113 results on '"Fabbrini, E"'
Search Results
2. Body-fat distribution and responsiveness of the pituitary-adrenal axis to corticotropin-releasing-hormone stimulation in sedentary and exercising women
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Fabbri, A., Giannini, D., Aversa, A., De Martino, M. U., Fabbrini, E., Franceschi, F., Moretti, C., Frajese, G., and Isidori, A.
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- 1999
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3. Reproducibility of glucose, fatty acid and VLDL kinetics and multi-organ insulin sensitivity in obese subjects with non-alcoholic fatty liver disease
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Magkos, F, Fabbrini, E, Korenblat, K, Okunade, A L, Patterson, B W, and Klein, S
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- 2011
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4. Decrease in hepatic very-low-density lipoprotein–triglyceride secretion after weight loss is inversely associated with changes in circulating leptin
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Magkos, F., Fabbrini, E., McCrea, J., Patterson, B. W., Eagon, J. C., and Klein, S.
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- 2010
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5. Reduction of risk factors for cardiovascular diseases in morbid-obese patients following biliary-intestinal bypass: 3 years' follow-up
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Lubrano, C, Cornoldi, A, Pili, M, Falcone, S, Brandetti, F, Fabbrini, E, Ginanni-Corradini, S, Eramo, A, Marini, M, Migliaccio, S, Giancotti, V, Badiali, M, Falsetto, N, Prossomariti, G, and Spera, G
- Published
- 2004
6. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction
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Aversa, A., Isidori, A. M., De Martino, M. U., Caprio, M., Fabbrini, E., Rocchietti-March, M., Frajese, G., and Fabbri, A.
- Published
- 2000
7. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)
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Mahaffey, KW, Neal, B, Perkovic, V, De Zeeuw, D, Fulcher, G, Erondu, N, Shaw, W, Fabbrini, E, Sun, T, Li, Q, Desai, M, Matthews, DR, CANVAS Program Collaborative Group, and Groningen Kidney Center (GKC)
- Subjects
Male ,Time Factors ,medicine.medical_treatment ,Placebo-controlled study ,RATIONALE ,030204 cardiovascular system & hematology ,PLACEBO-CONTROLLED TRIAL ,DISEASE ,0302 clinical medicine ,DESIGN ,Risk Factors ,Original Research Articles ,Clinical endpoint ,Secondary Prevention ,Myocardial infarction ,Canagliflozin ,OUTCOMES ,CANVAS Program Collaborative Group ,clinical trial ,Middle Aged ,Hospitalization ,Primary Prevention ,Treatment Outcome ,1117 Public Health And Health Services ,Cardiovascular Diseases ,SAFETY ,Cohort ,diabetes mellitus ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adult ,medicine.medical_specialty ,030209 endocrinology & metabolism ,1102 Cardiovascular Medicine And Haematology ,03 medical and health sciences ,Double-Blind Method ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,BASE-LINE CHARACTERISTICS ,medicine ,Hypoglycemic Agents ,Humans ,Renal replacement therapy ,Sodium-Glucose Transporter 2 Inhibitors ,Aged ,business.industry ,Type 2 Diabetes Mellitus ,1103 Clinical Sciences ,medicine.disease ,Surgery ,Cardiovascular System & Hematology ,Diabetes Mellitus, Type 2 ,business - Abstract
Supplemental Digital Content is available in the text., 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, P
- Published
- 2017
8. L'INSEQUESTRABILITÀ DEI BENI DI FAMIGLIA
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Fabbrini, E.
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- 1906
9. Response to Comment on Fabbrini et al. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects
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Fabbrini, E, Serafini, Mauro, and Klein, S.
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Inflammation ,Antioxidants ,Obesity - Published
- 2014
10. Ontogenesis of leptin receptor in rat leydig cells
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Caprio, M., Fabbrini, E., Ricci, G., Basciani, Sabrina, Gnessi, Lucio, Arizzi, M., Carta, A. R., De Martino, M. U., Isidori, Andrea, Frajese, G. V., Fabbri, A., Caprio, M, Fabbrini, E, Ricci, Giulia, Basciani, S, Gnessi, L, Arizzi, M, Carta, Ar, DE MARTINO, Mu, Isidori, Am, Frajese, Gv, and Fabbri, A.
