Magmas, a Gene Newly Identified as Overexpressed in Human and Mouse ACTH-Secreting Pituitary Adenomas, Protects Pituitary Cells from Apoptotic Stimuli

Federico Tagliati, Erica Gentilin, Mattia Buratto, Daniela Molè, Ettore Ciro degli Uberti and Maria Chiara Zatelli

Pituitary tumors are mostly benign, being locally invasive in 5–35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH-secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation.

Ir al artículo 

Low-Carbohydrate Diets and All-Cause and Cause-Specific Mortality Two Cohort Studies

Teresa T. Fung, Rob M. van Dam, Susan E. Hankinson, Meir Stampfer, Walter C. Willett and Frank B.

Background: Data on the long-term association between low-carbohydrate diets and mortality are sparse.

Objective: To examine the association of low-carbohydrate diets with mortality during 26 years of follow-up in women and 20 years in men.
Design: Prospective cohort study of women and men who were followed from 1980 (women) or 1986 (men) until 2006. Low-carbohydrate diets, either animal-based (emphasizing animal sources of fat and protein) or vegetable-based (emphasizing vegetable sources of fat and protein), were computed from several validated food-frequency questionnaires assessed during follow-up.

Setting: Nurses' Health Study and Health Professionals' Follow-up Study.

Participants: 85 168 women (aged 34 to 59 years at baseline) and 44 548 men (aged 40 to 75 years at baseline) without heart disease, cancer, or diabetes.

Measurements: Investigators documented 12 555 deaths (2458 cardiovascular-related and 5780 cancer-related) in women and 8678 deaths (2746 cardiovascular-related and 2960 cancer-related) in men.

Results: The overall low-carbohydrate score was associated with a modest increase in overall mortality in a pooled analysis (hazard ratio [HR] comparing extreme deciles, 1.12 [95% CI, 1.01 to 1.24]; P for trend = 0.136). The animal low-carbohydrate score was associated with higher all-cause mortality (pooled HR comparing extreme deciles, 1.23 [CI, 1.11 to 1.37]; P for trend = 0.051), cardiovascular mortality (corresponding HR, 1.14 [CI, 1.01 to 1.29]; P for trend = 0.029), and cancer mortality (corresponding HR, 1.28 [CI, 1.02 to 1.60]; P for trend = 0.089). In contrast, a higher vegetable low-carbohydrate score was associated with lower all-cause mortality (HR, 0.80 [CI, 0.75 to 0.85]; P for trend ≤ 0.001) and cardiovascular mortality (HR, 0.77 [CI, 0.68 to 0.87]; P for trend < 0.001).

Limitations: Diet and lifestyle characteristics were assessed with some degree of error. Sensitivity analyses indicated that results were probably not substantively affected by residual confounding or an unmeasured confounder. Participants were not a representative sample of the U.S. population.

Conclusion: A low-carbohydrate diet based on animal sources was associated with higher all-cause mortality in both men and women, whereas a vegetable-based low-carbohydrate diet was associated with lower all-cause and cardiovascular disease mortality rates.

Ir al artículo 

Genes involved in human premature ovarian failure

Luca Persani, Raffaella Rossetti and Chiara Cacciatore

Ir al artículo 

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Mikael Knip, M.D., D.M.Sc., Suvi M. Virtanen, M.D., D.M.Sc., Karri Seppä, M.Sc., Jorma Ilonen, M.D., D.M.Sc., Erkki Savilahti, M.D., D.M.Sc., Outi Vaarala, M.D., D.M.Sc., Antti Reunanen, M.D., D.M.Sc., Kari Teramo, M.D., D.M.Sc., Anu-Maaria Hämäläinen, M.D., D.M.Sc., Johanna Paronen, M.D., D.M.Sc., Hans-Michael Dosch, M.D., Timo Hakulinen, Ph.D., and Hans K. Åkerblom, M.D., D.M.Sc. for the Finnish TRIGR Study Group

Background: Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children.

Methods: In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk–based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age.

Results: The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups.

Conclusion:Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity — markers that may reflect an autoimmune process leading to type 1 diabetes. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00570102.)

Ir al artículo 

The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know

A. Catharine Ross, JoAnn E. Manson, Steven A. Abrams, John F. Aloia, Patsy M. Brannon, Steven K. Clinton, Ramon A. Durazo-Arvizu, J. Christopher Gallagher, Richard L. Gallo, Glenville Jones, Christopher S. Kovacs, Susan T. Mayne, Clifford J. Rosen, and Sue A. Shapses

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

Ir al artículo 

Effects of Aerobic and Resistance Training on Hemoglobin A1c Levels in Patients With Type 2 Diabetes

Timothy S. Church, MD, MPH, PhD; Steven N. Blair, PED; Shannon Cocreham, BS; Neil Johannsen, PhD; William Johnson, PhD; Kimberly Kramer, MPH; Catherine R. Mikus, MS; Valerie Myers, PhD; Melissa Nauta, BS; Ruben Q. Rodarte, MS, MBA; Lauren Sparks, PhD; Angela Thompson, MSPH; Conrad P. Earnest, PhD

Context: Exercise guidelines for individuals with diabetes include both aerobic and resistance training although few studies have directly examined this exercise combination.

Objective: To examine the benefits of aerobic training alone, resistance training alone, and a combination of both on hemoglobin A1c (HbA1c) in individuals with type 2 diabetes.

Design, Setting, and Participants: A randomized controlled trial in which 262 sedentary men and women in Louisiana with type 2 diabetes and HbA1c levels of 6.5% or higher were enrolled in the 9-month exercise program between April 2007 and August 2009.

Intervention: Intervention Forty-one participants were assigned to the nonexercise control group, 73 to resistance training 3 days a week, 72 to aerobic exercise in which they expended 12 kcal/kg per week; and 76 to combined aerobic and resistance training in which they expended 10 kcal/kg per week and engaged in resistance training twice a week.

Main Outcome: Change in HbA1c level. Secondary outcomes included measures of anthropometry and fitness.

Results: The study included 63.0% women and 47.3% nonwhite participants who were a mean (SD) age of 55.8 years (8.7 years) with a baseline HbA1c level of 7.7% (1.0%). Compared with the control group, the absolute mean change in HbA1c in the combination training exercise group was –0.34% (95% confidence interval [CI], –0.64% to –0.03%; P = .03). The mean changes in HbA1c were not statistically significant in either the resistance training (–0.16%; 95% CI, –0.46% to 0.15%; P = .32) or the aerobic (–0.24%; 95% CI, –0.55% to 0.07%; P = .14) groups compared with the control group. Only the combination exercise group improved maximum oxygen consumption (mean, 1.0 mL/kg per min; 95% CI, 0.5-1.5, P < .05) compared with the control group. All exercise groups reduced waist circumference from –1.9 to –2.8 cm compared with the control group. The resistance training group lost a mean of –1.4 kg fat mass (95% CI, –2.0 to –0.7 kg; P < .05) and combination training group lost a mean of –1.7 (–2.3 to –1.1 kg; P < .05) compared with the control group.

Conclusions: Among patients with type 2 diabetes mellitus, a combination of aerobic and resistance training compared with the nonexercise control group improved HbA1c levels. This was not achieved by aerobic or resistance training alone.

Ir al artículo 

Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis

Ronan Roussel, MD, PhD; Florence Travert, MD, PhD; Blandine Pasquet, MSc; Peter W. F. Wilson, MD; Sidney C. Smith Jr, MD; Shinya Goto, MD, PhD; Philippe Ravaud, MD, PhD; Michel Marre, MD, PhD; Avi Porath, MD, MPH; Deepak L. Bhatt, MD, MPH; P. Gabriel Steg, MD; for the Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators

Background: Metformin is recommended in type 2 diabetes mellitus because it reduced mortality among overweight participants in the United Kingdom Prospective Diabetes Study when used mainly as a means of primary prevention. However, metformin is often not considered in patients with cardiovascular conditions because of concerns about its safety.

Methods: We assessed whether metformin use was associated with a difference in mortality among patients with atherothrombosis. The study sample comprised 19 691 patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin. Multivariable adjustment and propensity score were used to account for baseline differences. The main outcome measure was 2-year mortality.

Results: The mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) with metformin and 9.8% 8.4%-11.2%) without metformin; the adjusted hazard ratio (HR) was 0.76 (0.65-0.89; P < .001). Association with lower mortality was consistent among subgroups, noticeably in patients with a history of congestive heart failure (HR, 0.69; 95% CI, 0.54-0.90; P = .006), patients older than 65 years (0.77; 0.62-0.95; P = .02), and patients with an estimated creatinine clearance of 30 to 60 mL/min/1.73 m2 (0.64; 95% CI, 0.48-0.86; P = .003) (to convert creatinine clearance to mL/s/m2, multiply by 0.0167).

Conclusions: Metformin use may decrease mortality among patients with diabetes when used as a means of secondary prevention, including subsets of patients in whom metformin use is not now recommended. Metformin use should be tested prospectively in this population to confirm its effect on survival.

Ir al artículo 

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

A Hébrant, W C G van Staveren, C Maenhaut, J E Dumont and J Leclère.

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

Ir al artículo 

Descargar artículo 

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Los autores de éste artículo proponen una nueva hipótesis surgida a partir de las observaciones realizadas en el curso del tratamiento combinado con pegvisomant (PEG) y análogos de la somatostatina de acción prolongada (SRL). Los SRL suprimen la secreción de GH, pero también inducen una disminución de los niveles de insulina portal y por ello provocan un estado de relativa resistencia hepática a la GH con disminución de la producción hepática de IGF-I. Como consecuencia, los niveles de IGF-I pueden ser normales sin que ello implique un adecuado control de la hipersecreción de GH en los tejidos periféricos. La adición de PEG al tratamiento con SRL puede permitir no solo la normalización de IGF-I, sino también el control de la “hiperactividad GH residual” en los tejidos periféricos.

Ignacio Bernabeu
Coordinador GNE/SEEN

Ir al artículo 

Descargar artículo 

Relative contribution of energy intake and energy expenditure to childhood obesity: a review of the literature and directions for future research

S N Bleich, R Ku and Y C Wang

Background: Understanding the relative importance of overconsumption and physical inactivity to excess weight gain among children and adolescents can contribute to the development and evaluation of interventions and policies to reduce childhood obesity. However, whether energy intake or expenditure is the dominant contributor to childhood obesity is a subject of debate. To date, no study has systematically reviewed the literature on this subject.

Methods: We searched PubMed and Ovid Medline (January 1970 to January 2010) for potentially relevant English-language abstracts and obtained full-text articles for the abstracts, which passed the initial inclusion–exclusion criteria. Reference lists of full-length articles were hand searched to identify additional studies potentially relevant for inclusion. Relevant studies were characterized into one of the following three categories: cross-sectional studies with a nationally representative sample, cross-sectional studies among population subgroups and longitudinal studies.

Results: This review identified 26 studies examining factors related to energy intake, energy expenditure and obesity among children and adolescents. Cross-sectional and longitudinal studies suggest that the primary determinant of energy imbalance at both the population and the individual levels is not definitive. Our findings further suggest that there is wide variation in data quality between studies. Future research in this area should aim to improve the accuracy of measures of energy intake, expenditure and their net balance over time; capitalize on under-utilized, non-traditional data sources, which have not been widely used; use modeling techniques to synthesize studies of shorter follow-up period and different outcome measures; and examine the unique determinants of energy imbalance among demographic groups at higher risk for obesity.

Conclusions: On the basis of the current evidence, there is no consensus on the main driver of secular trends on weight gain among US children and adolescents. More research and better methods are needed to identify the relative contribution of energy intake and energy expenditure to obesity in the pediatric population.

Ir al artículo 

Descargar artículo 

Adipocyte-derived factors suppress heart contraction

C Look, I Morano, M Ehrhart-Bornstein, S R Bornstein and V Lamounier-Zepter

Background: Obesity is strongly associated with cardiovascular diseases including systemic hypertension, coronary artery disease and heart failure. Despite several investigations the pathophysiological mechanisms involved remain unclear. We have previously shown that adipose tissue exerts a highly potent activity with an acute depressant effect on cardiomyocytes, thus suggesting direct involvement of adipose tissue in the development of heart dysfunction.

Objective and Design: This study investigates the effects of adipocyte factors obtained from subcutaneous adipose tissue on the whole cardiac function by using isolated perfused rat hearts in a Langendorff mode. We recorded changes in coronary flow, developed isovolumetric left ventricular pressure, contraction rate and relaxation rate.

Results: We observed a significant decrease in heart contractility parameters as well as in coronary flow within a few seconds of incubation with adipocyte factors. The cardiodepressant effects could not be blocked by the nonselective cyclooxygenase-inhibitor indomethacin. Human adipocytes release tumor necrosis factor-α, interleukin-6 (IL-6) and IL-1β into extracellular medium. These cytokines were tested for their potential effect but were, however, not responsible for the cardiodepressant effect observed.

Conclusions: These data indicate that human adipocytes secrete factors with a strong acute depressant effect on cardiac force generation and coronary flow due to contraction of the coronary vessels, thus suggesting a direct role of adipose tissue in the pathogenesis of cardiac dysfunction.

Ir al artículo 

Descargar artículo 

Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study

I Labayen, J R Ruiz, F B Ortega, J Dalongeville, D Jiménez-Pavón, M J Castillo, S De Henauw, M González-Gross, G Bueno, D Molnar, A Kafatos, L E Díaz, A Meirhaeghe and L A Moreno

We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6±1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml−1 per risk allele (95% confidence interval: 2.0, 5.9); adjusted P<0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity.

Ir al artículo 

Descargar artículo 

Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

Anna G Angelousi, Drosos E Karageorgopoulos, Anastasios M Kapaskelis and Matthew E Falagas

Introduction: The severity of critical illness is associated with various patterns of thyroid hormone abnormalities.We sought to evaluate whether the outcome of patients with, specifically, sepsis or septic shock is associated with the thyroid function tests evaluated at diagnosis or admission in the intensive care unit (ICU).

Methods: We performed a systematic review of relevant studies by searching PubMed.

Results: We included nine studies that all had a prospective cohort design. Seven involved children or neonates, and two involved adults. Mortality was the outcome evaluated in eight studies, while the length of ICU stay was evaluated in the remaining study. In univariate analysis, six of the nine included studies showed that either, free or total, triiodothyronine or thyroxine was lower in the group of patients with sepsis or septic shock who had unfavorable outcome than in those who had favorable outcome. Two other studies showed higher TSH values in the group of patients with unfavorable outcome. No significant relevant findings were observed in the remaining study. Regarding the correlation of sepsis prognostic scoring systems with thyroid function tests, the three studies that provided specific relevant data showed variable findings.

Discussion: Most of the relevant studies identified favor the concept that decreased thyroid function at baseline might be associated with a worse outcome of patients with sepsis or septic shock. Although these findings are not consistent, the role of thyroid function in affecting or merely predicting the outcome of sepsis or septic shock merits further investigation.

Descargar artículo 

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

James C. Yao, M.D., Manisha H. Shah, M.D., Tetsuhide Ito, M.D., Ph.D., Catherine Lombard Bohas, M.D., Edward M. Wolin, M.D., Eric Van Cutsem, M.D., Ph.D., Timothy J. Hobday, M.D., Takuji Okusaka, M.D., Jaume Capdevila, M.D., Elisabeth G.E. de Vries, M.D., Ph.D., Paola Tomassetti, M.D., Marianne E. Pavel, M.D., Sakina Hoosen, M.D., Tomas Haas, Ph.D., Jeremie Lincy, M.Sc., David Lebwohl, M.D., and Kjell Öberg

Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

Results: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

Conclusions: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.

Ir al artículo 

Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M., Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., Jen-Shi Chen, M.D., Dieter Hörsch, M.D., Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D., and Philippe Ruszniewski, M.D.

Background: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

Methods: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors–defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

Results: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

Conclusions: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)

Ir al artículo 

Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians

Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Roger Chou, MD; Vincenza Snow, MD; and Paul Shekelle, MD, PhD, for the Clinical Guidelines Committee of the American College of Physicians

Description: The American College of Physicians (ACP) developed this guideline to present the evidence for the link between the use of intensive insulin therapy to achieve different glycemic targets and health outcomes in hospitalized patients with or without diabetes mellitus.

Methods: Published literature on this topic was identified by using MEDLINE and the Cochrane Library. Additional articles were obtained from systematic reviews and the reference lists of pertinent studies, reviews, and editorials, as well as by consulting experts; unpublished studies on ClinicalTrials.gov were also identified. The literature search included studies published from 1950 through March 2009. Searches were limited to English-language publications. The primary outcomes of interest were short-term mortality and hypoglycemia. This guideline grades the evidence and recommendations by using the ACP clinical practice guidelines grading system.

Recommendation 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non–surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence).

Recommendation 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, highquality evidence).

Recommendation 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence).

Ir al artículo 

Intensive Insulin Therapy in Hospitalized Patients: A Systematic Review

Devan Kansagara, MD, MCR; Rongwei Fu, PhD; Michele Freeman, MPH; Fawn Wolf, MD; and Mark Helfand, MD, MPH

Background: The benefits and harms of intensive insulin therapy (IIT) titrated to strict glycemic targets in hospitalized patients remain uncertain.

Purpose: To evaluate the benefits and harms of IIT in hospitalized patients.

Data Sources: MEDLINE and Cochrane Database of Systematic Reviews from 1950 to January 2010, reference lists, experts, and unpublished sources.

Study Selection: English-language randomized, controlled trials comparing protocols titrated to strict or less strict glycemic targets.

Data Extraction: Two reviewers independently abstracted data from each study on sample, setting, glycemic control interventions, glycemic targets, mean glucose levels achieved, and outcomes. Results were grouped by patient population or setting. A randomeffects model was used to combine trial data on short-term mortality (
28 days), long-term mortality (90 or 180 days), infection, length of stay, and hypoglycemia. The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate the overall body of evidence for each outcome.

Data Synthesis: In a meta-analysis of 21 trials in intensive care unit, perioperative care, myocardial infarction, and stroke or brain injury settings, IIT did not affect short-term mortality (relative risk, 1.00 [95% CI, 0.94 to 1.07]). No consistent evidence showed that IIT reduced long-term mortality, infection rates, length of stay, or the need for renal replacement therapy. No evidence of benefit from IIT was reported in any hospital setting, although the best evidence for lack of benefit was in intensive care unit settings. Data combined from 10 trials showed that IIT was associated with a high risk for severe hypoglycemia (relative risk, 6.00 [CI, 4.06 to 8.87]; P < 0.001). Risk for IIT-associated hypoglycemia was increased in all hospital settings.

Limitations: Methodological shortcomings and inconsistencies limit the data in perioperative care, myocardial infarction, and stroke or brain injury settings. Differences in insulin protocols and patient and hospital characteristics may affect generalizability across treatment settings.

Conclusion: No consistent evidence demonstrates that IIT targeted to strict glycemic control compared with less strict glycemic control improves health outcomes in hospitalized patients. Furthermore, IIT is associated with an increased risk for severe hypoglycemia.

Primary Funding Source: U.S. Department of Veterans Affairs Health Services Research and Development Service.

Ir al artículo 

Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

The ACCORD Study Group

Background: Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.

Methods: We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.

Result: Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.

Conclusion: As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)

The members of the writing group (Hertzel C. Gerstein, M.D., McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Saul Genuth, M.D., Case Western Reserve University, Cleveland; Faramarz Ismail-Beigi, M.D., Ph.D., Case Western Reserve University, Cleveland; John B. Buse, M.D., Ph.D., University of North Carolina, Chapel Hill; David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Jeffrey L. Probstfield, M.D., University of Washington, Seattle; William C. Cushman, M.D., Memphis Veterans Affairs Medical Center, Memphis; Henry N. Ginsberg, M.D., Columbia University College of Physicians and Surgeons, New York; J. Thomas Bigger, M.D., Columbia University College of Physicians and Surgeons, New York; Richard H. Grimm, Jr., M.D., Ph.D, University of Minnesota, Berman Center for Outcomes and Clinical Research, Minneapolis; Robert P. Byington, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Yves D. Rosenberg, M.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and William T. Friedewald, M.D., Columbia University College of Physicians and Surgeons, New York) assume responsibility for the content of this article.

Supported by the National Heart, Lung, and Blood Institute (contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA#Y1-HC-9035, and IAA#Y1-HC-1010), and partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute and by General Clinical Research Centers at many sites; substudies within the ACCORD trial on cost-effectiveness and health-related quality of life were supported by the Centers for Disease Control and Prevention. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.

Dr. Bigger reports receiving consulting fees and travel support from Merck and Roche and patent fees and royalties from the Massachusetts Institute of Technology for risk-stratification software; Dr. Buse, receiving consulting fees from Novo Nordisk, Amylin, Becton Dickinson, Eli Lilly, Hoffmann–La Roche (now Genentech), Glyco-Mark, Wyeth, Daiichi Sankyo, Bristol-Myers Squibb, Bayhill Therapeutics, LipoScience, MannKind, Veritas, MicroIslet, GlaxoSmithKline, Abbott, Exsulin, and GI Dynamics and grant support from Amylin, Novo Nordisk, Medtronic, Eli Lilly, Novartis, Tolerex, Osiris, Halozyme, Pfizer, Hoffmann–La Roche, InterKrin, Merck, Sanofi-Aventis, Dexcom, Johnson & Johnson, Bristol-Myers Squibb, Fujisawa, and the American Academy of Family Practice Foundation, holding stock in Insulet, and providing expert testimony for Novo Nordisk; Dr. Cushman, receiving consulting fees from Novartis, Takeda, Sanofi-Aventis, Bristol-Myers Squibb, King, Daiichi-Sankyo, Gilead, Theravance, Pharmacopeia, and Sciele and institutional grant support to the Memphis Veterans Affairs Medical Center from Novartis, GlaxoSmithKline, and Merck; Dr. Genuth, receiving consulting fees from Merck and Daiichi Sankyo and holding stock in Novartis and Johnson & Johnson; Dr. Gerstein, receiving consulting fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Medtronic, Merck, Bayer, Bioavail, and Janssen-Ortho, institutional grant support to McMaster University from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Merck, Pronova, Roche, Eli Lilly, and Boehringer Ingelheim, and lecture fees from Sanofi-Aventis, GlaxoSmithKline, Solvay, Boehringer Ingelheim, Servier, Bayer, Eli Lilly, Novo Nordisk, and Takeda; Dr. Ginsberg, being a member of the board of Merck and Schering-Plough and the global advisory board of Bristol-Myers Squibb/AstraZeneca and receiving consulting fees from GlaxoSmithKline, Merck, Bristol-Myers Squibb, AstraZeneca, Regeneron/Sanofi-Aventis, Abbott, Roche, Isis/Genzyme, Novartis, and Pfizer, institutional grant support to the Columbia University College of Physicians and Surgeons from Merck, Roche, Isis/Genzyme, and AstraZeneca, and payment from Pfizer for development of an educational presentation; Dr. Goff, being a member of the data and safety monitoring board for Takeda and receiving institutional grant support to the Wake Forest University School of Medicine from Merck; Dr. Grimm, being a member of the board of Pfizer, receiving consulting fees from Pfizer, Merck, and Novartis, personal and institutional grants to the University of Minnesota from Pfizer, Merck, and Novartis, lecture fees from Pfizer, Merck, Novartis, Forest, Schering-Plough, and Takeda, and travel support from Takeda and Roche, and attending the AstraZeneca symposium at the Cleveland Clinic and investigator meetings for Merck, Novartis, and Pfizer; Dr. Ismail-Beigi, receiving consulting fees from Eli Lilly; Dr. Miller, receiving consulting fees from Roche; and Dr. Probstfield, receiving institutional grant support to the University of Washington School of Medicine from Sanofi-Aventis, Boehringer Ingelheim, and Abbott.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

Members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group are listed in the Supplementary Appendix, available at NEJM.org.

Ir al artículo 

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death

The Emerging Risk Factors Collaborationp

Background: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

Methods: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

Result: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

Conclusion: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)

Drs. Thompson, Di Angelantonio, Gao, and Sarwar contributed equally to this article.

The members of the writing committee (Sreenivasa Rao Kondapally Seshasai, M.D., Stephen Kaptoge, Ph.D., Alexander Thompson, Ph.D., Emanuele Di Angelantonio, M.D., Pei Gao, Ph.D., and Nadeem Sarwar, Ph.D., University of Cambridge, Cambridge, United Kingdom; Peter H. Whincup, F.R.C.P., St. George's University of London, London; Kenneth J. Mukamal, M.D., Harvard University, Boston; Richard F. Gillum, M.D., Centers for Disease Control and Prevention, Atlanta; Ingar Holme, Ph.D., Ullevål University Hospital, Oslo; Inger Njølstad, M.D., University of Tromsø, Tromsø, Norway; Astrid Fletcher, Ph.D., London School of Hygiene and Tropical Medicine, London; Peter Nilsson, M.D., Lund University, Lund, Sweden; Sarah Lewington, D.Phil., and Rory Collins, F.Med.Sci., University of Oxford, Oxford, United Kingdom; Vilmundur Gudnason, M.D., Icelandic Heart Association and the University of Iceland, Reykjavik; Simon G. Thompson, D.Sc., Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; Naveed Sattar, F.R.C.P., University of Glasgow, Glasgow, United Kingdom; Elizabeth Selvin, Ph.D., Johns Hopkins University, Baltimore; Frank B. Hu, M.D., Harvard University, Boston; and John Danesh, F.R.C.P., University of Cambridge, Cambridge, United Kingdom) of the Emerging Risk Factors Collaboration assume responsibility for the overall content and integrity of this article.

Supported by grants from the British Heart Foundation (RG/08/014), the U.K. Medical Research Council, and Pfizer (to the ERFC Coordinating Centre), as well as the Gates Cambridge Trust Scholarship, an Overseas Research Studentship Award, and an Addenbrooke's Charitable Trust Clinical Research Fellowship (to Dr. Kondapally Seshasai). Various sources have supported recruitment, follow-up, and laboratory measurements in the cohorts contributing to the ERFC. Investigators of several of these studies have contributed to a list (http://ceu.phpc.cam.ac.uk/research/erfc/studies) naming relevant funding sources.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The study investigators are listed in the Supplementary Appendix, available at NEJM.org.

