Publications by authors named "Elisa Fabbrini"

47 Publications

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass.

Cell Metab 2019 11 3;30(5):855-864.e3. Epub 2019 Oct 3.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA; Departments of Medicine and Pharmacology, University of California, San Diego, San Diego, CA, USA. Electronic address:

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate that compared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.
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http://dx.doi.org/10.1016/j.cmet.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876863PMC
November 2019

Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program.

Diabetologia 2019 06 12;62(6):926-938. Epub 2019 Mar 12.

The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia.

Aims/hypothesis: The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.

Methods: The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.

Results: There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.

Conclusions/interpretation: The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.
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http://dx.doi.org/10.1007/s00125-019-4839-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509073PMC
June 2019

Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Am J Physiol Gastrointest Liver Physiol 2019 03 29;316(3):G372-G386. Epub 2018 Nov 29.

Consiglio Nazionale delle Recerche Institute of Clinical Physiology, Pisa , Italy.

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min·1.73 m. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1152/ajpgi.00051.2018DOI Listing
March 2019

Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).

Circulation 2018 01 13;137(4):323-334. Epub 2017 Nov 13.

Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, UK (D.R.M.).

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.

Methods: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).

Results: Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, <0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; <0.001 for noninferiority, =0.02 for superiority) with no statistical evidence of heterogeneity (interaction value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction value=0.63).

Conclusions: Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777572PMC
January 2018

Effect of Weight Gain and Weight Loss on In Vivo Colonocyte Proliferation Rate in People with Obesity.

Obesity (Silver Spring) 2017 11;25 Suppl 2:S81-S86

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: To evaluate the effects of diet-induced changes in energy balance and body weight on in vivo colonocyte fractional proliferation rates (FPR) in people with obesity.

Methods: In vivo colonocyte FPR was assessed in 31 men and women with obesity (BMI: 35.4 ± 4.0 kg/m , age: 52.6 ± 8.9 years) before and after diet-induced weight loss, weight gain, or weight maintenance. Subjects ingested aliquots of H O (heavy water) daily for 4 to 7 days, followed by flexible sigmoidoscopy with colon biopsies to assess the incorporation of H into the DNA of dividing colonocytes.

Results: Colonocyte FPR averaged 12.7% ± 3.8% per day and correlated directly with intra-abdominal adipose tissue (IAAT) volume (r = 0.364, P = 0.044). Colonocyte FPR decreased in the weight loss group, did not change in the weight maintenance group, and increased in the weight gain group. The change in colonocyte FPR correlated directly with the percent change in body weight (r = 0.409, P = 0.028) and IAAT volume (r = 0.598, P = 0.001).

Conclusions: A high-calorie diet and weight gain increase, whereas a low-calorie diet and weight loss decrease, in vivo colonocyte proliferation rate in people with obesity. These results suggest that changes in energy balance influence the risk of developing colon cancer in people with obesity by regulating colonic mucosal growth rates.
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http://dx.doi.org/10.1002/oby.21983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679222PMC
November 2017

Effect of Duodenal-Jejunal Bypass Surgery on Glycemic Control in Type 2 Diabetes: A Randomized Controlled Trial.

Obesity (Silver Spring) 2015 Oct;23(10):1973-9

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: To determine whether upper gastrointestinal tract (UGI) bypass itself has beneficial effects on the factors involved in regulating glucose homeostasis in patients with type 2 diabetes (T2D).

Methods: A 12-month randomized controlled trial was conducted in 17 overweight/obese subjects with T2D, who received standard medical care (SC, n = 7, BMI = 31.7 ± 3.5 kg/m(2) ) or duodenal-jejunal bypass surgery with minimal gastric resection (DJBm) (n = 10; BMI = 29.7 ± 1.9 kg/m(2)). A 5-h modified oral glucose tolerance test was performed at baseline and at 1, 6, and 12 months after surgery or starting SC.