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Male ,Aging ,Reverse Transcriptase Polymerase Chain Reaction ,Leydig Cells ,Receptors, Cell Surface ,Embryo, Mammalian ,Immunohistochemistry ,Rats ,Rats, Sprague-Dawley ,Animals, Newborn ,Animals ,Receptors, Leptin ,RNA, Messenger ,Sexual Maturation - Abstract
There are still many controversies about the role of leptin in reproductive function and sexual development. We recently demonstrated that leptin receptors are expressed in rodent Leydig cells and that leptin has inhibitory effects on hCG-stimulated testosterone production by adult rat Leydig cells in culture. In this study, we evaluated the expression of leptin receptor (Ob-R) in rat testes from gestational to adult age in comparison with the pattern of expression of relaxin-like factor (RLF), a specific marker of Leydig cell differentiation status. Immunohistochemical analysis showed that, in prenatal life, Ob-R immunoreactivity was absent at early embryonic ages (E14.5) and appeared at a late embryonic age (E19.5); in postnatal life, immunoreactivity was evident only after sexual maturation (35-, 60-, and 90-days old), whereas it was absent in testes from sexually immature rats (7-, 14-, and 21-days old). Immunoreaction was always confined to Leydig cells and no signal of Ob-R was detected within the tubules. The pattern of expression of Ob-R during testicular development was similar with that of RLF immunoreactivity, which was present in mature fetal as well as adult-type Leydig cells. In contrast with the findings in the testis, in the hypothalamus, the immunohistochemical pattern of Ob-R was very similar between pre- and postpubertal life. Reverse transcription-polymerase chain reaction studies showed that Ob-R expression was present in embryonic, prepubertal, and adult rat testes; semiquantitative analysis showed that mRNA levels were much higher in late versus early embryonic testes, as well as in mature adults versus sexually immature testes, with a gradual increase from younger to older ages. Functional studies showed that, while leptin (150 ng/ml) significantly inhibited hCG-stimulated testosterone production in adult rat Leydig cells (46% reduction; P0.01), it did not modify prepubertal rat Leydig cells steroidogenic function in vitro. In conclusion, we showed that, in rat testis, Ob-R expression is characteristic of mature Leydig cells (fetal and adult type) and it is functional in adult but not prepubertal life.
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- 2003
11. Ontogenesis of leptin receptor in rodent Leydig cells
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CAPRIO M, FABBRINI E, BASCIANI S, ARIZZI M, GNESSI L, FABBRI A., RICCI, Giulia, Caprio, M, Fabbrini, E, Ricci, Giulia, Basciani, S, Arizzi, M, Gnessi, L, and Fabbri, A.
- Published
- 2002
12. Lorcaserin May Regulate Glucose Homeostasis Independent of Weight Loss
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Hoyle, B., primary and Fabbrini, E., additional
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- 2014
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13. Biochemical and hormonal modifications in super-obese patients during weight loss after biliary-intestinal by pass: 3 years follow up
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Cornoldi, A, Fabbrini, E, Brandetti, F, Falcone, Stefania, Badiali, Marco, Spera, Giovanni, and Lubrano, Carla
- Published
- 2003
14. Review of 50 papillary thyroid carcinomas: clinical and ultrasonographic features
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Intrieri, Francesco, Fabbrini, E, Cornoldi, A, Isidori, Andrea, Fierro, V, Nardi, Francesco, and Spera, Giovanni
- Published
- 2003
15. Changes in bone mineral density after lung volume reduction surgery for severe emphysema
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Ambrogi, V, Fabbri, A, Pompeo, E, Mineo, D, Fabbrini, E, and Mineo, Tc
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Settore MED/21 - Chirurgia Toracica - Published
- 2002
16. Evidence for a major effect of lean mass on bone mineral density in postmenopausal women
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Fabbrini, E., Mencacci, C., Frajese, Giovanni, Caprio, M., Isidori, A. M., Pastore, R., Aversa, A., and Fabbri, G. FRAJESE AND A.
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- 2001
17. Modificazioni endocrine e clinico nutrizionali in pazienti grandi obesi sottoposti ad intervento di by-pass bilio-intestinale
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Falcone, Stefania, Lubrano, Carla, Cornoldi, A, Brandetti, F, Fabbrini, E, Pili, M, Badiali, Marco, Cuzzolaro, Massimo, and Spera, Giovanni
- Published
- 2001
18. Different distribution of body fat in professional male soccer players and users of anabolic-androgens evaluated by dual-energy x-ray absorptiometry (DEXA)
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Mencacci, C., Fabbrini, E., Cerilli, M., Frajese, Giovanni, Fabbri, A., and Moretti, G. FRAJESE AND C.
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- 2001
19. Body composition and bone mineral density in postmenopausal women: evidence for a major effect of mass
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Fabbrini, E., Mencacci, C., Caprio, M., Frajese, Giovanni, Isidori, A. M., Pastore, R., Aversa, A., and Fabbri, G. FRAJESE AND A.
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- 2001
20. Valutazione della composizione corporea in atleti attraverso densitometria a raggi-x a doppia energia pulsata (DEXA)
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Moretti, C., Frajese, A., Fabbri, A., Cerilli, M., Fabbrini, E., Mencacci, C., Frajese, Giovanni, and Frajese, G.
