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/surgery , Gastrectomy/methods , Gastrointestinal Hormones/metabolism , Ghrelin/metabolism , Glucagon-Like Peptide 1/metabolism , Insulin/metabolism , Peptide YY/metabolismABSTRACT
BACKGROUND: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. OBJECTIVES: We hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. METHODS: A randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. RESULTS: Eleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: -46.6, -24.1) from 4.9% [2.4-11.0] (median interquartile range) to 2.9% [1.4-6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. CONCLUSIONS: Reduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.
Subject(s)
Cross-Over Studies , Liver , Obesity , Overweight , Triglycerides , Humans , Male , Triglycerides/metabolism , Liver/metabolism , Adult , Overweight/metabolism , Overweight/diet therapy , Obesity/metabolism , Obesity/diet therapy , Diet, Carbohydrate-Restricted , Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/metabolism , Young Adult , Middle Aged , Insulin ResistanceABSTRACT
Accumulation of hepatic triacylglycerol (TG) is highly associated with impaired whole-body insulin-glucose homeostasis and dyslipidemia. The summarized findings from human intervention studies investigating the effect of reduced dietary carbohydrate and increased fat intake (and in studies also increased protein) while maintaining energy intake at eucaloric requirements reveal a beneficial effect of carbohydrate reduction on hepatic TG content in obese individuals with steatosis and indices of insulin resistance. Evidence suggests that the reduction of hepatic TG content after reduced intake of carbohydrates and increased fat/protein intake in humans, results from regulation of fatty acid (FA) metabolism within the liver, with an increase in hepatic FA oxidation and ketogenesis, together with a concomitant downregulation of FA synthesis from de novo lipogenesis. The adaptations in hepatic metabolism may result from reduced intrahepatic monosaccharide and insulin availability, reduced glycolysis and increased FA availability when carbohydrate intake is reduced.
Subject(s)
Dietary Fats , Non-alcoholic Fatty Liver Disease , Humans , Triglycerides , Dietary Fats/metabolism , Fatty Acids , Liver/metabolism , Lipogenesis/physiology , Insulin , Dietary CarbohydratesABSTRACT
BACKGROUND: Macrophages are associated with metabolic complications to obesity including fatty liver disease and impaired hepatic and muscle insulin sensitivity (IS). Bariatric surgery induces weight loss and improves IS. We investigated associations between the macrophage activation marker soluble (s)CD163, alanine-aminotransferase (ALT), and IS before and after Roux-en-Y Gastric Bypass (RYGB). METHODS: We analyzed sCD163 from 10 type 2 diabetes (T2D) and 10 obese patients with normal glucose tolerance (NGT) undergoing RYGB for associations with hepatic, adipose tissue, and muscle IS and ALT after 1-week, 3, and 12 months postoperatively. IS was evaluated by hyperinsulinemic-euglycemic clamp in combination with glucose tracer technique. RESULTS: Preoperative sCD163 correlated with ALT (r = 0.58, p = 0.007) and tended to associate inversely with hepatic (r = -0.39, p = 0.1) and adipose tissue (r = -0.39, p = 0.09), but not muscle IS. Following RYGB, sCD163 decreased significantly in all patients. The decrease in sCD163 during the first 3 months correlated inversely with the improvement of hepatic IS (r = -0.65, p = 0.01) and tended to be associated with changes in muscle IS (r = -0.45, p = 0.09). After 3 months sCD163 remained associated with ALT (r = 0.75, p < 0.001) and inversely with hepatic IS (r = -0.39, p = 0.1), but not muscle or adipose tissue IS. One year after RYGB, sCD163 correlated with ALT (r = 0.61, p = 0.007), but not with hepatic, adipose tissue, or muscle IS. CONCLUSION: Macrophage activation is associated with liver injury and hepatic IS in obese patients. Improvements in these measures correlate during the first 3 months following RYGB, supporting a link between macrophages and hepatic IS in severe obesity and diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Gastric Bypass , Insulin Resistance , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/surgery , Gastric Bypass/adverse effects , Humans , Insulin/metabolism , Insulin Resistance/physiology , Liver/metabolism , Macrophage Activation , Obesity/complications , Obesity/metabolism , Obesity/surgeryABSTRACT
Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes.
