ABSTRACT
Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes (n = 132), ucOCN correlated negatively with fasting glucose (r = -0.18, P = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = -0.18, P = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with severe obesity (n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting glucose (r = -0.50, P = 0.046) and glycated hemoglobin (r = -0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp (P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and ß-cell dysfunction in humans.
Subject(s)
Glucose/metabolism , Insulin-Secreting Cells/metabolism , Osteocalcin/analysis , Osteocalcin/metabolism , Pancreatic Function Tests , Adolescent , Adult , Aged , Animals , Blood Glucose , Cohort Studies , Diabetes Mellitus, Type 2/metabolism , Female , Glucose Clamp Technique , Glycated Hemoglobin/analysis , Humans , Immunoassay/methods , Insulin Resistance , Male , Mice, Inbred BALB C , Middle Aged , Obesity/metabolism , Overweight/metabolismABSTRACT
Occurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m(2)). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation.
Subject(s)
Adipocytes/metabolism , Adipocytes/pathology , Obesity/metabolism , Obesity/pathology , Omentum/metabolism , Omentum/pathology , Ubiquinone/analogs & derivatives , Adipocytes/enzymology , Dietary Supplements , Female , Humans , Hypertrophy/metabolism , Intra-Abdominal Fat/metabolism , Intra-Abdominal Fat/pathology , Lipid Peroxidation , Middle Aged , Obesity/enzymology , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Subcutaneous Fat/enzymology , Subcutaneous Fat/metabolism , Subcutaneous Fat/pathology , Surveys and Questionnaires , Ubiquinone/metabolismABSTRACT
Metabolomic profiling of obese individuals revealed altered concentrations of many metabolites, especially branched-chain amino acids (BCAA), possibly linked to altered adipose tissue BCAA catabolism. We tested the hypothesis that some features of this metabolite signature relate closely to visceral obesity and concomitant alterations in cardiometabolic risk factors. We also postulated that alterations in BCAA-catabolizing enzymes are predominant in visceral adipose tissue. Fifty-nine women (BMI 20-41 kg/m(2)) undergoing gynecologic surgery were recruited and characterized for overall and regional adiposity, blood metabolite levels using targeted metabolomics, and cardiometabolic risk factors. Adipose samples (visceral and subcutaneous) were obtained and used for gene expression and Western blot analyses. Obese women had significantly higher circulating BCAA and kynurenine/tryptophan (Kyn/Trp) ratio than lean or overweight women (P < 0.01). Principal component analysis confirmed that factors related to AA and the Kyn/Trp ratio were positively associated with BMI, fat mass, visceral or subcutaneous adipose tissue area, and subcutaneous adipocyte size (P ≤ 0.05). AA-related factor was positively associated with HOMA-IR (P ≤ 0.01). Factors reflecting glycerophospholipids and sphingolipids levels were mostly associated with altered blood lipid concentrations (P ≤ 0.05). Glutamate level was the strongest independent predictor of visceral adipose tissue area (r = 0.46, P < 0.001). Obese women had lower expression and protein levels of BCAA-catabolizing enzymes in visceral adipose tissue than overweight or lean women (P ≤ 0.05). We conclude that among metabolites altered in obesity plasma concentrations of BCAA and the Kyn/Trp ratio are closely related to increased adiposity. Alterations in expression and protein levels of BCAA-catabolizing enzymes are predominant in visceral adipose tissue.
Subject(s)
Adipose Tissue/metabolism , Amino Acids, Branched-Chain/metabolism , Body Fat Distribution , Cardiovascular Diseases/metabolism , Obesity/metabolism , RNA, Messenger/metabolism , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , Adipocytes/pathology , Adipokines/metabolism , Adult , Amino Acids/metabolism , Blood Glucose/metabolism , Blotting, Western , Cell Size , Cholesterol, HDL/metabolism , Cholesterol, LDL/metabolism , Dyslipidemias/metabolism , Female , Gene Expression Profiling , Humans , Insulin Resistance , Intra-Abdominal Fat/metabolism , Kynurenine/metabolism , Metabolomics , Middle Aged , Overweight/metabolism , Risk Factors , Subcutaneous Fat/metabolism , Thinness/metabolism , Triglycerides/metabolism , Tryptophan/metabolismABSTRACT
Using a novel positron emission tomography (PET) method with oral administration of 14(R,S)-[¹8F]-fluoro-6-thia-heptadecanoic acid (¹8FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organ-specific postprandial dietary fatty acids partition using the oral ¹8FTHA method, and cardiac function and oxidative metabolic index using PET [¹¹C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects.