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- 2001
21. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction
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Antonio, Aversa, Isidori, Andrea, De Martino, M. U., Caprio, M., Fabbrini, E., Rocchietti March, M., Frajese, G., and Fabbri, Andrea
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Male ,Estradiol ,Muscle Relaxation ,Luteinizing Hormone ,Middle Aged ,Muscle, Smooth, Vascular ,Vasodilation ,Cross-Sectional Studies ,Double-Blind Method ,Erectile Dysfunction ,Sex Hormone-Binding Globulin ,Linear Models ,Humans ,Testosterone ,Ultrasonography, Doppler, Color ,Penis ,Retrospective Studies - Abstract
Androgens are essential in the maintenance of nitric oxide-mediated erectile activity in the rat. The objective of the present study was to investigate the role of androgens in regulating trabecular smooth muscle relaxation in the corpus cavernosum in response to vasoactive challenge in men with erectile dysfunction (ED).Retrospective, double-blind correlation analyses.Fifty-two impotent patients without confounding risk factors for ED were obtained from a total of 250 undergoing diagnostic evaluation.All patients had dynamic colour duplex ultrasound (D-CDU) and hormonal evaluation for LH, total and free testosterone, SHBG and oestradiol.Based upon D-CDU results patients were diagnosed as having arteriogenic (AR, n = 18; mean age 51) or corporeal venocclusive (CVO, n = 13; mean age 49) ED; in other patients (n = 21, mean age 43) a diagnosis of psychogenic (P)-ED was made by comprehensive psychogenic testing and confirmed by normal D-CDU results. AR and CVO patients had altered compliance of cavernous arteries recorded by D-CDU [20-25% lower resistive index (RI) than patients with psychogenic ED], and lower free testosterone (FT) levels than psychogenic patients [42.3 +/-3.5 SE and 49.3+/-5.2 vs. 75.2+/-7.6 pmol/l, respectively; P0.01]. More important, in all patients there was a strong direct correlation between resistive index values and FT levels (r = 0.47, P = 0.002); the relationship was maintained also when adjusted for age, SHBG and oestradiol (r = 0.37, P = 0.02).These results indicate that in men with erectile dysfunction low free testosterone may correlate independently of age with the impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge. These findings give clinical support to the experimental knowledge of the importance of androgens in regulating smooth muscle function in the penis.
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- 2000
22. Reproducibility of glucose, fatty acid and VLDL kinetics and multi-organ insulin sensitivity in obese subjects with non-alcoholic fatty liver disease
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Magkos, F, primary, Fabbrini, E, additional, Korenblat, K, additional, Okunade, A L, additional, Patterson, B W, additional, and Klein, S, additional
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- 2010
- Full Text
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23. Decrease in hepatic very-low-density lipoprotein-triglyceride secretion after weight loss is inversely associated with changes in circulating leptin
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Magkos, F., primary, Fabbrini, E., additional, McCrea, J., additional, Patterson, B. W., additional, Eagon, J. C., additional, and Klein, S., additional
- Published
- 2009
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24. 57 EFFECTS OF FENOFIBRATE AND LONG-ACTING NICOTINIC ACID ON INTRAHEPATIC TRIGLYCERIDE CONTENT AND ADIPOSE TISSUE INSULIN SENSITIVITY IN OBESE HUMAN SUBJECTS
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Korenblat, K., primary, Fabbrini, E., additional, Mohammed, B.S., additional, Patterson, B., additional, and Klein, S., additional
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- 2009
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25. Methods for assessing intrahepatic fat content and steatosis.
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Fabbrini E, Conte C, Magkos F, Fabbrini, Elisa, Conte, Caterina, and Magkos, Faidon
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- 2009
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26. Fundamentals of cardiometabolic risk factor reduction: achieving and maintaining weight loss with pharmacotherapy or bariatric surgery.
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Fabbrini E and Klein S
- Abstract
Obesity is a major health problem in the United States and many other countries because of its high prevalence and causal relationship with serious medical comorbidities. The therapeutic options currently available to help obese patients lose weight are: (1) therapeutic lifestyle change (behavioral, dietary, and physical activity modification); (2) pharmacotherapy; and (3) bariatric surgery. Lifestyle modification is the first therapeutic choice; however, achieving a successful long-term weight loss with lifestyle intervention alone is difficult. There is increasing interest, therefore, in the use of pharmacotherapy and surgery to treat obesity. Although there are a number of antiobesity medications available, the only medications approved in the United States for long-term treatment of obesity are sibutramine and orlistat. Use of these medications results in 3% to 5% more weight loss compared with placebo after 1 year. Bariatric surgery is an effective weight loss option for obese patients, but it is restricted to patients who are considered morbidly obese (ie, with a body mass index [BMI] >/=40 kg/m(2) or a BMI of 35-39.9 kg/m(2) with >/=1 severe obesity-related medical complication). [ABSTRACT FROM AUTHOR]
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- 2008
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27. Reduction of risk factors for cardiovascular diseases in morbid-obese patients following biliary-intestinal bypass: 3 years'follow-up.