ABSTRACT
INTRODUCTION: The worldwide prevalence of obesity and type 2 diabetes (T2D) constitutes an epidemic that is a threat to public health. Bariatric surgery, including Roux en-Y gastric bypass (RYGB), is currently the most effective treatment to induce long-term weight loss and remission of co-morbid conditions. Surgery, however, comes with an added risk of complications, highlighting the need to understand the comparative effectiveness and risks of surgical versus conventional approaches to the treatment of obesity and T2D. AREAS COVERED: Positive and negative outcomes of RYGB surgery in patients with T2D are assessed, with a primary focus on RYGB surgery versus standard non-surgical treatment of obese patients with T2D in randomized clinical trials or high-quality observational cohorts. Searches were conducted in the PubMed database up to 11 April 2019 for relevant studies. EXPERT OPINION: High-level evidence reveals that RYGB ameliorates the clinical manifestations of T2D to a significantly higher degree than medical therapy. Postoperative incidence of beneficial effects and complications, however, differ across subgroups of patients with different preoperative characteristics. Key knowledge gaps, particularly on long-term complications, microvascular- and macrovascular events, and mortality should be addressed, so treatment with RYGB can be applied in an individualized approach to maximize benefits and minimize complications.
Subject(s)
Body Mass Index , Diabetes Mellitus, Type 2/surgery , Gastric Bypass/adverse effects , Obesity/surgery , Diabetes Mellitus, Type 2/complications , Humans , Obesity/complications , Randomized Controlled Trials as Topic , Remission Induction , Treatment Outcome , Weight LossABSTRACT
BACKGROUND: Postprandial hypoglycemia is a risk after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: We speculated that a carbohydrate-reduced, high-protein (CRHP) diet might reduce the risk of hypoglycemia and therefore compared the acute effects of a conventionally recommended (CR) diet and CRHP diet [55/30 energy percent (E%) carbohydrate and 15/30 E% protein, respectively] in RYGB patients. METHODS: Ten individuals (2 males, 8 females, mean ± SD age 47 ± 7 y; stable body mass index 31 ± 6 kg/m2; 6 ± 3 y post-RYGB) with recurrent postprandial hypoglycemia documented by plasma glucose (PG) ≤3.4 mmol/L were examined on 2 d with isoenergetic CRHP or CR diets comprising a breakfast and subsequent lunch meal. RESULTS: Peak PG was significantly reduced on the CRHP diet after breakfast and lunch by 11% and 31% compared with the CR diet. Nadir PG increased significantly on CRHP (by 13% and 9%). Insulin secretion was reduced, and glucagon secretion increased on the CRHP diet after both meals. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide secretion were lower after lunch but unaltered after breakfast on CRHP; ß-cell function and insulin clearance were unchanged. CONCLUSIONS: The CRHP diet lowered glucose excursions and reduced insulin secretion and incretin hormone responses, but enhanced glucagon responses compared with the CR diet. Taken together, the results may explain the decreased glucose variability and lower risk of postprandial hypoglycemia. This study was registered at clinicaltrials.gov as NCT02665715.
Subject(s)
Diet, High-Protein Low-Carbohydrate , Gastric Bypass , Hypoglycemia/prevention & control , Adult , Blood Glucose , C-Peptide/blood , Cross-Over Studies , Female , Humans , Insulin/blood , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Middle Aged , Postoperative CareABSTRACT
BACKGROUND: Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor ß (TGF-ß) superfamily, including activin A, which causes atrophy. TGF-ß superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. METHODS: To elucidate if TGF-ß superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB). RESULTS: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. CONCLUSIONS: We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-ß superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans.
Subject(s)
Follistatin/blood , Follistatin/genetics , Muscular Atrophy/metabolism , Obesity/surgery , Adult , Animals , Dependovirus , Female , Gastric Bypass , Genetic Vectors/pharmacology , HEK293 Cells , Humans , Inhibin-beta Subunits/antagonists & inhibitors , Inhibin-beta Subunits/blood , Insulin Resistance , Male , Mice , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Obesity/blood , Parvovirinae/genetics , Rats , Signal TransductionABSTRACT
Bariatric surgery induces large and sustainable weight loss in obese patients and improves glycaemic control in patients with Type 2 diabetes. Eleven randomized controlled trials have shown superior glycaemic outcomes after bariatric procedures vs. medical therapy/intensive lifestyle interventions in obese patients with Type 2 diabetes. Furthermore, many patients experience remission of Type 2 diabetes after surgery but relapse may occur during follow-up. Data from observational studies show reduced incidence of micro- and macrovascular complications in addition to reduced cardiovascular and total mortality after surgery.