Results: Body weight decreased progressively after DJBm (7.9 ± 4.1%, 9.6 ± 4.2%, and 10.2 ± 4.3% at 1, 6, and 12 months, respectively) but remained stable in the SC group (P < 0.001). DJBm, but not SC, improved: (1) oral glucose tolerance (decreased 2-h glucose concentration, P = 0.039), (2) insulin sensitivity (decreased homeostasis model assessment of insulin resistance, P = 0.013), (3) early insulin response to a glucose load (increased insulinogenic index, P = 0.022), and (4) overall glycemic control (reduction in HbA1c with fewer diabetes medications).

Conclusions: DJBm causes moderate weight loss and improves metabolic function in T2D. However, our study cannot separate the benefits of moderate weight loss from the potential therapeutic effect of UGI tract bypass itself on the observed metabolic improvements.
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http://dx.doi.org/10.1002/oby.21190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603288PMC
October 2015

Physiological Mechanisms of Weight Gain-Induced Steatosis in People With Obesity.

Gastroenterology 2016 Jan 12;150(1):79-81.e2. Epub 2015 Sep 12.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St Louis, Missouri. Electronic address:

Weight gain is associated with an increase in intrahepatic triglycerides (IHTGs), and is the primary cause of nonalcoholic fatty liver disease in obese individuals. We combined imaging and stable isotope tracer techniques to evaluate the physiologic mechanisms of weight gain-induced steatosis in 27 obese people. Weight gain appeared to increase IHTG content by generating an imbalance between hepatic fatty acid availability and disposal, and resulted in increased hepatic de novo lipogenesis, decreased intrahepatic fatty acid oxidation, and inadequate increases in IHTG export via very low-density lipoprotein secretion. ClinicalTrials.gov ID NCT01184170.
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http://dx.doi.org/10.1053/j.gastro.2015.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691551PMC
January 2016

Non-Alcoholic Steatohepatitis: Pathogenesis and Clinical Management.

Biomed Res Int 2015 28;2015:153276. Epub 2015 Jul 28.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA.

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http://dx.doi.org/10.1155/2015/153276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531156PMC
April 2016

Hepatic Steatosis as a Marker of Metabolic Dysfunction.

Nutrients 2015 Jun 19;7(6):4995-5019. Epub 2015 Jun 19.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.
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http://dx.doi.org/10.3390/nu7064995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488828PMC
June 2015

Metabolically normal obese people are protected from adverse effects following weight gain.

J Clin Invest 2015 Feb 2;125(2):787-95. Epub 2015 Jan 2.

BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.
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http://dx.doi.org/10.1172/JCI78425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319438PMC
February 2015

Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss.

Obesity (Silver Spring) 2015 Feb 18;23(2):329-34. Epub 2014 Oct 18.

Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou, China; Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

Objectives: An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. It was evaluated whether monomethyl branched-chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity.

Methods: Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion in nine lean and nine obese subjects, and in a separate group of nine obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state.

Results: Total adipose tissue mmBCFA content was ∼30% lower in obese than lean subjects (P=0.02) and increased by ∼65% after weight loss in the RYGB group (P=0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R(2) =35%, P=0.01, n=18).

Conclusions: These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association.
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http://dx.doi.org/10.1002/oby.20923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310778PMC
February 2015

Response to Comment on Fabbrini et al. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976-981.

Diabetes 2014 Sep;63(9):e19

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO

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http://dx.doi.org/10.2337/db14-0885DOI Listing
September 2014

Adipose and muscle tissue profile of CD36 transcripts in obese subjects highlights the role of CD36 in fatty acid homeostasis and insulin resistance.

Diabetes Care 2014 Jul 1;37(7):1990-7. Epub 2014 May 1.

Department of Medicine, Center for Human Nutrition, Washington University, St Louis, MO

Objective: Fatty acid (FA) metabolism is tightly regulated across several tissues and impacts insulin sensitivity. CD36 facilitates cellular FA uptake, and CD36 genetic variants associate with lipid abnormalities and susceptibility to metabolic syndrome. The objective of this study was to gain insight regarding the in vivo metabolic influence of muscle and adipose tissue CD36. For this, we determined the relationships between CD36 alternative transcripts, which can reflect tissue-specific CD36 regulation, and measures of FA metabolism and insulin resistance.