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Lubrano, C, Cornoldi, A, Pili, M, Falcone, S, Brandetti, F, Fabbrini, E, Ginanni-Corradini, S, Eramo, A, Marini, M, Migliaccio, S, Giancotti, V, Badiali, M, Falsetto, N, Prossomariti, G, and Spera, G
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CARDIOVASCULAR diseases ,OVERWEIGHT persons ,MONOSACCHARIDES ,BODY fluid pressure ,METABOLISM ,ANTHROPOMETRY - Abstract
BACKGROUND:: Obese patients are often affected by hypertension, dyslipidaemia, impaired glucose metabolism, and suffer from cardiovascular disease (CVD), related to the characteristic metabolic alterations. AIM OF THE STUDY:: To evaluate reduction of risk factors for CVDs in morbid-obese patients (body mass index (BMI)>40kg/m
2 ) after weight loss upon bariatric surgery intervention of biliary-intestinal bypass. SUBJECTS:: 45 (17 men, 28 women) morbid-obese patients (age: 19-49?y, BMI>40?kg/m2 ). All patients were selected on the basis of medical history, physical and biochemical evaluation and of psychiatric tests, which were performed on all individuals admitted to our Day Hospital to verify the safety of surgical intervention. MEASUREMENTS:: Body weight, body composition (by dual X-ray absorptiometry, DXA), blood pressure, lipid profile, fibrinogen and glucose metabolism were monitored at baseline and 1, 3, 6, 9, 12, 24 and 36 months after surgery. RESULTS:: A significant and persistent weight loss was present in all patients at the end of the 3?y follow-up period (P<0.001), with a progressive reduction of total and trunk fat mass as evaluated by means of DXA. Additionally, a parallel significant reduction in systolic (P<0.001) and diastolic (P<0.001) blood pressure was observed. Total and LDL cholesterol were significantly reduced (P<0.001), while HDL showed no modifications; triglycerides declined progressively during the 3?y follow-up (P<0.001). Fibrinogen decreased from 364.5±82.4 to 266.4±45.7?mg/dl at the end of the period (P<0.001). Fasting glucose levels and glucose levels 120?min after an oral glucose tolerance test were reduced from 95.1±20.3 to 78.6±9.1?mg/dl (P<0.001) and from 116.9±34.7 to 77.6±15.5?mg/dl (P<0.001), respectively, at baseline and at the end of the study. Moreover, fasting insulin decreased from 30.0±20.4 to 8.6±2.9?µUI/ml (P<0.001) after 3?y, while insulin levels after (120?min) oral glucose load decreased from 105.5±61.5 to 12.0±6.0?µUI/ml (P<0.001). CONCLUSION:: Our results show that biliary-intestinal bypass may represent a valid and alternative therapeutic approach in patients with morbid obesity since it induces a significant and stable reduction of body weight and obesity-related risk factors for CVD.International Journal of Obesity (2004) 28, 1600-1606. doi:10.1038/sj.ijo.0802782 [ABSTRACT FROM AUTHOR]- Published
- 2004
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28. Free-Flow of Data: Is International Trade Law the Appropriate Answer?
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vincenzo zeno-zencovich, F. Fabbrini, E. Celeste, J. Quinn, and ZENO ZENCOVICH, Vincenzo
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data, data protection, international trade, WTO, MFN, NTP, ITU, OECD, G20 - Abstract
The paper - presented in a Conference organized in March 2020 at Dublin City University on "Data Protection Imperialism and Data Sovereignty" - points out that free-flow of data is a growing issue of contention in international relations and that there is an urgent need for agreements on the issue. It doubts however that traditional international trade law instruments (typically GATT and GATS, and related regional agreements) are the appropriate tools, while surely international trade fora have the experience to come up with ad hoc solutions based on national sovereignty, reciprocity and involvement of other international organizations such as ITU. The paper also posits that from a FFD perspective there is little difference – nor a significant difference can be made – between “personal data” and “non-personal data”.
- Published
- 2020
29. Gastric bypass and banding equally improve insulin sensitivity and β cell function.
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Bradley D, Conte C, Mittendorfer B, Eagon JC, Varela JE, Fabbrini E, Gastaldelli A, Chambers KT, Su X, Okunade A, Patterson BW, Klein S, Bradley, David, Conte, Caterina, Mittendorfer, Bettina, Eagon, J Christopher, Varela, J Esteban, Fabbrini, Elisa, Gastaldelli, Amalia, and Chambers, Kari T
- Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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30. Multiorgan Insulin Sensitivity in Lean and Obese Subjects
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Bettina Mittendorfer, Elisa Fabbrini, Bruce W. Patterson, Samuel Klein, Caterina Conte, Marleen Kars, Interne Geneeskunde, RS: NUTRIM - R1 - Metabolic Syndrome, Conte, C, Fabbrini, E, Kars, M, Mittendorfer, B, Patterson, B, and Klein, S
- Subjects
Blood Glucose ,Male ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Adipose tissue ,FATTY-ACID-METABOLISM ,Body Mass Index ,GLUCOSE ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Hyperinsulinemia ,Insulin ,Medicine ,IN-VIVO ,Original Research ,0303 health sciences ,HUMANS ,Skeletal ,Middle Aged ,MUSCLE ,Glucose clamp technique ,Adipose Tissue ,Liver ,CARDIOVASCULAR-DISEASE ,Sedentary Lifestyle ,Muscle ,Female ,Human ,Adult ,medicine.medical_specialty ,Lipolysis ,LIPOPROTEIN-LIPASE ,030209 endocrinology & metabolism ,03 medical and health sciences ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,Obesity ,Pathophysiology/Complications ,Muscle, Skeletal ,Triglycerides ,Dyslipidemias ,030304 developmental biology ,Advanced and Specialized Nursing ,business.industry ,Settore MED/13 - ENDOCRINOLOGIA ,DIABETES-MELLITUS ,medicine.disease ,Lipolysi ,Fatty Liver ,Endocrinology ,Dyslipidemia ,Glucose Clamp Technique ,HUMAN ADIPOSE ,Insulin Resistance ,Sedentary Behavior ,business ,RESISTANCE - Abstract
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/m2, mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m2) 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 Ra in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose Ra was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate Ra (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 Ra and glucose Ra 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 Rd 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.