Subject(s)
Dietary Fats/metabolism , Glucose Intolerance/prevention & control , Heart Ventricles/physiopathology , Life Style , Obesity/therapy , Ventricular Dysfunction, Left/prevention & control , Weight Loss , Acetic Acid , Body Mass Index , Carbon Radioisotopes , Combined Modality Therapy , Diet, Reducing , Fatty Acids , Female , Fluorine Radioisotopes , Glucose Intolerance/etiology , Heart Ventricles/diagnostic imaging , Heart Ventricles/metabolism , Humans , Male , Middle Aged , Motor Activity , Obesity/diet therapy , Obesity/metabolism , Obesity/physiopathology , Positron-Emission Tomography , Postprandial Period , Radionuclide Ventriculography , Radiopharmaceuticals , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/etiologyABSTRACT
Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.
Subject(s)
Non-alcoholic Fatty Liver Disease , Obesity, Morbid , Amino Acids, Branched-Chain/metabolism , Humans , Keto Acids , Obesity, Morbid/complications , Obesity, Morbid/surgery , RNA, MessengerABSTRACT
A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered (18)FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant (18)FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of (18)FTHA in the distal thoracic duct, reaching a peak at time 240 min. (18)FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating (18)F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received (18)FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity.
Subject(s)
Dietary Fats/pharmacokinetics , Fatty Acids/pharmacokinetics , Adolescent , Adult , Animals , Blood Glucose/metabolism , Chylomicrons/metabolism , Diabetes Mellitus, Type 2/metabolism , Fatty Acids, Nonesterified/blood , Humans , Insulin/blood , Insulin Resistance/physiology , Male , Middle Aged , Palmitates/metabolism , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Rats , Rats, Wistar , Tomography, Emission-Computed , Triazoles/pharmacokinetics , Triglycerides/blood , Triglycerides/metabolism , Whole-Body Counting , Young AdultABSTRACT
Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.
Subject(s)
Bariatric Surgery , Biochemical Phenomena/physiology , Insulin-Like Growth Factor Binding Protein 2/metabolism , Obesity, Morbid/surgery , Animals , Bariatric Surgery/methods , Biliopancreatic Diversion/methods , Gastrectomy/methods , Gastric Bypass/methods , Humans , Mice , Obesity/surgery , Obesity, Morbid/metabolismABSTRACT
PURPOSE: Bone may regulate glucose homeostasis via uncarboxylated bioactive osteocalcin (ucOCN). This study explored whether changes in ucOCN and bone remodeling are associated with change in glucose homeostasis after biliopancreatic diversion (BPD). METHODS: In this secondary exploratory analysis of a 1-year prospective observational study, 16 participants (11 men/5 women; 69% with type 2 diabetes; mean BMI 49.4 kg/m2) were assessed before, 3 days, 3 months and 12 months after BPD. Changes in plasma ucOCN and bone markers (C-terminal telopeptide (CTX), total osteocalcin (OCN)) were correlated with changes in insulin resistance or sensitivity indices (HOMA-IR; adipose tissue insulin resistance index (ADIPO-IR) and insulin sensitivity index (SI) from the hyperinsulinemic-euglycemic clamp), insulin secretion rate (ISR) from the hyperglycemic clamp, and disposition index (DI: SI × ISR) using Spearman correlations before and after adjustment for weight loss. RESULTS: ucOCN was unchanged at 3 days but increased dramatically at 3 months (+257%) and 12 months (+498%). Change in ucOCN correlated significantly with change in CTX at 3 months (r = 0.62, p = 0.015) and 12 months (r = 0.64, p = 0.025) before adjustment for weight loss. It also correlated significantly with change in fasting insulin (r = -0.53, p = 0.035), HOMA-IR (r = -0.54, p = 0.033) and SI (r = 0.52, p = 0.041) at 3 days, and ADIPO-IR (r = -0.69, p = 0.003) and HbA1c (r = -0.69, p = 0.005) at 3 months. Change in OCN did not correlate with any glucose homeostasis indices. Results were similar after adjustment for weight loss. CONCLUSION: The increase in ucOCN may be associated with the improvement in insulin resistance after BPD, independently of weight loss. These findings need to be confirmed in larger, less heterogeneous populations.
Subject(s)
Biliopancreatic Diversion , Diabetes Mellitus, Type 2 , Insulin Resistance , Blood Glucose , Female , Glucose , Homeostasis , Humans , Insulin/metabolism , Male , OsteocalcinABSTRACT
BACKGROUND: This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). METHODS: Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. RESULTS: CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (- 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = - 0.63, p = 0.009) and 12 months (r = - 0.58, p = 0.039), and total BMD decrease (r = - 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. CONCLUSION: BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.