Research Design And Methods: The relative abundance of alternative CD36 transcripts in adipose tissue and skeletal muscle from 53 nondiabetic obese subjects was measured and related to insulin sensitivity and FA metabolism assessed by hyperinsulinemic-euglycemic clamps and isotopic tracers for glucose and FA.

Results: Transcript 1C, one of two major transcripts in adipose tissue, that is restricted to adipocytes predicted systemic and tissue (adipose, liver, and muscle) insulin sensitivity, suggesting adipocyte CD36 protects against insulin resistance. Transcripts 1B and 1A, the major transcripts in skeletal muscle, correlated with FA disposal rate and triglyceride clearance, supporting importance of muscle CD36 in clearance of circulating FA. Additionally, the common CD36 single nucleotide polymorphism rs1761667 selectively influenced CD36 transcripts and exacerbated insulin resistance of glucose disposal by muscle.

Conclusions: Alternative CD36 transcripts differentially influence tissue CD36 and consequently FA homeostasis and insulin sensitivity. Adipocyte CD36 appears to be metabolically protective, and its selective upregulation might have therapeutic potential in insulin resistance.
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http://dx.doi.org/10.2337/dc13-2835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067395PMC
July 2014

Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects.

Diabetes 2014 Mar 18;63(3):976-81. Epub 2013 Dec 18.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

Oxidative stress is purported to be involved in the pathogenesis of obesity-associated insulin resistance. We evaluated whether alterations in levels of circulating uric acid (UA), a systemic antioxidant, affects the following: 1) systemic (plasma and saliva) nonenzymatic antioxidant capacity (NEAC); 2) markers of systemic (urinary 8-iso-prostaglandin-F2α) and muscle (carbonylated protein content) oxidative stress; and 3) whole-body insulin sensitivity (percentage increase in glucose uptake during a hyperinsulinemic-euglycemic clamp procedure). Thirty-one obese subjects (BMI 37.1 ± 0.7 kg/m(2)) with either high serum UA (HUA; 7.1 ± 0.4 mg/dL; n = 15) or normal serum UA (NUA; 4.5 ± 0.2 mg/dL; n = 16) levels were studied; 13 subjects with HUA levels were studied again after reduction of serum UA levels to 0 by infusing a recombinant urate oxidase. HUA subjects had 20-90% greater NEAC, but lower insulin sensitivity (40%) and levels of markers of oxidative stress (30%) than subjects in the NUA group (all P < 0.05). Acute UA reduction caused a 45-95% decrease in NEAC and a 25-40% increase in levels of systemic and muscle markers of oxidative stress (all P < 0.05), but did not affect insulin sensitivity (from 168 ± 25% to 156 ± 17%, P = NS). These results demonstrate that circulating UA is a major antioxidant and might help protect against free-radical oxidative damage. However, oxidative stress is not a major determinant of insulin action in vivo.
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http://dx.doi.org/10.2337/db13-1396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931399PMC
March 2014

Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.

Gastroenterology 2013 Aug 15;145(2):366-74.e1-3. Epub 2013 Apr 15.

Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Background & Aims: An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure.

Methods: We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors.

Results: Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes.

Conclusions: Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.
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http://dx.doi.org/10.1053/j.gastro.2013.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756481PMC
August 2013

Metabolic response to high-carbohydrate and low-carbohydrate meals in a nonhuman primate model.

Am J Physiol Endocrinol Metab 2013 Feb 26;304(4):E444-51. Epub 2012 Dec 26.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-¹³C]glucose tracer was added to the meal, and a [6,6-²H₂]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P < 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity.
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http://dx.doi.org/10.1152/ajpendo.00347.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566507PMC
February 2013

Gastric bypass and banding equally improve insulin sensitivity and β cell function.

J Clin Invest 2012 Dec 26;122(12):4667-74. Epub 2012 Nov 26.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide-1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.
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http://dx.doi.org/10.1172/JCI64895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512168PMC
December 2012

Relationship between Changes in Plasma Adiponectin Concentration and Insulin Sensitivity after Niacin Therapy.

Cardiorenal Med 2012 Aug 18;2(3):211-217. Epub 2012 Jul 18.

Division of Geriatrics and Nutritional Science, Center for Human Nutrition, Washington University School of Medicine, St. Louis, Mo., Tex., USA.

BACKGROUND: Niaspan® (extended-release niacin) is a nicotinic acid formulation used to treat dyslipidemia in obese subjects. Niaspan binds to the GPR109A receptor in adipose tissue and stimulates adiponectin secretion, which should improve insulin sensitivity. However, Niaspan therapy often causes insulin resistance. The purpose of this study was to evaluate whether Niaspan-induced changes in plasma adiponectin concentration are associated with a blunting of Niaspan's adverse effect on insulin action in obese subjects with non-alcoholic fatty liver disease (NAFLD). METHODS: A hyperinsulinemic-euglycemic clamp procedure was used to assess muscle insulin sensitivity before and after 16 weeks of Niaspan therapy in 9 obese subjects with NAFLD [age 43 ± 5 years; BMI 35.1 ± 1.3 (means ± SEM)]. RESULTS: Niaspan therapy did not affect body weight (99.1 ± 4.2 vs. 100 ± 4.4 kg) or percent body fat (37.8 ± 2.5 vs. 37.0 ± 2.5%). However, Niaspan therapy caused a 22% reduction in insulin-mediated glucose disposal (p < 0.05). The deterioration in glucose disposal was inversely correlated with the Niaspan-induced increase in plasma adiponectin concentration (r = 0.67, p = 0.05). CONCLUSIONS: These results demonstrate that Niaspan causes skeletal muscle insulin resistance, independent of changes in body weight or body fat, and the Niaspan-induced increase in plasma adiponectin concentration might partially ameliorate Niaspan's adverse effect on insulin action in obese subjects with NAFLD.
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http://dx.doi.org/10.1159/000340037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433009PMC
August 2012

Very Low Density Lipoprotein Metabolism in Patients with Chronic Kidney Disease.

Cardiorenal Med 2012 Feb 26;2(1):57-65. Epub 2012 Jan 26.

Center for Human Nutrition, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Mo., USA.

BACKGROUND: Hypertriglyceridemia is a common metabolic complication of chronic kidney disease (CKD) and an important risk factor for coronary heart disease in this patient population. The mechanisms responsible for the development of hypertriglyceridemia in subjects with CKD are not clear. METHODS: We studied very low density lipoprotein triglyceride (VLDL-TG) and VLDL-apolipoprotein B-100 (VLDL-apoB-100) kinetics in vivo in 6 subjects with non-dialysis-dependent CKD (CKD-ND), 6 subjects with CKD treated with peritoneal dialysis (CKD-PD) and 24 sex-, age- and body mass index-matched control subjects with normal renal function (12 control subjects each matched with the CKD-ND and CKD-PD group, respectively). RESULTS: The secretion rates of VLDL-TG and VLDL-apoB-100 into plasma were not different between CKD-ND or CKD-PD and their respective control groups. The mean residence times of VLDL-TG and VLDL-apoB-100 in plasma, which represents the time VLDL-TG and VLDL-apoB-100 spend in the circulation after secretion by the liver, tended to be greater in subjects with CKD-ND than in control subjects (222 ± 38 vs. 143 ± 21 min, p = 0.07, and 352 ± 102 vs. 200 ± 20 min, p = 0.06, respectively) and were about two-fold greater in subjects with CKD-PD compared with their control group (248 ± 51 vs. 143 ± 21 min and 526 ± 116 vs. 182 ± 16 min, respectively; both p ≤ 0.01). CONCLUSION: Impaired plasma clearance of VLDL-TG and VLDL-apoB-100 is the major abnormality associated with hypertriglyceridemia in patients with either CKD-ND or CKD-PD.
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http://dx.doi.org/10.1159/000335509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318940PMC
February 2012

Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women.

J Clin Endocrinol Metab 2012 Jul 6;97(7):E1219-23. Epub 2012 Apr 6.

Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St. Louis, Missouri 63110, USA.

Context: Increased adipose tissue lipolytic activity is considered an important factor in the pathogenesis of skeletal muscle insulin resistance associated with obesity.