- Published
- 2012
31. Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects
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Samuel Klein, Bettina Mittendorfer, Bruce W. Patterson, Adewole L. Okunade, Faidon Magkos, Elisa Fabbrini, Caterina Conte, Fabbrini, E, Magkos, F, Conte, C, Mittendorfer, B, Patterson, B, Okunade, A, and Klein, S
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Palmitates ,Adipose tissue ,QD415-436 ,White adipose tissue ,Biology ,Biochemistry ,adipose tissue insulin sensitivity ,hyperinsulinemic-euglycemic clamp ,Body Mass Index ,palmitate rate of appearance ,Endocrinology ,Insulin resistance ,Internal medicine ,Methods ,medicine ,Humans ,Obesity ,chemistry.chemical_classification ,fatty acid kinetics ,Insulin ,Fatty acid ,Skeletal muscle ,Settore MED/13 - ENDOCRINOLOGIA ,Cell Biology ,Middle Aged ,Glucose clamp technique ,medicine.disease ,stable isotope tracers ,medicine.anatomical_structure ,suppression of lipolysis ,Adipose Tissue ,chemistry ,Basal (medicine) ,Glucose Clamp Technique ,Female ,Insulin Resistance ,Human - Abstract
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.
- Published
- 2012
32. Adipose and muscle tissue profile of CD36 transcripts in obese subjects highlights the role of CD36 in fatty acid homeostasis and insulin resistance
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Samuel Klein, Bruce W. Patterson, Caterina Conte, Timothy Schappe, Latisha Love-Gregory, Nada A. Abumrad, Terri A. Pietka, Elisa Fabbrini, Pietka, T, Schappe, T, Conte, C, Fabbrini, E, Patterson, B, Klein, S, Abumrad, N, and Love-Gregory, L
- Subjects
Adult ,CD36 Antigens ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,030209 endocrinology & metabolism ,Carbohydrate metabolism ,cd36 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Adipocyte ,parasitic diseases ,Internal Medicine ,Adipocytes ,Medicine ,Homeostasis ,Humans ,Obesity ,Fatty acid homeostasis ,Muscle, Skeletal ,Pathophysiology/Complications ,Triglycerides ,030304 developmental biology ,Advanced and Specialized Nursing ,0303 health sciences ,business.industry ,Fatty Acids ,Skeletal muscle ,Settore MED/13 - ENDOCRINOLOGIA ,hemic and immune systems ,Glucose clamp technique ,medicine.disease ,adipose tissue ,medicine.anatomical_structure ,Endocrinology ,Glucose ,chemistry ,Adipose Tissue ,Liver ,Glucose Clamp Technique ,Female ,Metabolic syndrome ,Insulin Resistance ,business - Abstract
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.
- Published
- 2014
33. Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals
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Elisa Fabbrini, Faidon Magkos, David Bradley, Zhouji Chen, J. Christopher Eagon, Steve A. Mccartney, Marina Cella, Caterina Conte, Samuel Klein, Dong Ho Han, Bruce W. Patterson, Gemma Fraterrigo, Nada A. Abumrad, Terri A. Pietka, Anja Fuchs, Brian N. Finck, Marco Colonna, Fabbrini, E, Cella, M, Mccartney, Sa, Fuchs, A, Abumrad, Na, Pietka, Ta, Chen, Z, Finck, Bn, Han, Dh, Magkos, F, Conte, Caterina, Bradley, D, Fraterrigo, G, Eagon, Jc, Patterson, Bw, Colonna, M, and Klein, S.
- Subjects
CD4-Positive T-Lymphocytes ,FFM ,nonalcoholic fatty liver disease ,Male ,medicine.medical_treatment ,Adipose tissue ,White adipose tissue ,Body Mass Index ,T-Lymphocyte Subsets ,Receptors ,Nonalcoholic fatty liver disease ,Hepatocyte ,Lymphocytes ,GIF ,Receptors, Interleukin-17 ,interleukin ,Interleukin-17 ,Gastroenterology ,interferon ,Skeletal ,Glucose clamp technique ,Middle Aged ,Cytokine ,medicine.anatomical_structure ,Liver ,metabolically normal insulin-sensitive obese ,CD4-Positive T-Lymphocyte ,MAO ,Cytokines ,metabolically abnormal insulin-resistant obese ,Muscle ,Lymphocyte ,Female ,Case-Control Studie ,Human ,Receptor ,Adult ,medicine.medical_specialty ,MNO ,Adipose tissue macrophages ,Subcutaneous Fat ,glucose infusion rate ,T-Lymphocyte Subset ,Biology ,fat free ma ,IFN ,Article ,Insulin resistance ,Internal medicine ,NAFLD ,medicine ,Animals ,Humans ,Obesity ,Muscle, Skeletal ,Hepatology ,Metabolically Abnormal Obesity ,Animal ,Interleukin-6 ,Interleukins ,c-Jun kinase ,Skeletal muscle ,Settore MED/13 - ENDOCRINOLOGIA ,IL ,Receptors, Interleukin ,medicine.disease ,Rats ,Endocrinology ,Glucose ,Case-Control Studies ,Hepatocytes ,Glucose Clamp Technique ,fat free mass ,Rat ,Th17 Cells ,JNK ,Insulin Resistance ,Metabolically Normal Obesity - Abstract
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.
- Published
- 2013
34. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects
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J. Christopher Eagon, Bruce W. Patterson, Elizabeth M. Brunt, Faidon Magkos, Xiong Su, Caterina Conte, David Bradley, Samuel Klein, J. Esteban Varela, Elisa Fabbrini, Magkos, F, Su, X, Bradley, D, Fabbrini, E, Conte, C, Eagon, J, Varela, J, Brunt, E, Patterson, B, and Klein, S
- Subjects
Adult ,Male ,medicine.medical_specialty ,Ceramide ,Diglyceride ,medicine.medical_treatment ,Carbohydrate metabolism ,Biology ,Ceramides ,Article ,Diglycerides ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,Carnitine ,Nonalcoholic fatty liver disease ,medicine ,Humans ,Obesity ,Morbid ,Diacylglycerol kinase ,Hepatology ,Insulin ,Gastroenterology ,Settore MED/13 - ENDOCRINOLOGIA ,medicine.disease ,Obesity, Morbid ,Endocrinology ,Glucose ,chemistry ,Liver ,Female ,Insulin Resistance ,Body mass index ,medicine.drug ,Human - Abstract
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/m 2 ). 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.
- Published
- 2012
35. Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women
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Samuel Klein, Faidon Magkos, Caterina Conte, Bruce W. Patterson, Elisa Fabbrini, Magkos, F, Fabbrini, E, Conte, C, Patterson, B, and Klein, S
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Adult ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Lipolysis ,Clinical Biochemistry ,Palmitic Acid ,Adipose tissue ,Carbohydrate metabolism ,Biology ,Fatty Acids, Nonesterified ,Biochemistry ,Young Adult ,Endocrinology ,Insulin resistance ,Internal medicine ,Radioactive Tracer ,medicine ,Diabetes Mellitus ,Humans ,Insulin ,Obesity ,Radioactive Tracers ,Muscle, Skeletal ,Aged ,Biochemistry (medical) ,Skeletal muscle ,Diabetes Mellitu ,Settore MED/13 - ENDOCRINOLOGIA ,Skeletal ,JCEM Online: Brief Reports ,Glucose clamp technique ,Middle Aged ,medicine.disease ,Lipolysi ,medicine.anatomical_structure ,Basal (medicine) ,Adipose Tissue ,Nonesterified ,Glucose Clamp Technique ,Muscle ,Female ,Insulin Resistance ,Fatty Acid ,Human - Abstract
Increased adipose tissue lipolytic activity is considered an important factor in the pathogenesis of skeletal muscle insulin resistance associated with obesity.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.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.Basal (r(s) = -0.379, P0.001) and insulin-suppressed (r(s) = -0.631, P0.001) 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, P0.001).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.
- Published
- 2012
36. Methods for assessing intrahepatic fat content and steatosis
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Elisa Fabbrini, Caterina Conte, Faidon Magkos, Fabbrini, E, Conte, C, and Magkos, F
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medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Fat content ,Settore MED/12 - GASTROENTEROLOGIA ,Biopsy ,Medicine (miscellaneous) ,Nonalcoholic fatty liver disease ,Quantitative assessment ,Medicine ,Humans ,Body Fat Distribution ,Tomography ,Triglycerides ,Ultrasonography ,Nutrition and Dietetics ,medicine.diagnostic_test ,business.industry ,Settore MED/09 - MEDICINA INTERNA ,Fatty liver ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,X-Ray Computed ,Fatty Liver ,Liver ,Liver biopsy ,Radiology ,Steatosis ,business ,Tomography, X-Ray Computed ,Human - Abstract
Purpose of review Intrahepatic fat content is increasingly being recognized as an integral part of metabolic dysfunction. This article reviews available methods for the assessment of hepatic steatosis. Recent findings Apart from liver biopsy, there are several noninvasive radiologic modalities for evaluating nonalcoholic fatty liver disease. Ultrasonography, computed tomography, and traditional MRI remain largely qualitative methods for detecting mild to severe degrees of steatosis rather than quantitative methods for measuring liver fat content, even though novel attempts to collect objective quantitative information have recently been developed. Still, their sensitivity at mild degrees of steatosis is poor. Undoubtedly, most methodological advances have occurred in the field of MRI and magnetic resonance spectroscopy, which currently enable the accurate quantification of intrahepatic fat even at normal or near normal levels. Xenon computed tomography was also recently shown to offer another objective tool for the quantitative assessment of steatosis, although more validation studies are required. Summary Several modalities can be used for measuring intrahepatic fat and assessing steatosis; the choice will ultimately depend on the intended use and available resources.
- Published
- 2009
37. Gonadotropin and Testosterone Dynamics in Cryptorchidism: Clinical, Cytogenetical, Hormonal and Histological studies
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Faggiano,Michelangelo, Criscuolo,Tullio, Amici,Giuseppe, Maresca,Francesco, Santangelo, Lucio Venditto, Teresa, Salernitano,E, Fioretti, Gian Paolo, MARTE, Antonio, A. Fabbrini E. Steinberger, Faggiano, Michelangelo, Criscuolo, Tullio, Amici, Giuseppe, Maresca, Francesco, Marte, Antonio, Santangelo, Lucio, Venditto, Teresa, Salernitano, E, and Fioretti, Gian Paolo
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endocrine system ,urogenital system - Abstract
Evaluation of Hypotalamo-pituitary-gonadal axisin a group of 36 patients of either prepuberal or puberal age with cryptorchidism
- Published
- 1978
38. Phase 1 Trials of PNPLA3 siRNA in I148M Homozygous Patients with MAFLD.
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Fabbrini E, Rady B, Koshkina A, Jeon JY, Ayyar VS, Gargano C, DiProspero N, Wendel S, Hegge J, Hamilton H, Ding ZM, Afrazi M, Nicholas A, Pei T, Nakano M, Ouchi S, Saito Y, Yamashita A, Tamamura R, Salazar H, Shapiro C, Yoshihara T, Yonemura T, Inoue S, Matsuoka O, Erion M, Pocai A, and Makimura H
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- Humans, Hyperlipoproteinemia Type I genetics, Hyperlipoproteinemia Type I therapy, Mutation, Male, Female, Child, Adolescent, Adult, Acyltransferases, Phospholipases A2, Calcium-Independent, Lipase genetics, Homozygote, RNA, Small Interfering therapeutic use, Membrane Proteins genetics
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- 2024
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39. Physiological interindividual variability in endogenous estradiol concentration does not influence adipose tissue and hepatic lipid kinetics in women.
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Magkos F, Fabbrini E, Patterson BW, Mittendorfer B, and Klein S
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- Adipose Tissue metabolism, Adult, Apolipoprotein B-100 metabolism, Fatty Acids, Nonesterified, Female, Humans, Kinetics, Progesterone, Triglycerides, Estradiol, Lipoproteins, VLDL
- Abstract
Objective: Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known., Design and Methods: We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group)., Results: Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19)., Conclusions: Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.
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- 2022
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40. Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass.
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Harris LA, Kayser BD, Cefalo C, Marini L, Watrous JD, Ding J, Jain M, McDonald JG, Thompson BM, Fabbrini E, Eagon JC, Patterson BW, Mittendorfer B, Mingrone G, and Klein S
- Subjects
- Bile Acids and Salts metabolism, Blood Glucose metabolism, Fatty Acids metabolism, Follow-Up Studies, Humans, Insulin blood, Insulin Resistance, Insulin-Secreting Cells metabolism, Intestinal Absorption, Postprandial Period, Treatment Outcome, Weight Loss, Biliopancreatic Diversion methods, Gastric Bypass methods, Obesity, Morbid metabolism, Obesity, Morbid surgery
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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41. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program.
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Matthews DR, Li Q, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Desai M, Hiatt WR, Nehler M, Fabbrini E, Kavalam M, Lee M, and Neal B
- Subjects
- Administration, Oral, Aged, Amputation, Surgical, Canagliflozin administration & dosage, Diabetes Mellitus, Type 2 metabolism, Diabetic Foot drug therapy, Female, Humans, Male, Middle Aged, Multivariate Analysis, Canagliflozin therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents therapeutic use
- Abstract
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.
- Published
- 2019
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42. Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.
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Nunez DJ, Alexander M, Yerges-Armstrong L, Singh G, Byttebier G, Fabbrini E, Waterworth D, Meininger G, Galwey N, Wallentin L, White HD, Vannieuwenhuyse B, Alazawi W, Kendrick S, Sattar N, and Ferrannini E
- Subjects
- Adult, Aged, Body Mass Index, Body Weight drug effects, Female, Glycated Hemoglobin drug effects, Glycated Hemoglobin metabolism, Humans, Liver drug effects, Male, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease drug therapy, Obesity complications, Obesity drug therapy, Alanine Transaminase therapeutic use, Aspartate Aminotransferases therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Liver enzymology
- Abstract
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
1c 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 ·1.73 m-2 . ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c . 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 HbA1c 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, HbA1c , 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.- Published
- 2019
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43. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).
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Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M, and Matthews DR
- Subjects
- Adult, Aged, Canagliflozin adverse effects, Cardiovascular Diseases diagnosis, Cardiovascular Diseases mortality, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 mortality, Double-Blind Method, Female, Hospitalization, Humans, Male, Middle Aged, Risk Factors, Sodium-Glucose Transporter 2 Inhibitors adverse effects, Time Factors, Treatment Outcome, Canagliflozin therapeutic use, Cardiovascular Diseases prevention & control, Diabetes Mellitus, Type 2 drug therapy, Primary Prevention methods, Secondary Prevention methods, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
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, P <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; P <0.001 for noninferiority, P =0.02 for superiority) with no statistical evidence of heterogeneity (interaction P 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 P 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 P 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 P 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., (© 2017 The Authors.)
- Published
- 2018
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44. Effect of Weight Gain and Weight Loss on In Vivo Colonocyte Proliferation Rate in People with Obesity.
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Magkos F, Sullivan S, Fitch M, Smith G, Fabbrini E, Mittendorfer B, Hellerstein M, and Klein S
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- Biopsy, Body Composition, Body Weight, Cell Proliferation, Colon pathology, Female, Humans, Male, Middle Aged, Risk, Colon cytology, Colonic Neoplasms etiology, Obesity, Abdominal complications, Weight Gain, Weight Loss
- Abstract
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
2 , age: 52.6 ± 8.9 years) before and after diet-induced weight loss, weight gain, or weight maintenance. Subjects ingested aliquots of2 H2 O (heavy water) daily for 4 to 7 days, followed by flexible sigmoidoscopy with colon biopsies to assess the incorporation of2 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., (© 2017 The Obesity Society.)- Published
- 2017
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45. Physiological Mechanisms of Weight Gain-Induced Steatosis in People With Obesity.
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Fabbrini E, Tiemann Luecking C, Love-Gregory L, Okunade AL, Yoshino M, Fraterrigo G, Patterson BW, and Klein S
- Subjects
- Adult, Body Mass Index, Case-Control Studies, Fatty Acids metabolism, Fatty Liver diagnostic imaging, Female, Humans, Lipoproteins, VLDL metabolism, Male, Middle Aged, Obesity physiopathology, Radionuclide Imaging, Reference Values, Risk Assessment, Body Composition, Fatty Liver metabolism, Lipid Metabolism physiology, Obesity metabolism, Weight Gain physiology
- Abstract
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., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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46. Effect of Duodenal-Jejunal Bypass Surgery on Glycemic Control in Type 2 Diabetes: A Randomized Controlled Trial.
- Author
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Petry TZ, Fabbrini E, Otoch JP, Carmona MA, Caravatto PP, Salles JE, Sarian T, Correa JL, Schiavon CA, Patterson BW, Cohen R, and Klein S
- Subjects
- Adult, Aged, Blood Glucose metabolism, Diabetes Mellitus, Type 2 metabolism, Female, Gastric Bypass methods, Glucose Tolerance Test, Humans, Insulin Resistance physiology, Male, Middle Aged, Obesity metabolism, Weight Loss physiology, Diabetes Mellitus, Type 2 surgery, Duodenum surgery, Jejunum surgery, Obesity surgery
- Abstract
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., (© 2015 The Obesity Society.)
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- 2015
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47. Hepatic Steatosis as a Marker of Metabolic Dysfunction.
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Fabbrini E and Magkos F
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- Blood Glucose metabolism, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 physiopathology, Fatty Acids blood, Humans, Insulin Resistance, Lipid Metabolism, Liver pathology, Metabolic Diseases complications, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease diagnosis, Obesity complications, Obesity physiopathology, Prevalence, Triglycerides blood, Metabolic Diseases physiopathology, Non-alcoholic Fatty Liver Disease physiopathology
- Abstract
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.
- Published
- 2015
- Full Text
- View/download PDF
48. Metabolically normal obese people are protected from adverse effects following weight gain.
- Author
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Fabbrini E, Yoshino J, Yoshino M, Magkos F, Tiemann Luecking C, Samovski D, Fraterrigo G, Okunade AL, Patterson BW, and Klein S
- Subjects
- Adult, Apolipoprotein B-100 blood, Female, Humans, Lipoproteins, VLDL blood, Male, Middle Aged, Muscle, Skeletal metabolism, Muscle, Skeletal physiopathology, Adipose Tissue metabolism, Adipose Tissue physiopathology, Adiposity, Body Mass Index, Insulin Resistance, Lipogenesis, Obesity blood, Obesity physiopathology
- Abstract
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.
- Published
- 2015
- Full Text
- View/download PDF
49. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss.
- Author
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Su X, Magkos F, Zhou D, Eagon JC, Fabbrini E, Okunade AL, and Klein S
- Subjects
- Adult, Cross-Sectional Studies, Female, Gastric Bypass, Glucose Clamp Technique, Humans, Insulin Resistance physiology, Longitudinal Studies, Male, Middle Aged, Adipose Tissue metabolism, Fatty Acids metabolism, Insulin metabolism, Obesity metabolism, Weight Loss physiology
- Abstract
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., (© 2014 The Obesity Society.)
- Published
- 2015
- Full Text
- View/download PDF
50. Non-Alcoholic Steatohepatitis: Pathogenesis and Clinical Management.
- Author
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Salomone F, Zelber-Sagi S, Galvano F, and Fabbrini E
- Subjects
- Humans, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease therapy
- Published
- 2015
- Full Text
- View/download PDF
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