Subject(s)
Diabetes Mellitus, Type 2 , Obesity , Bariatric Surgery , Blood Glucose/analysis , Diabetes Complications/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/surgery , Glycated Hemoglobin/analysis , Humans , Life Style , Obesity/complications , Obesity/drug therapy , Obesity/surgery , Recurrence , Remission Induction , Weight LossABSTRACT
Roux-en-Y gastric bypass (RYGB) surgery induces weight loss of 20-30% that is maintained for 20 years. In patients with type 2 diabetes, the glucose-lowering effect of RYGB is superior to conventional antidiabetic therapy and often occurs within days after surgery. The aim of the thesis was to investigate the physiological mechanisms responsible for improved glycaemic control with special focus on the early postoperative period. We therefore investigated insulin sensitivity, insulin clearance and pancreatic islet-cell function in patients with type 2 diabetes and in glucose tolerant subjects prior to and at 1 week, 3 months and 1 year after RYGB. Hepatic insulin sensitivity measured with a glucose tracer increased already 1 week after RYGB, whereas peripheral insulin sensitivity estimated with the hyperinsulinaemic euglycaemic clamp was unchanged. Concomitant increases in insulin clearance at 1 week further highlights the liver as an important organ responsible for the early effects on glucose metabolism after surgery since insulin predominantly is cleared by the liver. Rapid improvements in hepatic insulin sensitivity is a common observation after calorie restriction in obese patients and has been observed as early as after 48 hours in absence of major weight loss and changes in peripheral insulin sensitivity. Thus, calorie restriction is a likely explanation for our findings of early improvements in hepatic insulin sensitivity and insulin clearance after RYGB. Peripheral insulin sensitivity increased along with weight loss at 3 months and 1 year after RYGB. Beta-cell function increased after RYGB in patients with type 2 diabetes in response to oral glucose, whereas insulin secretion was unchanged in response to an intravenous (iv) glucose-glucagon test throughout the first year after surgery. In glucose tolerant subjects, the insulin response to iv glucose-glucagon declined after RYGB likely as an adaptation to increased insulin sensitivity. The secretion of glucagon-like peptide 1 (GLP-1) increased substantially in both groups in response to oral glucose, whereas the secretion of glucose-dependent insulinotropic poly-peptide (GIP) was largely unchanged postoperatively. The insulinotropic effects of the incretin hormones were preserved after surgery during iv infusion in glucose tolerant subjects. Increased insulin secretion postoperatively was thus linked to the oral and not the iv route of administration highlighting the importance of the changed gastrointestinal anatomy and the exaggerated GLP-1 secretion and not supporting major changes in intrinsic beta-cell function after RYGB. Changes in alpha-cell function did not seem to contribute substantially to the improved glycaemic control after RYGB, as glucagon secretion increased paradoxically after oral glucose, and suppression of glucagon in response to iv infusions of glucose, GIP, GLP-1 and insulin was largely unchanged postoperatively. In conclusion, improved glycaemic control after Roux-en-Y gastric bypass can be explained by early enhancements of hepatic insulin sensitivity and later improvements in peripheral insulin sensitivity in combination with increased postprandial insulin secretion linked to exaggerated postprandial GLP-1 secretion. Surgical changes in gut anatomy are likely to explain the increased GLP-1 secretion and hence the increased postprandial insulin secretion, whereas calorie restriction and subsequent weight loss may be the major cause of improved insulin sensitivity.
Subject(s)
Blood Glucose/analysis , Body Mass Index , Gastric Bypass/methods , Insulin Resistance/physiology , Obesity, Morbid/surgery , Anastomosis, Roux-en-Y/methods , Denmark , Female , Follow-Up Studies , Glucagon/metabolism , Glucagon-Like Peptide 1/blood , Humans , Insulin-Secreting Cells/physiology , Male , Obesity, Morbid/blood , Quality of Life , Treatment Outcome , Weight Loss/physiologyABSTRACT
PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are referred to as 'metabolic surgery' due to hormonal shifts with impacts on diabetes remission and weight loss. The purpose of this review is to summarize recent findings in mechanisms underlying beneficial effects of weight loss surgery. RECENT FINDINGS: Importantly, gut hormone secretion is altered after RYGB and sleeve gastrectomy due to accelerated transit of nutrients to distal parts of the small intestine, leading to excessive release of L-cell peptide hormones [e.g. glucagon-like peptide-1 (GLP-1), peptide YY].Improved glucose metabolism after RYGB and sleeve gastrectomy involves several mechanisms: early increased hepatic insulin sensitivity, resulting from reduced liver fat content in response to the postoperative caloric restriction, improved beta-cell function mediated by exaggerated postprandial GLP-1 secretion; as demonstrated by relapse of impaired glucose tolerance in studies blocking the GLP-1 receptor by exendin 9-39, and later after major weight loss increased peripheral insulin sensitivity. Gut hormone secretion changes towards a more anorectic profile and is likely important for less caloric intake and weight loss. SUMMARY: Changes in gut hormone secretion after RYGB and sleeve gastrectomy surgery induce the beneficial effects on weight and glycemic control through the influence on appetite regulation and insulin secretion.