Objective: The objective of the study was to evaluate the relationship between the rate of release of free fatty acids (FFA) into plasma and skeletal muscle insulin sensitivity in human subjects.

Methods: We determined the palmitate rate of appearance (Ra) per kilogram fat-free mass (an index of FFA availability to lean tissues) during basal conditions and during insulin infusion (to simulate postprandial insulin concentrations) and skeletal muscle insulin sensitivity, defined as the percent increase in the glucose rate of disappearance, in 110 nondiabetic women (body mass index 20.6-46.4 kg/m(2)) by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer methods.

Results: Basal (r(s) = -0.379, P < 0.001) and insulin-suppressed (r(s) = -0.631, P < 0.001) palmitate Ra correlated negatively with skeletal muscle insulin sensitivity. However, the strength of the correlation was greater for palmitate Ra during insulin infusion than palmitate Ra during basal conditions (P = 0.0007) when lipolytic rates and FFA availability were reduced to less than 20% of basal values. The relative suppression of palmitate Ra correlated directly with the relative stimulation of glucose rate of disappearance during insulin infusion (r(s) = 0.530, P < 0.001).

Conclusion: These data suggest that the correlation between FFA kinetics and muscle glucose metabolism is due to multiorgan insulin resistance rather than a direct effect of FFA itself on skeletal muscle insulin action and challenge the view that increased adipose tissue lipolytic rate is an important cause of insulin resistance.
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http://dx.doi.org/10.1210/jc.2012-1035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387393PMC
July 2012

Multiorgan insulin sensitivity in lean and obese subjects.

Diabetes Care 2012 Jun 3;35(6):1316-21. Epub 2012 Apr 3.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance.

Research Design And Methods: The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m(2), mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m(2)) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations.

Results: In obese subjects, palmitate and glucose R(a) in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose R(a) was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate R(a) (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate R(a) and glucose R(a) were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose R(d) was greater in lean than obese subjects across the entire physiological range of plasma insulin.

Conclusions: Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.
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http://dx.doi.org/10.2337/dc11-1951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357234PMC
June 2012

Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects.

Gastroenterology 2012 Jun 13;142(7):1444-6.e2. Epub 2012 Mar 13.

Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Data from studies in animal models indicate that certain lipid metabolites, particularly diacylglycerol, ceramide, and acylcarnitine, disrupt insulin action. We evaluated the relationship between the presence of these metabolites in the liver (assessed by mass spectrometry) and hepatic insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp with stable isotope tracer infusion) in 16 obese adults (body mass index, 48 ± 9 kg/m²). There was a negative correlation between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol (r = -0.609; P = .012), but not with intrahepatic ceramide or acylcarnitine. These data indicate that intrahepatic diacylglycerol is an important mediator of hepatic insulin resistance in obese people with nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1053/j.gastro.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564653PMC
June 2012

Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver.

J Lipid Res 2012 May 6;53(5):990-9. Epub 2012 Mar 6.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA.

Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes (MOGAT1, MOGAT2, and MOGAT3) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a significant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and NAFLD.
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http://dx.doi.org/10.1194/jlr.P025536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329399PMC
May 2012

Moderate effect of duodenal-jejunal bypass surgery on glucose homeostasis in patients with type 2 diabetes.

Obesity (Silver Spring) 2012 Jun 19;20(6):1266-72. Epub 2012 Jan 19.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