Subject(s)
Biliopancreatic Diversion , Biomarkers/blood , Bone Remodeling/physiology , Hormones/blood , Obesity, Morbid/surgery , Adiponectin/blood , Adult , Aged , Biliopancreatic Diversion/methods , Biomarkers/analysis , Bone Density/physiology , Cohort Studies , Female , Hormones/analysis , Humans , Male , Middle Aged , Obesity, Morbid/blood , Osteocalcin/blood , Osteoprotegerin/blood , Weight Loss/physiology , Young AdultABSTRACT
Autotaxin (ATX), an adipose tissue-derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short- (24 h, 5 days) and longer-term (6 and 12 months) impact of bariatric surgery; as well as the short-term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2 ), before and after biliopancreatic diversion with duodenal switch surgery (BPD-DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3-day CR protocol before their BPD-DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA-IR) as well as insulin and leptin levels and negatively with fat-free mass. ATX concentrations decreased 26.2% at 24 h after BPD-DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD-DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow-up in the control group (P = 0.4), and not influenced by short-term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery-induced CR.
Subject(s)
Bariatric Surgery , Obesity/surgery , Phosphoric Diester Hydrolases/blood , Adiposity , Adult , Bariatric Surgery/adverse effects , Biomarkers/blood , Body Mass Index , Caloric Restriction , Case-Control Studies , Down-Regulation , Female , Humans , Male , Middle Aged , Obesity/blood , Obesity/diagnosis , Obesity/physiopathology , Severity of Illness Index , Time Factors , Treatment Outcome , Weight LossABSTRACT
Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-ß transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.
Subject(s)
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , ATP Citrate (pro-S)-Lyase/metabolism , Amino Acids, Branched-Chain/metabolism , Lipogenesis , Obesity/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Disease Models, Animal , Female , HEK293 Cells , Humans , Male , Middle Aged , Protein Phosphatase 2C , Rats , Rats, Wistar , Rats, ZuckerABSTRACT
The introduction of bariatric surgery into clinical practice in the 1980s was followed by a relatively long watch-and-wait period before the very rapid accumulation of scientific literature, over the past decade, concerning its clinical effectiveness and safety and its mechanisms of action in the treatment of obesity. These surgical procedures now emerge as the most effective therapeutic modality to induce long-term remission of type 2 diabetes. Recent research has shed light on the potential mechanisms leading to the profound improvement of glucose homeostasis following most bariatric surgery procedures. These mechanisms can be classified as weight loss dependent and independent, both playing sequential and then synergistic antidiabetes roles. Many groups, including our own, have contributed to our understanding of the relative roles of these mechanisms at differing time periods following these procedures. Here we summarize what we currently know about the mechanisms underlying the very rapid, weight loss-independent improvement in glucose homeostasis after bariatric surgery. Beyond its impact in the field of bariatric surgery, this new knowledge about the very rapid in vivo "reverse engineering" of type 2 diabetes actually provides unique insights into the intricate and complex mechanisms linking nutrition and obesity with the development of this disease.
Subject(s)
Bariatric Surgery/trends , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/surgery , Obesity/metabolism , Obesity/surgery , Diabetes Mellitus, Type 2/diagnosis , Humans , Obesity/diagnosis , Remission Induction , Time Factors , Treatment Outcome , Weight Loss/physiologyABSTRACT
Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss-dependent and -independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA-insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues.
Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2/metabolism , Fatty Acids, Nonesterified/metabolism , Obesity/surgery , Triglycerides/metabolism , Adipocytes/cytology , Adult , Cell Size , Diabetes Mellitus, Type 2/blood , Fatty Acids, Nonesterified/blood , Female , Humans , Male , Middle Aged , Triglycerides/bloodABSTRACT
OBJECTIVE: The aim of this study was to compare the short-term effect of sleeve gastrectomy (SG) and biliopancreatic diversion with duodenal switch (DS) in order to determine if exclusion of the upper gastrointestinal tract confers greater metabolic improvement, independent of weight loss. METHODS: Standard meals were administered before and on day 3 and 4 after SG to assess insulin sensitivity, ß-cell function and gastrointestinal hormone responses in matched normoglycemic (NG) and type 2 diabetes (T2D) participants. A third group of matched T2D participants who underwent DS with the same meal test administered prior to and 3days after surgery was also recruited. RESULTS: Despite significant metabolic improvement, T2D participants failed to fully normalize insulin resistance and ß-cell dysfunction 3 and 4days after SG. Our results demonstrate the superiority of DS over SG in terms of short-term improvement in postprandial glucose excursion and ß-cell function 3days after the surgery, with similar improvement in hepatic insulin sensitivity. CONCLUSION: Our findings support the notion that caloric restriction represents an important mechanism to explain the very early anti-diabetic effects observed after bariatric surgery. However, exclusion of the upper gastrointestinal tract also provides further metabolic improvements, possibly mediated by gastrointestinal hormonal responses and altered postprandial glucose absorption.