Ir al artículo 

Trans fatty acids and weight gain

A K Thompson, A-M Minihane and C M Williams

Increasing rates of obesity have stimulated research into possible contributing factors, including specific dietary components such as trans fatty acids (TFAs). This review considers the evidence for an association between TFA intake and weight gain. It concludes that there is limited but consistent evidence from epidemiological studies, and from a primate model, that increased TFA consumption may result in a small additional weight gain. Data from a long-term study in a primate model suggest that TFA may have a greater adipogenic effect than cis monounsaturated fatty acids; however, there are currently inadequate mechanistic data to provide a comprehensive and plausible explanation for any such metabolic differences between the types of fatty acids.

Ir al artículo 

Descargar artículo 

Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial

Bernard Zinman MD, Greg Fulcher MD, Paturi V Rao MD, Nihal Thomas FRCP, Lars A Endahl PhD, Thue Johansen MD, Rebecka Lindh PhD, Andrew Lewin MD, Prof Julio Rosenstock MD, Prof Michel Pinget MD, Prof Chantal Mathieu MD

Background: Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs.

Methods: In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18—75 years with type 2 diabetes and glycosylated haemoglobin (HbA1C) of 7·0—11·0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer-generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA1C after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884.

Findings: Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA1C levels were much the same across treatment groups, at 7·3% (SD 1·1), 7·4% (1·0), 7·5% (1·1), and 7·2% (0·9), respectively. Estimated mean HbA1C treatment differences from insulin degludec by comparison with insulin glargine were 0·08% (95% CI −0·23 to 0·40) for the three dose per week schedule, 0·17% (−0·15 to 0·48) for group A, and 0·28% (−0·04 to 0·59) for group B. Few participants had hypoglycaemia and the number of adverse events was much the same across groups, with no apparent treatment-specific pattern.

Interpretation: Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile.

Funding: Novo Nordisk.

Ir al artículo 

Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies

The Emerging Risk Factors Collaboration

Background: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

Methods: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4·56 kg/m2 higher BMI, 12·6 cm higher waist circumference, and 0·083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

Results: Individual records were available for 221 934 people in 17 countries (14 297 incident cardiovascular disease outcomes; 1·87 million person-years at risk). Serial adiposity assessments were made in up to 63 821 people (mean interval 5·7 years [SD 3·9]). In people with BMI of 20 kg/m2 or higher, HRs for cardiovascular disease were 1·23 (95% CI 1·17—1·29) with BMI, 1·27 (1·20—1·33) with waist circumference, and 1·25 (1·19—1·31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1·07 (1·03—1·11) with BMI, 1·10 (1·05—1·14) with waist circumference, and 1·12 (1·08—1·15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of −0·0001, −0·0001, and 0·0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement −0·19%, −0·05%, and −0·05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0·95, 95% CI 0·93—0·97) than for waist circumference (0·86, 0·83—0·89) or waist-to-hip ratio (0·63, 0·57—0·70).

Interpretation: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

Funding: British Heart Foundation and UK Medical Research Council.

Ir al artículo 

Metabolite profiles and the risk of developing diabetes

Thomas J Wang, Martin G Larson, Ramachandran S Vasan, Susan Cheng, Eugene P Rhee, Elizabeth McCabe, Gregory D Lewis, Caroline S Fox, Paul F Jacques, Céline Fernandez, Christopher J O'Donnell, Stephen A Carr, Vamsi K Mootha, Jose C Florez, Amanda Souza, Olle Melander, Clary B Clish & Robert E Gerszten

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography–tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.

Ir al artículo 

Short- and Long-Term Efficacy of Combined Cabergoline and Octreotide Treatment in Controlling IGF-I Levels in Acromegaly

Short- and Long-Term Efficacy of Combined Cabergoline and Octreotide Treatment in Controlling IGF-I Levels in Acromegaly

Neuroendocrinology 2010;92:120-127 Comentario por el Dr. Cormarc Juan Bustillo Tur

Se ha demostrado que en el tratamiento médico de la Acromegalia utilizando análogos de la Somatostatina u agonistas de la Dopamina como la Cabergolina de forma aislada un 40 % de los pacientes mantienen elevados los valores de GH e IGF/I.Sin embargo, la combinación con ambos fármacos normaliza en un 33/56% los valores de IGF/I en estudios a corto plazo. En la investigación los autores demostraron que la adición de la Cabergolina al tratamiento con Octreotide fue efectiva en el control tanto a corto como a largo plazo de los niveles de IGF/I especialmente en los pacientes que mantenían valores discretos o moderadamente elevados de GH e IGF/I durante el tratamiento con Octreotide.

Ir al artículo 

Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

Ralph A. DeFronzo, M.D., Devjit Tripathy, M.D., Ph.D., Dawn C. Schwenke, Ph.D., MaryAnn Banerji, M.D., George A. Bray, M.D., Thomas A. Buchanan, M.D., Stephen C. Clement, M.D., Robert R. Henry, M.D., Howard N. Hodis, M.D., Abbas E. Kitabchi, M.D., Ph.D., Wendy J. Mack, Ph.D., Sunder Mudaliar, M.D., Robert E. Ratner, M.D., Ken Williams, M.Sc., Frankie B. Stentz, Ph.D., Nicolas Musi, M.D., and Peter D. Reaven, M.D.

Background: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.

Methods: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.

Results: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima–media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).

Conclusions: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.)

Supported by Takeda Pharmaceuticals, grants from the General Clinical Research Center (GCRC) at the University of Tennessee Health Science Center (MO1-RR-00221) and the GCRC at the University of Southern California Keck School of Medicine (MO1-RR-00043), and by the Veterans Affairs institutions in Phoenix and San Diego, which contributed their resources and the use of their facilities.

Dr. Banerji reports receiving consulting fees from BMS, Novartis, Boehringer Ingelheim, Sanofi-Aventis, Merck, and Roche, and lecture fees from Merck and Sanofi-Aventis; Dr. Buchanan reports receiving consulting fees and lecture fees from Takeda and reports that the University of Southern California Keck School of Medicine has received grant support from Takeda; Dr. DeFronzo reports receiving payments for board membership from Amylin, Takeda, ISIS, and Boehringer Ingelheim and reports that the University of Texas Health Science Center at San Antonio has received grant support from Takeda, Amylin, and Eli Lilly; Dr. Henry reports receiving consulting fees, lecture fees, and payment for expert testimony from Takeda; Dr. Musi reports receiving consulting fees from Merck, Daiichi-Sankyo, Takeda, and Novartis; Dr. Ratner reports that the Medstar Research Institute has received consulting fees from Amylin, NovoNordisk, Sanofi-Aventis, and Genentech–Roche and grant support from Amylin, NovoNordisk, GlaxoSmithKline, Bayhill, Halozyme, and Integrium; Dr. Reaven reports receiving consulting fees from BMS, lecture fees from Merck, and payment for the development of educational presentations from Amylin; Dr. Reaven reports that the Carl T. Hayden Veterans Affairs Medical Center has received grant support from Amylin; and Dr. Tripathy reports receiving grant support from Takeda Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. DeFronzo and Tripathy contributed equally to this article.

We thank our nurses and other technical staff for their expert help, without whom this study would not have been possible; the 602 patients who participated in this study; and Joel Michalek, Ph.D., and Lee Ann Zarzabal, Ph.D., of the Department of Epidemiology and Biostatistics at the University of Texas Health Science Center at San Antonio for help in the initial statistical analyses.

Ir al artículo 

Adolescent BMI Trajectory and Risk of Diabetes versus Coronary Disease

Amir Tirosh, M.D., Ph.D., Iris Shai, R.D., Ph.D., Arnon Afek, M.D., M.H.A., Gal Dubnov-Raz, M.D., Nir Ayalon, M.D., Barak Gordon, M.D., Estela Derazne, M.Sc., Dorit Tzur, M.B.A., Ari Shamis M.D., M.P.A., Shlomo Vinker, M.D., and Assaf Rudich, M.D., Ph.D.

Background: The association of body-mass index (BMI) from adolescence to adulthood with obesity-related diseases in young adults has not been completely delineated.

Methods: We conducted a prospective study in which we followed 37,674 apparently healthy young men for incident angiography-proven coronary heart disease and diabetes through the Staff Periodic Examination Center of the Israeli Army Medical Corps. The height and weight of participants were measured at regular intervals, with the first measurements taken when they were 17 years of age.

Results: During approximately 650,000 person-years of follow-up (mean follow-up, 17.4 years), we documented 1173 incident cases of type 2 diabetes and 327 of coronary heart disease. In multivariate models adjusted for age, family history, blood pressure, lifestyle factors, and biomarkers in blood, elevated adolescent BMI (the weight in kilograms divided by the square of the height in meters; mean range for the first through last deciles, 17.3 to 27.6) was a significant predictor of both diabetes (hazard ratio for the highest vs. the lowest decile, 2.76; 95% confidence interval [CI], 2.11 to 3.58) and angiography-proven coronary heart disease (hazard ratio, 5.43; 95% CI, 2.77 to 10.62). Further adjustment for BMI at adulthood completely ablated the association of adolescent BMI with diabetes (hazard ratio, 1.01; 95% CI, 0.75 to 1.37) but not the association with coronary heart disease (hazard ratio, 6.85; 95% CI, 3.30 to 14.21). After adjustment of the BMI values as continuous variables in multivariate models, only elevated BMI in adulthood was significantly associated with diabetes (β=1.115, P=0.003; P=0.89 for interaction). In contrast, elevated BMI in both adolescence (β=1.355, P=0.004) and adulthood (β=1.207, P=0.03) were independently associated with angiography-proven coronary heart disease (P=0.048 for interaction).

Conclusions: An elevated BMI in adolescence — one that is well within the range currently considered to be normal — constitutes a substantial risk factor for obesity-related disorders in midlife. Although the risk of diabetes is mainly associated with increased BMI close to the time of diagnosis, the risk of coronary heart disease is associated with an elevated BMI both in adolescence and in adulthood, supporting the hypothesis that the processes causing incident coronary heart disease, particularly atherosclerosis, are more gradual than those resulting in incident diabetes. (Funded by the Chaim Sheba Medical Center and the Israel Defense Forces Medical Corps.)

Supported by a grant from the Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel (to Dr. Tirosh), and by the Israel Defense Forces Medical Corps.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

Drs. Tirosh and Shai contributed equally to this article.

Ir al artículo 

ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

Alberico L. Catapano†, Corresponding Author Contact Information, E-mail The Corresponding Author, EAS Chairperson, Italy, Željko Reiner Corresponding Author Contact Information, E-mail The Corresponding Author, ESC Chairperson, Croatia, Guy De Backer, Belgium, Ian Graham, Ireland, Marja-Riitta Taskinen, Finland, Olov Wiklund, Sweden, Stefan Agewall, Norway, Eduardo Alegria, Spain, M. John Chapman, France, Paul Durrington, UK, Serap Erdine, Turkey, Julian Halcox, UK, Richard Hobbs, UK, John Kjekshus, Norway, Pasquale Perrone Filardi, Italy, Gabriele Riccardi, Italy, Robert F. Storey, UK, David Wood, UK and Authors/Task Force Members: ESC Committee for Practice Guidelines (CPG) 2008–2010 and 2010–2012 Committees: Jeroen Bax (CPG Chairperson 2010–2012) (The Netherlands) and Alec Vahanian (CPG Chairperson 2008–2010) (France) and Angelo Auricchio (Switzerland) and Helmut Baumgartner (Germany) and Claudio Ceconi (Italy) and Veronica Dean (France) and Christi Deaton (UK) and Robert Fagard (Belgium) and Gerasimos Filippatos (Greece) and Christian Funck-Brentano (France) and David Hasdai (Israel) and Richard Hobbs (UK) and Arno Hoes (The Netherlands) and Peter Kearney (Ireland) and Juhani Knuuti (Finland) and Philippe Kolh (Belgium) and Theresa McDonagh (UK) and Cyril Moulin (France) and Don Poldermans (The Netherlands) and Bogdan Popescu (Romania) and Željko Reiner (Croatia) and Udo Sechtem (Germany) and Per Anton Sirnes (Norway) and Michal Tendera (Poland) and Adam Torbicki (Poland) and Panos Vardas (Greece) and Petr Widimsky (Czech Republic) and Stephan Windecker (Switzerland).

Background: The association of body-mass index (BMI) from adolescence to adulthood with obesity-related diseases in young adults has not been completely delineated.

Methods: We conducted a prospective study in which we followed 37,674 apparently healthy young men for incident angiography-proven coronary heart disease and diabetes through the Staff Periodic Examination Center of the Israeli Army Medical Corps. The height and weight of participants were measured at regular intervals, with the first measurements taken when they were 17 years of age.

Results: During approximately 650,000 person-years of follow-up (mean follow-up, 17.4 years), we documented 1173 incident cases of type 2 diabetes and 327 of coronary heart disease. In multivariate models adjusted for age, family history, blood pressure, lifestyle factors, and biomarkers in blood, elevated adolescent BMI (the weight in kilograms divided by the square of the height in meters; mean range for the first through last deciles, 17.3 to 27.6) was a significant predictor of both diabetes (hazard ratio for the highest vs. the lowest decile, 2.76; 95% confidence interval [CI], 2.11 to 3.58) and angiography-proven coronary heart disease (hazard ratio, 5.43; 95% CI, 2.77 to 10.62). Further adjustment for BMI at adulthood completely ablated the association of adolescent BMI with diabetes (hazard ratio, 1.01; 95% CI, 0.75 to 1.37) but not the association with coronary heart disease (hazard ratio, 6.85; 95% CI, 3.30 to 14.21). After adjustment of the BMI values as continuous variables in multivariate models, only elevated BMI in adulthood was significantly associated with diabetes (β=1.115, P=0.003; P=0.89 for interaction). In contrast, elevated BMI in both adolescence (β=1.355, P=0.004) and adulthood (β=1.207, P=0.03) were independently associated with angiography-proven coronary heart disease (P=0.048 for interaction).

Conclusions: An elevated BMI in adolescence — one that is well within the range currently considered to be normal — constitutes a substantial risk factor for obesity-related disorders in midlife. Although the risk of diabetes is mainly associated with increased BMI close to the time of diagnosis, the risk of coronary heart disease is associated with an elevated BMI both in adolescence and in adulthood, supporting the hypothesis that the processes causing incident coronary heart disease, particularly atherosclerosis, are more gradual than those resulting in incident diabetes. (Funded by the Chaim Sheba Medical Center and the Israel Defense Forces Medical Corps.)

Supported by a grant from the Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel (to Dr. Tirosh), and by the Israel Defense Forces Medical Corps.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

Drs. Tirosh and Shai contributed equally to this article.

Ir al artículo 

Foto del XVII Curso de Actualización en Nutrición

Consorcio Europeo para el Estudio del Pseudohipoparatiroidismo

Auspiciado por la European Society for Pediatric Endocrinology

Los miembros de dicho consorcio son:

• Agnes Linglart y Caroline Silve, en París, Francia.
• Olaf Hiort, Susanne Thiele y Stefan Fischer, en Lübeck, Alemania.
• Luisa de Sanctis y Anna Spada, en Milan y Turín, Italia.
• Guiomar Pérez de Nanclares, en Vitoria-Gasteiz, España gnanclares@osakidetza.net
• Kathleen Freson, en Lovaina, Bélgica.

Objetivos

1. Permitir la descripción conjunta de los parámetros clínicos, bioquímicos y moleculares así como su evolución con el envejecimiento.
2. Expandir el diagnóstico de PHP a todos los pacientes a través de una combinación de ensayos genéticos, epigenéticos y funcionales incluyendo el intercambio de muestras biológicas.
3. Mejorar el cuidado a través de un mejor conocimiento de las enfermedades.
4. Permitir ensayos clínicos en PHP. Las tres consecuencias más importantes de la enfermedad (estatura reducida, obesidad y osificaciones heterotópicas) afectan la calidad de vida de los pacientes y requieren el desarrollo de nuevas terapias.