Gastric bypass surgery causes resolution of type 2 diabetes (T2DM), which has led to the hypothesis that upper gastrointestinal (UGI) tract diversion, itself, improves glycemic control. The purpose of this study was to determine whether UGI tract bypass without gastric exclusion has therapeutic effects in patients with T2DM. We performed a prospective trial to assess glucose and β-cell response to an oral glucose load before and at 6, 9, and 12 months after duodenal-jejunal bypass (DJB) surgery. Thirty-five overweight or obese adults (BMI: 27.0 ± 4.0 kg/m(2)) with T2DM and 35 sex-, age-, race-, and BMI-matched subjects with normal glucose tolerance (NGT) were studied. Subjects lost weight after surgery, which was greatest at 3 months (6.9 ± 4.9%) with subsequent regain to 4.2 ± 5.3% weight loss at 12 months after surgery. Glycated hemoglobin (HbA(1c)) decreased from 9.3 ± 1.6% before to 7.7 ± 2.0% at 12 months after surgery (P < 0.001), in conjunction with a 20% decrease in the use of diabetes medications (P < 0.05); 7 (20%) subjects achieved remission of diabetes (no medications and HbA(1c) <6.5%). The area under the curve after glucose ingestion was ~20% lower for glucose but doubled for insulin and C-peptide at 12 months, compared with pre-surgery values (all P < 0.01). However, the β-cell response was still 70% lower than subjects with NGT (P < 0.001). DJB surgery improves glycemic control and increases, but does not normalize the β-cell response to glucose ingestion. These findings suggest that altering the intestinal site of delivery of ingested nutrients has moderate therapeutic effects by improving β-cell function and glycemic control.
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http://dx.doi.org/10.1038/oby.2011.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619418PMC
June 2012

Subclinical hypothyroidism and hyperthyroidism have opposite effects on hepatic very-low-density lipoprotein-triglyceride kinetics.

J Clin Endocrinol Metab 2012 Mar 11;97(3):E414-8. Epub 2012 Jan 11.

Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St Louis, Missouri 63110, USA.

Context: Clinically overt thyroid dysfunction is associated with alterations in triglyceride (TG) metabolism. The effect of subclinical thyroid disease on very-low-density lipoprotein (VLDL) kinetics is not known.

Objective: Our objective was to investigate whether subclinical thyroid disease is associated with alterations in hepatic VLDL metabolism. DESIGN AND OUTCOMES: We measured VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics by infusing stable isotopically labeled tracers, in conjunction with mathematical modeling.

Setting And Participants: Ten women with subclinical hypothyroidism, 10 women with subclinical hyperthyroidism, and 25 euthyroid women, matched on age, body mass index, and percent body fat, were studied in the Clinical Research Unit at Washington University School of Medicine.

Results: Plasma VLDL-TG concentrations were 0.75±0.13, 0.51±0.06, and 0.37±0.07 mmol/liter (P=0.029), and hepatic VLDL-TG secretion rates were 6.5±0.7, 5.0±0.4, and 4.1±0.6 μmol/liter·min (P=0.026) in hypothyroid, euthyroid, and hyperthyroid women, respectively. The differences in VLDL-TG secretion rates were due to differences in the incorporation of systemic plasma free fatty acids into VLDL-TG (4.3±0.3, 3.1±0.3, and 2.5±0.3 μmol/liter·min in hypothyroid, euthyroid, and hyperthyroid women, respectively; P=0.005). Plasma VLDL-apoB-100 concentration and hepatic secretion rate did not differ among groups (P>0.400), so the molar ratios of VLDL-TG to VLDL-apoB-100 secretion rates were 21,469±3,477, 16,025±1,273, and 11,889±1,319 in hypothyroid, euthyroid, and hyperthyroid women, respectively (P=0.019).

Conclusions: Subclinical thyroid disease affects hepatic VLDL-TG but not VLDL-apoB-100 metabolism: subclinical hypothyroidism increases, whereas subclinical hyperthyroidism decreases, hepatic VLDL-TG secretion rate compared with the euthyroid state. Plasma VLDL-TG concentration is greater in subclinical hypothyroid than euthyroid and hyperthyroid subjects, due to greater secretion of large, TG-rich VLDL particles from the liver.
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http://dx.doi.org/10.1210/jc.2011-2777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319204PMC
March 2012

Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects.