Subject(s)
Biliopancreatic Diversion/methods , Diabetes Mellitus, Type 2/surgery , Gastrectomy/methods , Adult , Biliopancreatic Diversion/standards , Blood Glucose , Case-Control Studies , Female , Gastrectomy/standards , Hormones , Humans , Insulin-Secreting Cells/physiology , Liver/metabolism , Male , Middle Aged , Postprandial PeriodABSTRACT
Context: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol (LDL-C) concentrations. In patients with severe obesity, biliopancreatic diversion with duodenal switch (BPD-DS) surgery induces substantial weight loss and influences lipoprotein metabolism. The effect of BPD-DS on PCSK9 levels is unknown. Objectives: To determine the acute and chronic impact of BPD-DS on PCSK9 levels and whether the acute impact of BPD-DS could be explained by BPD-DS-associated caloric restriction (CR). Design, Settings, and Participants: PCSK9 levels were measured in 20 men and 49 women (age, 41.5 ± 11.1 years) with severe obesity before, 24 hours, 5 days, and 6 and 12 months after BPD-DS and in a comparable control group (n = 31) at baseline and at 6 and 12 months. PCSK9 levels were also measured during 3-day CR in patients (n = 7) with severe obesity and type 2 diabetes. Results: PCSK9 levels increased 13.4% after 24 hours (248.7 ± 64.8 to 269.7 ± 63.8 ng/mL; P = 0,02) and decreased 9.5% at 12 months compared with baseline (217.6 ± 43.0 ng/mL; P < 0,0001). LDL-C levels decreased 36.2% after 24 hours (2.6 ± 0.7 to 1.7 ± 0.6 mmol/L; P < 0.0001) and 30% at 12 months compared with baseline (1.7 ± 0.5 mmol/L; P < 0.0001). Compared with baseline levels, PCSK9 levels were lower at day 2 but not at day 1 or 3 after CR. Conclusion: BPD-DS is associated with acute increases in PCSK9 levels that do not appear to be explained by CR but may be due to an acute response following surgery. BPD-DS induces chronic reductions in both PCSK9 and LDL-C levels.
Subject(s)
Bariatric Surgery , Cholesterol, LDL/blood , Obesity, Morbid/surgery , Proprotein Convertase 9/blood , Adult , Bariatric Surgery/adverse effects , Bariatric Surgery/rehabilitation , Caloric Restriction , Case-Control Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/surgery , Female , Humans , Male , Middle Aged , Obesity, Morbid/blood , Obesity, Morbid/complications , Obesity, Morbid/diet therapy , Time FactorsABSTRACT
OBJECTIVE: To assess the rapid improvement of insulin sensitivity and ß-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes. METHODS: Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS. RESULTS: Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants. CONCLUSIONS: Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and ß-cell function after BPD-DS in type 2 diabetes.
Subject(s)
Biliopancreatic Diversion , Caloric Restriction , Insulin Resistance , Insulin/metabolism , Adult , Blood Glucose/analysis , Diabetes Mellitus, Type 2/complications , Duodenum/surgery , Female , Gastric Inhibitory Polypeptide/blood , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Glucose Tolerance Test , Humans , Insulin Secretion , Insulin-Secreting Cells/cytology , Male , Middle Aged , Obesity, Morbid/surgery , Peptide YY/blood , Pilot ProjectsABSTRACT
Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[(¹8F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGTâº) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGTâ»). Measured by [¹¹C]acetate with PET, IGT⺠subjects have a significant increase in myocardial oxidative index. IGT⺠subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT⺠directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT⺠versus IGTâ». The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism.
Subject(s)
Dietary Fats/metabolism , Fatty Acids/metabolism , Glucose Intolerance/metabolism , Heart/physiopathology , Lipid Metabolism , Myocardium/metabolism , Ventricular Dysfunction, Left/etiology , Adult , Dietary Fats/adverse effects , Early Diagnosis , Female , Glucose Intolerance/complications , Glucose Intolerance/etiology , Glucose Intolerance/physiopathology , Heart/diagnostic imaging , Humans , Intra-Abdominal Fat/metabolism , Male , Middle Aged , Obesity, Abdominal/physiopathology , Organ Specificity , Overweight/physiopathology , Positron-Emission Tomography , Prediabetic State/complications , Prediabetic State/etiology , Prediabetic State/metabolism , Prediabetic State/physiopathology , Radiopharmaceuticals , Subcutaneous Fat, Abdominal/metabolism , Ventricular Dysfunction, Left/diagnostic imagingABSTRACT
OBJECTIVE: Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. RESEARCH DESIGN AND METHODS: Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [(11)C]acetate and 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. RESULTS: In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol·g(-1)·min(-1), P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol·g(-1)·min(-1), P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). CONCLUSIONS: Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon.