Publications by authors named "Jose M Carrascosa"

31 Publications

Drug Survival of IL-12/23, IL-17 and IL-23 Inhibitors for Psoriasis Treatment: A Retrospective Multi-Country, Multicentric Cohort Study.

Am J Clin Dermatol 2021 Jul 30;22(4):567-579. Epub 2021 Mar 30.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis-ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab-and to identify clinical predictors that can influence the drug survival of these drugs.

Methods: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models.

Results: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418-0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257-1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective.

Conclusion: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower.
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http://dx.doi.org/10.1007/s40257-021-00598-4DOI Listing
July 2021

Frequency of sensitization to the individual fragrances of fragrance mix I and II according to the factors included in the MOAHLFA index.

Contact Dermatitis 2021 Jun 28;84(6):395-406. Epub 2021 Feb 28.

Department of Dermatology, Hospital General Universitario de Alicante-ISABIAL, Alicante, Spain.

Background: Fragrances constitute the second most frequent cause of allergic contact dermatitis in Spain.

Objectives: To determine the rate of sensitization to the individual fragrances of fragrance mix (FM) I and FM II for each of the demographic and clinical factors included in the MOAHLFA (male, occupational dermatitis, atopic dermatitis, hand dermatitis, leg dermatitis, facial dermatitis, age) index.

Methods: We conducted a 5-year retrospective study in 23 Spanish centres. We identified the patients who had undergone patch testing with a specific fragrance series after reacting positively to fragrance markers in a baseline series. We obtained the MOAHLFA index items in this population, then calculated for each demographic and clinical factor the frequencies of sensitization to the individual fragrances of FM I and FM II.

Results: A specific fragrance series was patch tested in 1013 patients. The most frequent allergens in men, women, children, and retired people were Evernia prunastri (16%), geraniol (16.6%), isoeugenol (17.9%), and geraniol (22.4%), respectively. Citral (20.5%) and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) (14.5%) were the most common allergens in occupational eczemas and were also associated with a large proportion of hand and facial dermatitis.

Conclusions: Frequency of sensitization to the individual fragrances of FM I and FM II varies with age, sex, affected body region, and history of occupational or atopic dermatitis.
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http://dx.doi.org/10.1111/cod.13801DOI Listing
June 2021

Aging in Male Wistar Rats Associates With Changes in Intestinal Microbiota, Gut Structure, and Cholecystokinin-Mediated Gut-Brain Axis Function.

J Gerontol A Biol Sci Med Sci 2021 10;76(11):1915-1921

Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, Spain.

Aging in mammals is characterized by failure of the homeostatic mechanisms that regulate energy balance. Several mechanisms have been proposed such as the presence of a low-grade chronic inflammation in different tissues, as well as leptin and insulin resistance, but the primary alteration is not fully elucidated. The gut microbiota has recently emerged as a key player in a variety of metabolic and neurological disorders. A main concept in this context is the gut-brain axis that refers to alterations in the gut that mediate effects in the central nervous system, including those related with the control of energy balance. Using 16S rRNA analysis, we demonstrate that aged male Wistar rats have increased presence of mucin-degrading and lipopolysaccharide (LPS)-producing bacteria. In addition, old animals exhibit a lower number of neutral mucin secreting goblet cells, and a decrease of tight junctions and adherens junctions marker proteins, zonula occludens protein-1 (ZO-1) and β-catenin, respectively. These data are compatible with a thinner mucus layer and a weaker gut barrier in older animals that likely facilitate LPS leakage. Our data also show that cholecystokinin (CCK) satiating effect is impaired in aged rats, one of the expected effects of increased LPS leakage. In contrast, no overt signs of gut or systemic inflammation are observed. Changes in microbiota in old male Wistar rats present features of situations of increased adiposity, but different from those of obese animals. These could partly explain the increased adiposity and fat deposition in liver and heart as observed here.
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http://dx.doi.org/10.1093/gerona/glaa313DOI Listing
October 2021

Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort.

Acta Derm Venereol 2021 01 4;101(1):adv00354. Epub 2021 Jan 4.

Department of Dermatology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain. E-mail:

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.
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http://dx.doi.org/10.2340/00015555-3711DOI Listing
January 2021

Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice.

Mol Metab 2020 05 6;35:100954. Epub 2020 Feb 6.

Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain. Electronic address:

Objective: Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice.

Methods: Gut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice.

Results: We found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition.

Conclusion: Altogether our results have unraveled a potential role of PTP1B in the gut-liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value.
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http://dx.doi.org/10.1016/j.molmet.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082558PMC
May 2020

Effectiveness and safety of ustekinumab 90 mg in patients weighing 100 kg or less: a retrospective, observational, multicenter study.

J Dermatolog Treat 2020 May 2;31(3):222-226. Epub 2019 Apr 2.

Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Badalona, Spain.

Scant information from clinical practice is available on the effectiveness and safety of ustekinumab (UST) 90 mg in patients with psoriasis weighing 100 kg or less. To assess the effectiveness and safety at weeks 16 and 24 of UST 90 mg in patients with psoriasis weighing ≤100 kg, and to study the impact on clinical outcomes of body mass index (BMI) and prior exposure to UST 45 mg. A retrospective, observational, and multicenter study of 74 adult patients who were treated with UST 90 mg at least 24 weeks. Mean (standard deviation [SD]) score on psoriasis area and severity index (PASI) was 7.9 (4.8) at baseline, 3.3 (3.5) at week 16, and 2.2 (2.4) at week 24, when 69.7% of the patients had a PASI under 3. Overweight and obese patients achieved a mean PASI of 2.2 by week 24 (= .995). In patients who had previously been treated with UST 45 mg (52/74) with insufficient response, mean (SD) absolute PASI score was 2.7 (2.6) at week 24. No serious adverse events were reported. In patients who weigh 100 kg or less but are overweight or obese and do not present an adequate response with UST 45 mg, increasing the dose to UST 90 mg could be an alternative option.
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http://dx.doi.org/10.1080/09546634.2019.1597245DOI Listing
May 2020

Sensitization to fragrances in Spain: A 5-year multicentre study (2011-2015).

Contact Dermatitis 2019 Feb 14;80(2):94-100. Epub 2018 Nov 14.

Department of Dermatology, Hospital Universitario de Santiago de Compostela, Spain.

Background: Fragrance chemicals constitute the second most frequent cause of contact allergy in Spain. There are no data available concerning the individual fragrances that are most frequently involved.

Objectives: To describe the diagnostic contribution provided by specific fragrance series to the results obtained with baseline series fragrance markers by correlating the results of both series.

Materials And Methods: We performed a 5-year retrospective study of fragrance marker-positive patients tested with specific fragrance series in 23 Spanish centres. We collected the demographic and clinical characteristics, and compared the results of patch tests obtained from different suppliers.

Results: Of 19 588 patients patch tested with the Spanish baseline series, 1590 (8.1%) reacted positively to a fragrance marker. Of these, 1013 (63.7%) were patch tested with a fragrance series, and 664 patients reacted positively to at least one individual fragrance other than hydroxyisohexyl 3-cyclohexene carboxaldehyde. Geraniol was the most frequent allergen. Positive reactions to substances not included in fragrance mix (FM) I or FM II were found in 230 patients. Of the 436 FM I-positive patients and the 419 FM II-positive patients, 184 (42%) and 64 (39.1%), respectively, had no positive reactions to fragrance series. In the case of FM I, negative results were more common when individual fragrances were patch tested at low concentrations.

Conclusions: We recommend patch testing all patients positive for any fragrance marker with a specific fragrance series. The correlation between the results of baseline series and fragrance series could be improved by increasing the concentrations of individual fragrances.
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http://dx.doi.org/10.1111/cod.13152DOI Listing
February 2019

Actinic lichen planus triggered by drug photosensitivity.

Photodermatol Photoimmunol Photomed 2019 03 19;35(2):124-126. Epub 2018 Nov 19.

Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

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http://dx.doi.org/10.1111/phpp.12435DOI Listing
March 2019

Toll-like receptor 9 promoter polymorphism as a predictive factor of narrow-band UVB phototherapy response in patients with psoriasis.

Photodermatol Photoimmunol Photomed 2015 Mar 19;31(2):98-103. Epub 2015 Jan 19.

Department of Dermatology, Consorci Sanitari Parc Taulí, Autonomous University of Barcelona, Sabadell, Spain.

Background: Prediction of response to ultraviolet B (UVB) phototherapy in psoriatic patients mainly relies on clinical criteria, although some genetic predictors have been identified. Toll-like receptors (TLRs) have been involved in psoriasis pathogenesis through activation of the innate immune system. Their polymorphisms may condition not only the clinical profile of psoriasis but also the response to therapy.

Methods: We analyzed the role of functional single-nucleotide polymorphisms (SNPs) of TLR2, 5, 4, and 9 in clinical response to a standard narrow-band UVB (NBUVB) therapy in 39 patients with moderate to severe psoriasis.

Results: We found a significant relationship between TLR9-1486T/C SNP variants and a better response to NBUVB phototherapy. Patients with TC and CC genotype showed a higher improvement of Psoriasis Area and Severity Index (PASI) than patients with TT genotype. Results of multivariate analysis indicate that the differences in PASI improvement at the end of phototherapy attributed to TRL9 SNP genotype were not dependent on the patients' phototype, age, gender, body mass index, basal PASI, or disease evolution.

Conclusions: We describe a functional genetic variant in TLR9 gene that might affect the susceptibility to antipsoriatic treatment. The search of genetic predictive factors may be helpful in therapy selection and optimization of therapeutic regimes in psoriatic patients.
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http://dx.doi.org/10.1111/phpp.12160DOI Listing
March 2015

Effects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats.

Exp Gerontol 2014 Dec 1;60:183-9. Epub 2014 Nov 1.

Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain.

Background And Aims: Aging is associated with alterations in the cardiovascular system such as increased vasoconstriction and decreased vasodilatation. Some of these changes are partially reversed by caloric restriction. Endothelin-1 is a potent vasoconstrictor which levels increased with age. The aim of this study is to analyze the role of endothelin-1 in the cardiac and coronary changes induced by age and whether these changes may be attenuated by a three-month caloric restriction.

Methods And Results: Hearts from young (3 months old), aged (24 months old) and aged rats after 3 months of caloric restriction were perfused according to the Langendorff technique. Coronary vasoconstriction to endothelin-1 was reduced in old rats, and endothelin-1 increased myocardial contractility (dP/dt) and heart rate in old but not in young rats. These changes observed in old rats were partly reversed by caloric restriction. Also, in the myocardial tissue of old rats the gene expression of endothelin-1, inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-a) was increased, and the gene expression of endothelin ETB receptors and endothelial nitric oxide syntase (eNOS) was reduced, compared with young rats. Aging induced changes in the expression of ETB receptors and eNOS were reversed by caloric restriction.

Conclusions: These results suggest that aging produces alterations in myocardial and coronary responses to endothelin-1, that may be related to changes in expression of nitric oxide synthases and/or endothelin receptor subtypes, with some of these changes being prevented by caloric restriction.
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http://dx.doi.org/10.1016/j.exger.2014.10.018DOI Listing
December 2014

Cardiovascular risk factors and cardiovascular diseases in patients with moderate to severe psoriasis under systemic treatment. PSO-RISK, descriptive study.

Eur J Dermatol 2014 Nov-Dec;24(6):662-9

Dpt of Dermatology, Hospital de la St Creu i S Pau, Barcelona, Spain.

Background: The prevalence of cardiovascular risk factors (CVRF) in psoriasis has not been studied in large Spanish samples.

Objective: To assess the prevalence of major CVRFs in psoriasis patients requiring systemic treatments.