J Lipid Res 2012 Feb 5;53(2):321-4. Epub 2011 Dec 5.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Insulin resistance in adipose tissue increases the release of free fatty acids into the circulation, which likely contributes to impaired insulin action in liver and skeletal muscle associated with obesity. However, reliable assessment of adipose tissue insulin resistance requires performing a hyperinsulinemic-euglycemic clamp procedure in conjunction with a fatty acid tracer infusion to determine insulin-mediated suppression of lipolytic rate. We developed a simpler method for evaluating adipose tissue insulin resistance in vivo, determined as the product of palmitate rate of appearance into the bloodstream and plasma insulin concentration during basal conditions. We validated our Adipose Tissue Insulin Resistance Index (ATIRI) by comparison with an assessment of adipose tissue insulin resistance determined by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with a palmitate tracer infusion in 47 obese nondiabetic subjects (body mass index: 40.1 ± 9.3 kg/m(2)). We found the ATIRI correlated closely with adipose tissue insulin resistance assessed during the clamp procedure (r =-0.854, P < 0.001). These results demonstrate that the ATIRI provides a reliable index of adipose tissue insulin resistance in obese subjects.
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http://dx.doi.org/10.1194/jlr.D020321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269158PMC
February 2012

Lack of a relationship between plasma PCSK9 concentrations and hepatic lipoprotein kinetics in obese people.

Transl Res 2011 Nov 19;158(5):302-6. Epub 2011 Jul 19.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Obesity is associated with unfavorable alterations in plasma lipid concentrations. Data obtained from studies in cultured cells and rodent models show that Protein Convertase Subtilisn/Kexin 9 (PCSK9), a secreted protein that leads to degradation of LDL receptors in the liver, is an important regulator of plasma LDL cholesterol concentrations. Recent evidence suggests that PCSK9 may also regulate the very low density lipoprotein (VLDL) receptor expression and VLDL-triglyceride (TG) metabolism. The purpose of this study was to determine whether circulating PCSK9 concentrations are correlated with VLDL-triglyceride kinetics in obese people. Plasma PCSK9 concentration and VLDL-TG kinetics were evaluated in 39 nondiabetic, obese subjects (body mass index 36.9 ± 4.3 kg/m(2)). Body composition was assessed by using dual-energy x-ray absorptiometry, and VLDL-TG kinetics were assessed by using stable isotopically labeled tracer infusion. We found that plasma PCSK9 concentrations correlated significantly with percent body fat (r = 0.322, P = 0.046) and serum LDL-cholesterol concentrations (r = 0.333, P = 0.036), but not with VLDL-TG secretion rate (r = 0.083, P = 0.614) or clearance rate (r = 0.032, P = 0.845). These data suggest that PCSK9 is likely involved in LDL-cholesterol metabolism, but it is not a clinically important regulator of VLDL kinetics in obese individuals.
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http://dx.doi.org/10.1016/j.trsl.2011.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200562PMC
November 2011

Portal vein and systemic adiponectin concentrations are closely linked with hepatic glucose and lipoprotein kinetics in extremely obese subjects.

Metabolism 2011 Nov 31;60(11):1641-8. Epub 2011 May 31.

Center for Human Nutrition, Washington University School of Medicine, St Louis, MO 63110, USA.

Low systemic plasma adiponectin concentrations are associated with abnormalities in hepatic glucose and lipoprotein metabolism in obese people. However, the relationship between the delivery of adiponectin to the liver via the portal vein and hepatic glucose and lipoprotein metabolism is not known. We examined the relationship between hepatic substrate metabolism (glucose rate of appearance into plasma and hepatic very low-density lipoprotein [VLDL]-triglyceride [TG] and VLDL-apolipoprotein B-100 [apoB-100] secretion rates, determined by using stable isotope-labeled tracer techniques) and portal vein adiponectin concentration, in 8 insulin-resistant, extremely obese subjects (body mass index, 65 ± 7 kg/m(2)). Portal vein adiponectin concentration was inversely associated with basal glucose rate of appearance (r = -0.820, P = .013) and VLDL-TG (r = -0.823, P = .012) and VLDL-apoB-100 (r = -0.787, P = .020) secretion rates. Very similar correlations were obtained for radial artery adiponectin as a result of a mirroring relationship between portal and arterial adiponectin concentrations (r = 0.899, P = .002) and the absence of significant arteriovenous concentration differences (P = .570). Insulin resistance, assessed with the homeostasis model assessment score, was also strongly associated with hepatic glucose and lipid metabolic parameters, as well as with adiponectin concentrations in the portal vein and radial artery. These results suggest that adiponectin delivery to the liver, whether via the portal or the systemic circulation, may be an important regulator of basal hepatic glucose, VLDL-TG, and VLDL-apoB-100 production rates in obese people, possibly through direct effects on the liver or changes in hepatic insulin sensitivity. However, portal vein adiponectin does not appear to be superior to arterial adiponectin as a marker of hepatic metabolic dysregulation. Additional studies are needed to elucidate the mechanism(s) responsible for the strong association we observed between adiponectin and hepatic substrate metabolism.
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http://dx.doi.org/10.1016/j.metabol.2011.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166552PMC
November 2011