Material And Methods: Cross-sectional study in psoriasis patients from 33 hospital dermatology offices throughout Spain. Blood pressure (BP) was measured and a fasting lab test was performed. Each CVRF was diagnosed according to the recommendations of international societies.

Results: In 368 patients (mean age 48 years old, 36% women), 80.2% had at least one CVRF. The prevalence of each CVRF was similar in men and women and slightly higher in patients with psoriatic arthritis and in patients with a history of more severe disease. The percentage of patients treated with drugs to control CVRF was low (∼ 50% of those with each CVRF). A total of 20.7% had experienced some cardiovascular disease (CVD) episode.

Conclusion: The prevalence of CVRF was high, higher than in the general Spanish population, and 20% had already suffered CVD. However, the percentage with drug treatments for CVRF was low.
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http://dx.doi.org/10.1684/ejd.2014.2440DOI Listing
October 2015

Impairment of skeletal muscle insulin action with aging in Wistar rats: role of leptin and caloric restriction.

Mech Ageing Dev 2012 May 16;133(5):306-16. Epub 2012 Mar 16.

Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Facultad de Ciencias, Universidad Autónoma, 28049 Madrid, Spain.

Insulin resistance develops with aging in rats in parallel to fat mass accretion, central leptin resistance and hyperleptinemia. Previous studies demonstrated that insulin resistance appears earlier in adipose tissue than in muscle during aging and pointed to a role of hyperleptinemia in the impairment of insulin action. Here we explored the evolution along aging of insulin sensitivity in soleus and EDL muscles by analyzing insulin signaling in vivo and insulin-dependent glucose transport ex vivo. A decrease in insulin action was observed in both muscles. Caloric restriction improves insulin sensitivity at early aging but not in older animals. We also tested the role of leptin on insulin action in skeletal muscle. Short-term pretreatment with leptin inhibits in vivo muscle insulin signaling and insulin-dependent glucose transport in isolated muscle strips. This effect is mediated by its action on early insulin signaling as well as by the inhibition of p38. In contrast, chronic central administration of leptin elicits an insulin sensitizing effect on soleus. These data suggest that leptin can act as muscle insulin sensitizer, when acting at central level, and as insulin antagonistic when interacting directly with soleus muscle. This effect may be relevant in situations of hyperleptinemia such as aging.
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http://dx.doi.org/10.1016/j.mad.2012.03.006DOI Listing
May 2012

Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging.

Aging Cell 2012 Apr 1;11(2):284-96. Epub 2012 Feb 1.

Institute of Biomedicine Alberto Sols (CSIC/UAM), Madrid, Spain.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B(-/-) mice maintained on mixed genetic background (C57Bl/6J × 129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B(-/-) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B(-/-) animals. Leanness in 16-month-old PTP1B(-/-) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM.
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http://dx.doi.org/10.1111/j.1474-9726.2011.00786.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306541PMC
April 2012

Age-associated decrease of SIRT1 expression in rat hippocampus: prevention by late onset caloric restriction.

Exp Gerontol 2012 Feb 26;47(2):198-201. Epub 2011 Nov 26.

Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain.

We have studied the effect of aging and late onset caloric restriction (CR) on the expression of SIRT1 in hippocampus and cerebral cortex of the rat. Quantitative analysis showed that there is a significant reduction of SIRT1 protein levels in hippocampus with aging. Late onset, moderate CR prevented the deleterious effect of aging on SIRT1 content. Examination of SIRT1 immunoreactivity in coronal sections from hippocampus supported these results, and confirmed that old animals are able to respond to the beneficial effects of CR by regulating SIRT1 protein expression. Differences in the amounts of SIRT1 transcripts among animal groups were not found, which suggest that post-transcriptional mechanisms could be involved in the effects of aging and CR on SIRT1 expression.
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http://dx.doi.org/10.1016/j.exger.2011.11.010DOI Listing
February 2012

Age-associated development of inflammation in Wistar rats: Effects of caloric restriction.

Arch Physiol Biochem 2011 Jul 2;117(3):140-50. Epub 2011 Jun 2.

Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, 28922, Madrid, Spain.

Context: Insulin resistance and type 2 Diabetes have been associated to a low grade of inflammation and their prevalence increase with ageing.

Objective: To analyse the development of inflammation in adipose tissue, liver, muscle and hypothalamus during ageing and the effects of caloric restriction.

Materials And Methods: We have analysed the expression of inflammatory cytokines (TNFα, IL1-β, IL-12B and IL-6), proteins involved in macrophage recruitment (MCP-1, CCR2), TLR4 and macrophage markers (CD11c, CD11b and arginase1). Immunohistochemistry of macrophages has also been performed.

Results: All studied tissues present signs of inflammation during ageing, but with different pattern and intensity. Caloric restriction decreases the expression of most of inflammatory markers.

Discussion And Conclusions: These data indicate a role of adiposity in the development of inflammation and insulin resistance during ageing. Dietetic intervention could be a useful tool to ameliorate the development of inflammation and insulin resistance associated with ageing.
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http://dx.doi.org/10.3109/13813455.2011.577435DOI Listing
July 2011

Development of insulin resistance during aging: involvement of central processes and role of adipokines.

Curr Protein Pept Sci 2011 Jun;12(4):305-15

Centro de Biología Molecular, Severo Ochoa (UAM-CSIC), Universidad Autónoma, 28049 Madrid, Spain.

Aging in mammals associates with the development of peripheral insulin resistance. Additionally, adiposity usually increases with aging and this could play a relevant role in the gradual impairment of insulin action. In fact, fat accretion leads to changes in the expression and circulating concentrations of factors originated in adipose tissue like leptin, resistin and inflammatory cytokines which have been shown to modulate insulin signaling in insulin target tissues acting both, directly or through the central nervous system. Even insulin action on peripheral target tissues has been recently demonstrated to be partially mediated by its central action, suggesting that a decrease in central insulin action could be involved in the development of peripheral insulin resistance. In the present review we analyze the available research data on aging-associated insulin resistance making emphasis in the following aspects: 1) The time-course of development of overall insulin resistance and the evolution of changes in circulating adipokines; 2) The effect of caloric restriction and the decrease of adiposity in insulin action; 3) The influence of changes in the central action of factors like leptin or insulin in the development and maintenance of insulin resistance during aging.
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http://dx.doi.org/10.2174/138920311795906655DOI Listing
June 2011

Regulation of insulin-stimulated glucose uptake in rat white adipose tissue upon chronic central leptin infusion: effects on adiposity.

Endocrinology 2011 Apr 1;152(4):1366-77. Epub 2011 Feb 1.

Area de Bioquímica, Facultad de Químicas, Regional Centre for Biomedical Research, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain.

Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 μg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [(3)H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity.
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http://dx.doi.org/10.1210/en.2010-0858DOI Listing
April 2011

S-resistin inhibits adipocyte differentiation and increases TNFalpha expression and secretion in 3T3-L1 cells.

Biochim Biophys Acta 2010 Oct 17;1803(10):1131-41. Epub 2010 Jul 17.

Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Toledo, Spain.