Insulin sensitivity is not associated with palmitoleate availability in obese humans.

J Lipid Res 2011 Apr 25;52(4):808-12. Epub 2011 Jan 25.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO, USA.

We evaluated whether insulin resistance in obese people is associated with decreased plasma palmitoleate availability. Palmitoleate content (percentage and absolute concentrations) in FFA and VLDL was measured in obese subjects who were either insulin resistant (IR) or insulin sensitive (IS), based on assessment of multiorgan (skeletal muscle, liver, and adipose tissue) insulin sensitivity by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with infusion of stable isotopically labeled tracers. Plasma palmitoleate concentration and the relative contribution of palmitoleate to total plasma FFA concentration in the IS group (0.018 ± 0.002 mmol/l and 4.4% ± 0.2%, respectively) were not significantly different than values in the IR group (0.023 ± 0.003 mmol/l and 4.4% ± 0.4%, respectively). Plasma VLDL-triglyceride palmitoleate concentration and the proportion of VLDL fatty acids as palmitoleate in the IS group (0.09 ± 0.02 mmol/l and 5.7 ± 0.3%, respectively) were also not significantly different than those in the IR group (0.16 ± 0.04 mmol/l and 5.0% ± 0.4%, respectively). These data demonstrate that decreased palmitoleate in plasma and in VLDL is not associated with insulin resistance in skeletal muscle, liver, or adipose tissue in obese people.
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http://dx.doi.org/10.1194/jlr.M013599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053209PMC
April 2011

Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults.

Gastroenterology 2010 Aug 7;139(2):448-55. Epub 2010 May 7.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St Louis, Missouri, USA.

Background & Aims: Visceral adipose tissue (VAT) is an important risk factor for the metabolic complications associated with obesity. Therefore, a reduction in VAT is considered an important target of obesity therapy. We evaluated whether reducing VAT mass by surgical removal of the omentum improves insulin sensitivity and metabolic function in obese patients.

Methods: We conducted a 12-month randomized controlled trial to determine whether reducing VAT by omentectomy in 22 obese subjects increased their improvement following Roux-en-Y gastric bypass (RYGB) surgery in hepatic and skeletal muscle sensitivity to insulin study 1. Improvement was assessed by using the hyperinsulinemic-euglycemic clamp technique. We also performed a 3-month, longitudinal, single-arm study to determine whether laparoscopic omentectomy alone, in 7 obese subjects with type 2 diabetes mellitus (T2DM), improved insulin sensitivity study 2. Improvement was assessed by using the Frequently Sampled Intravenous Glucose Tolerance Test.

Results: The greater omentum, which weighed 0.82 kg (95% confidence interval: 0.67-0.97), was removed from subjects who had omentectomy in both studies. In study 1, there was an approximate 2-fold increase in muscle insulin sensitivity (relative increase in glucose disposal during insulin infusion) and a 4-fold increase in hepatic insulin sensitivity 12 months after RYGB alone and RYGB plus omentectomy, compared with baseline values (P<.001). There were no significant differences between groups (P>.87) or group x time interactions (P>.36). In study 2, surgery had no effect on insulin sensitivity (P=.844) or use of diabetes medications.

Conclusions: These results demonstrate that decreasing VAT through omentectomy, alone or in combination with RYGB surgery, does not improve metabolic function in obese patients.
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http://dx.doi.org/10.1053/j.gastro.2010.04.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910849PMC
August 2010