S-resistin is a non-secretable resistin spliced variant described in white adipose tissue from Wistar rats. Since resistin has been implicated in adipogenesis regulation, here we have investigated the possible role of this new isoform in this process. For that, we have studied the adipocyte development in 3T3-L1 pre-adipocyte cell line stably expressing s-resistin and resistin. Both isoforms are able to restrain 3T3-L1 pre-adipocyte differentiation though affecting differently the expression pattern of pro-adipogenic transcription factors such CCAAT/enhancer binding proteins alpha and beta (C/EBPalpha and C/EBPbeta) and peroxisome proliferator-activated receptor gamma (PPARgamma), as well of proteins implicated in lipid metabolism such perilipin, fatty acid synthase (FAS), adipocyte lipid binding protein (ALBP/aP2) and carnitine palmitoyltransferase1 (CPT1). Likewise, both resistin isoforms impair insulin-stimulated glucose transport by decreasing glucose transport 4 (GLUT4) expression but to a different degree. In addition, s-resistin expressing 3T3-L1 cells display other remarkable differences. Thus, in these cells, endogenous resistin expression falls down while tumor necrosis factor alpha (TNFalpha) and interleukine 6 (IL-6) productions are increased along differentiation. These findings indicate that s-resistin isoform also impairs adipocyte differentiation affecting the expression pattern of key pro-adipogenic transcription factors and insulin sensitivity. Additionally, s-resistin may play a role in inflammatory processes.
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http://dx.doi.org/10.1016/j.bbamcr.2010.06.012DOI Listing
October 2010

Basal cell carcinoma.

Cancer Treat Res 2009 ;146:263-78

Department of Dermatology, Hospital Universitario Germans Trias i Pujol, Badalona, Spain.

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http://dx.doi.org/10.1007/978-0-387-78574-5_22DOI Listing
September 2010

The expression of rat resistin isoforms is differentially regulated in visceral adipose tissues: effects of aging and food restriction.

Metabolism 2009 Feb;58(2):204-11

Area de Bioquímica, Centro Regional de Investigaciones Biomédicas (CRIB), Facultad de Ciencias del Medio Ambiente, Universidad de Castilla-La Mancha, Av Carlos III s/n 45071 Toledo, Spain.

Two variants of the adipose hormone resistin are generated by alternative splicing in Wistar rats. Here we analyzed the expression of these resistin variants in 2 main visceral adipose depots, epididymal and retroperitoneal, as well as the resistin serum concentration during aging and food restriction. Total protein levels of resistin were also analyzed in extracts from both visceral adipose depots. Resistin variants show similar patterns of relative expression in visceral adipose tissues in 3-month-old rats, representing the short variant, s-resistin, which is 15% of the full-length transcript. However, only epididymal, but not retroperitoneal, fat pad shows a decrease in both messenger RNA and protein levels of resistin isoforms with aging. Food restriction decreases adiposity index in 8- and 24-month-old animals to values even lower than those of 3-month-old animals. Food restriction decreases resistin expression in both adipose tissues in 8-month-old but not in 24-month-old rats. Interestingly, concomitant with the improvement of insulin sensitivity asserted by homeostasis model assessment, resistin serum levels decrease only in food-restricted 8-month-old animals. In contrast, food restriction up-regulates s-resistin messenger RNA in epididymal adipose tissue, whereas no significant changes are appreciated in retroperitoneal adipose tissue. These data indicate that both forms of resistin are differentially regulated by fat depot location, aging, and even nutritional status, suggesting that alternative splicing plays a key role in this differential regulation.
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http://dx.doi.org/10.1016/j.metabol.2008.09.014DOI Listing
February 2009

The effect of aging on insulin signalling pathway is tissue dependent: central role of adipose tissue in the insulin resistance of aging.

Mech Ageing Dev 2009 Mar 21;130(3):189-97. Epub 2008 Nov 21.

Area de Bioquímica, Facultad de Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain.

Insulin resistance progressively increases with age, resulting in excessively high incidence of T2D in the elderly population. To investigate the molecular mechanisms underlying insulin resistance of aging, we carried out a comparative study of insulin signalling cascade in adipose tissue, liver and skeletal muscle. We measured the protein levels in different subcellular compartments and the phosphorylation status of key components of the insulin signalling pathway in response to in vivo insulin infusion. White adipose tissue (WAT) from old rats shows altered subcellular distribution of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) and a marked reduction in the insulin-stimulated IR tyrosine phosphorylation. Furthermore, activation of Akt, as well as GLUT4 translocation to the plasma membrane, is impaired. Quadriceps muscle from old rats also has a defect in GLUT4 trafficking but, in contrast to WAT, insulin signalling at the level of IR and Akt is increased. In liver, we found no major differences in the ability of insulin to induce autophosphorylation of the IR or activation of Akt between adult and old animals. These data, therefore, show at the molecular level that insulin resistance in adipose tissue precedes the development of liver and muscle insulin resistance in aged rats.
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http://dx.doi.org/10.1016/j.mad.2008.11.005DOI Listing
March 2009

Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging.

Exp Gerontol 2009 Jan-Feb;44(1-2):20-5. Epub 2008 May 20.

Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Nicolás Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain.

Energy balance in mammals is modulated by peripheral signals that inform the brain about the magnitude of fat stores, the amount of food in the gastrointestinal tract, and the level of nutrients such as glucose in the circulation. Among these, insulin and leptin are considered adiposity signals involved in the long-term maintenance of fat stores. Here we review the mechanisms of action of leptin and insulin in the hypothalamus and how these mechanisms are altered during aging in rat models. Aged rats are characterized by increased fat mass, central leptin and insulin resistance, and hyperleptinemia. Leptin resistance is manifested by its failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose tissue, and increase energy expenditure. Moreover, leptin and insulin signaling are decreased in hypothalamus from aged rats. Calorie restriction and fasting studies provide controversial data on the cause-effect interrelationship between increased adiposity and development of central leptin resistance. Although in the absence of obesity leptin resistance seems to be a characteristic of aged animals, adiposity could either reinforce it or cause an early onset of this resistance. More studies are necessary to clarify the role of the hypothalamus in the development of age-associated obesity and insulin resistance.
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http://dx.doi.org/10.1016/j.exger.2008.05.005DOI Listing
August 2009

Effects of chronic acarbose treatment on adipocyte insulin responsiveness, serum levels of leptin and adiponectin and hypothalamic NPY expression in obese diabetic Wistar rats.

Clin Exp Pharmacol Physiol 2008 Mar;35(3):256-61

Centre of Molecular Biology Severo Ochoa, Faculty of Sciences, Autonomous University.

1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phosphorylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus.
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http://dx.doi.org/10.1111/j.1440-1681.2007.04809.xDOI Listing
March 2008

Impaired central insulin response in aged Wistar rats: role of adiposity.

Endocrinology 2007 Nov 2;148(11):5238-47. Epub 2007 Aug 2.

Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda Atenas s/n, Alcorcón, 28922, Madrid, Spain.

Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.
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http://dx.doi.org/10.1210/en.2007-0543DOI Listing
November 2007

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity.

J Endocrinol 2007 Jul;194(1):131-41

Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.

Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocyte-derived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8- but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.
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http://dx.doi.org/10.1677/joe.1.07043DOI Listing
July 2007

[Consensus document on phototherapy: PUVA therapy and narrow-band UVB therapy].

Actas Dermosifiliogr 2005 Dec;96(10):635-58

Hospital Universitari Germans Trías i Pujol, Badalona, Spain.

It is essential to develop a consensus document on phototherapy in order to adapt this procedure to the specific characteristics, needs and reality of our milieu. Using a review of existing literature on the subject and the experience of its own members as a reference, the Spanish Photobiology Group (GEF) of the Spanish Academy of Dermatology and Venereology (AEDV) has developed some therapeutic guidelines for the most widely used modes of phototherapy: PUVA therapy and narrow-band UVB (NBUVB) therapy. These guidelines deal with generalities about the equipment, calibration and regulation in phototherapy booths, and the concept and indications for these forms of treatment are reviewed. Recommendations are also proposed regarding patient selection, therapeutic procedures, associated pharmacological agents of interest and the prevention and management of adverse effects. The consensus document is designed as a flexible and practical instrument intended for use in daily clinical practice, aimed at optimizing the possibilities of phototherapy while reducing risks for patients and therapists.
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http://dx.doi.org/10.1016/s0001-7310(05)73153-7DOI Listing
December 2005

[Generalized hyperpigmented, hyperkeratotic plaques].

Actas Dermosifiliogr 2005 Sep;96(7):473-4

Servicio de Dermatología, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

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http://dx.doi.org/10.1016/s0001-7310(05)73117-3DOI Listing
September 2005

Altered subcellular distribution of IRS-1 and IRS-3 is associated with defective Akt activation and GLUT4 translocation in insulin-resistant old rat adipocytes.

Biochim Biophys Acta 2006 Feb 4;1763(2):197-206. Epub 2006 Jan 4.

Area de Bioquímica, Facultad de Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10 13071, Ciudad Real, Spain.

Insulin receptor signal transduction depends on the precise intracellular localization of signalling molecules. This study examines the compartmentalization and the insulin-induced translocation and tyrosine phosphorylation of insulin receptor substrates (IRS-1 and IRS-3) in epididymal white adipose tissue from adult and insulin-resistant old rats. We found that insulin induces the translocation of IRS-1 from plasma membrane (PM) and light microsomes (LM) to cytosol, whereas IRS-3 translocates from PM to LM and cytosol upon insulin stimulation. Old rat adipocytes are characterized by higher relative levels of IRS proteins, under basal conditions, in those fractions where they are intended to translocate in response to insulin and exhibit a higher phosphotyrosine content of IRS-1 and -3 in basal conditions and a lower maximal phosphorylation in response to insulin. Furthermore, old rat adipocytes are also characterized by a reduced ability of insulin to stimulate both, Akt/PKB activity and translocation of GLUT4 to the PM. We conclude that the lower stimulation of downstream insulin signalling involved in glucose metabolism in old rat adipocytes may be explained, at least in part, by the altered subcellular distribution of IRS-1 and -3 proteins. In addition, our data suggest that the mechanism of turning on/off insulin receptor-mediated signal is impaired with aging.
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http://dx.doi.org/10.1016/j.bbamcr.2005.12.005DOI Listing
February 2006

ObRa and ObRe are differentially expressed in adipose tissue in aged food-restricted rats: effects on circulating soluble leptin receptor levels.

Endocrinology 2005 Nov 21;146(11):4934-42. Epub 2005 Jul 21.

Area de Bioquímica, Facultad de Químicas, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain.

In rodents, soluble leptin receptor (SLR) may be generated by alternative splicing of ObR mRNA and/or as a cleavage product of ObR membrane-anchored receptors. In this study, we investigated the contribution of both processes on the generation of SLR in 3-, 8-, and 24-month-old Wistar rats fed ad libitum (AL) or under food restriction (FR). To this end, we determined serum SLR levels and analyzed ObRa and ObRe mRNA expression under these physiological conditions. Additionally, we studied the cellular distribution of ObRa and the generation of SLR by N-ethyl-maleimide-induced shedding from ObRa membrane receptors in isolated adipocytes. Serum SLR levels were significantly increased in 8- and 24-month-old rats under FR, whereas similar amounts were found in rats of different ages fed AL. ObRa and ObRe mRNA expression in epididymal adipose tissue increased with aging. In contrast, after FR, ObRe mRNA expression decreased, whereas ObRa mRNA expression further increased compared with 8- and 24-month-old rats fed AL. Additionally, FR promoted a change in the distribution of ObRa between internal and plasma membranes in isolated adipocytes, increasing its presence at the cell surface. Finally, the generation of SLR by N-ethyl-maleimide-induced shedding from ObRa was also increased under FR. These data suggest that shedding of ObRa membrane-anchored receptors, rather than ObRe expression, might preferentially contribute to the generation of the increased levels of SLR in serum under conditions of FR.
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http://dx.doi.org/10.1210/en.2005-0220DOI Listing
November 2005

Leptin impairs insulin signaling in rat adipocytes.

Diabetes 2004 Feb;53(2):347-53

Centre of Molecular Biology Severo Ochoa, Autonomous University, Madrid, Spain.

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.
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http://dx.doi.org/10.2337/diabetes.53.2.347DOI Listing
February 2004
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