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Habitual Physical Activity Is Associated With Intrahepatic Fat Content in Humans Gianluca Perseghin , MD 1 2 3 , Guido Lattuada , PHD 1 , Francesco De Cobelli , MD 2 4 , Francesca Ragogna , PHD 1 , Georgia Ntali , MD 1 , Antonio Esposito , MD 4 , Elena Belloni , MD 4 , Tamara Canu 4 , Ileana Terruzzi , PHD 1 , Paola Scifo , PHD 5 , Alessandro Del Maschio , MD 2 4 6 and Livio Luzi , MD 1 2 3 1 Internal Medicine, Section of Nutrition/Metabolism, San Raffaele Scientific Institute, Milan, Italy 2 Unit of Clinical Spectroscopy, San Raffaele Scientific Institute, Milan, Italy 3 Center “Physical Exercise for Health and Wellness,” Faculty of Exercise Sciences, Università degli Studi di Milano, Milan, Italy 4 Diagnostic Radiology, San Raffaele Scientific Institute, Milan, Italy 5 Nuclear Medicine, San Raffaele Scientific Institute, Milan, Italy 6 Università Vita e Salute San Raffaele, Milan, Italy Address correspondence and reprint requests to Gianluca Perseghin, MD, Faculty of Exercise Sciences, Università degli Studi di Milano and San Raffaele Scientific Institute, Internal Medicine, via Olgettina 60, 20132, Milan, Italy. E-mail: perseghin.gianluca{at}hsr.it Abstract OBJECTIVE —Fatty liver may be involved in the pathogenesis of type 2 diabetes. Physical exercise is a tool to improve insulin sensitivity, but little is known about its effect on intrahepatic fat (IHF) content. The purpose of this study was to examine the association of habitual physical activity, insulin resistance, and adiponectin with IHF content. RESEARCH DESIGN AND METHODS —Participants were 191 (77 female and 114 male) apparently healthy, nonalcoholic individuals (aged 19–62 years; BMI 17.0–35.5 kg/m 2 ). IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1 H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of >5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes. RESULTS —A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25, 11, 25, and 2% in quartile 1, 2, 3, and 4, respectively; χ 2 = 15.63; P = 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson’s r = −0.27; P < 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r = −0.25; P < 0.001). CONCLUSIONS —This study demonstrated that a higher level of habitual physical activity is associated with a lower IHF content and suggested that this relationship may be due to the effect of exercise per se. FFA, free fatty acid HOMA, homeostasis model assessment HOMA2-%B, HOMA2-derived index of β-cell insulin sensitivity HOMA2-%S, HOMA2-derived index of insulin sensitivity IHF, intrahepatic fat MRS, magnetic resonance spectroscopy NAFLD, nonalcoholic fatty liver disease TSH, thyroid-stimulating hormone Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted November 30, 2006. Received October 2, 2006. DIABETES CARE

An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56 bright NK cells in T1D. Furthermore, a non-selective decrease of CD3 + CD56 + regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS: MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 ± 12 years, BMI 30.1 ± 6.6 kg/m², 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS: At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS: In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

OBJECTIVE:--Perturbations in cardiac energy metabolism might represent early alterations in diabetes preceding functional and pathological changes. We evaluated left ventricular (LV) structure/geometry and function in relation to energy metabolism and cardiovascular risk factors in overweight/obese men using magnetic resonance techniques. RESEARCH DESIGN AND METHODS--We studied 81 healthy men (aged 22-55 years, with BMI between 19 and 35 kg/m²) by means of cardiac magnetic resonance imaging and ³¹P-magnetic resonance spectroscopy in the resting and fasted conditions and stratified them in quartiles of BMI (cut offs: 23.2, 25.5 and 29.0 kg/m²). RESULTS:--LV mass increased across quartiles of BMI; meanwhile, the volumes did not differ. Parameters of LV systolic and diastolic function were not different among quartiles. The phosphocreatine-to-ATP ratio was reduced across increasing quartiles of mean ± SD BMI (2.25 ± 0.52, 1.89 ± 0.26, 1.99 ± 0.38, and 1.79 ± 0.29; P < 0.006) in association with insulin sensitivity (computer homeostasis model assessment 2 model); this relation was independent of age, BMI, blood pressure, wall mass, HDL cholesterol, triglycerides, smoking habits, and metabolic syndrome. CONCLUSIONS:--Abnormal LV energy metabolism was detectable in obese men in the presence of normal function, supporting the hypothesis that metabolic remodeling in insulin resistant states precedes functional and structural/geometrical remodeling of the heart regardless of the onset of overt hyperglycemia.

OBJECTIVE: Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS: Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: <30 kg/m²; obese: ≥30 kg/m²) and estimated insulin resistance (insulin sensitive: homeostasis model assessment of insulin resistance <2.5; insulin resistant ≥2.5). RESULTS: Obese insulin-sensitive subjects represented 11% (95% CI 8.1-14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08-1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46-2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS: In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

Postabsorptive and Insulin-Stimulated Energy Homeostasis and Leucine Turnover in Offspring of Type 2 Diabetic Patients Guido Lattuada , PHD 1 , Lucia Piceni Sereni , MD 1 , Dora Ruggieri , PHD 1 , Antonella Scollo , RN 1 , Stefano Benedini , MD, PHD 1 , Francesca Ragogna , PHD 1 , Federica Costantino , PHD 1 , Alberto Battezzati , MD, PHD 1 2 , Livio Luzi , MD 1 2 3 4 and Gianluca Perseghin , MD 1 3 1 Internal Medicine, Section of Nutrition/Metabolism, Istituto Scientifico H San Raffaele, Milan, Italy 2 International Center for the Assessment of Nutritional Status, Milan, Italy 3 Unit of Clinical Spectroscopy, Istituto Scientifico H San Raffaele, Milan Italy 4 Faculty of Exercise Sciences, Università degli Studi di Milano, Milan, Italy Address correspondence and reprint requests to Gianluca Perseghin, MD, Istituto Scientifico H San Raffaele, Internal Medicine, Section of Nutrition/Metabolism & Unit of Clinical Spectroscopy via Olgettina 60, 20132, Milan, Italy. E-mail: perseghin.gianluca{at}hsr.it Abstract OBJECTIVE —This study was performed to ascertain whether insulin resistance with respect to protein metabolism is an additional primary metabolic abnormality affecting insulin-resistant offspring of type 2 diabetic parents, along with insulin resistance with respect to glucose and lipid metabolism. RESEARCH DESIGN AND METHODS —We studied 18 young, nonobese offspring of type 2 diabetic parents and 27 healthy matched (by means of dual-energy X-ray absorption) individuals with the bolus plus continuous infusion of [6,6- 2 H 2 ]glucose and [1- 13 C]leucine in combination with the insulin clamp (40 mU · m –2 · min −1 ). RESULTS —Fasting plasma leucine, phenylalanine, alanine, and glutamine concentrations, as well as the glucose and leucine turnover (reciprocal pool model: 155 ± 10 vs. 165 ± 5 μmol · kg lean body mass –1 · h −1 in offspring of type 2 diabetic patients and healthy matched individuals, respectively), were also not different. During the clamp, glucose turnover rates were significantly reduced in offspring of type 2 diabetic patients (7.1 ± 0.5) in comparison with healthy matched individuals (9.9 ± 0.6 mg · kg lean body mass –1 · min −1 ; P < 0.01). Also, the suppression of leucine turnover was impaired in offspring of type 2 diabetic patients (12 ± 1%) in comparison with healthy matched individuals (17 ± 1%; P = 0.04) and correlated with the degree of the impairment of insulin-stimulated glucose metabolism ( R 2 = 0.13; P = 0.02). CONCLUSIONS —Nonobese, nondiabetic, insulin-resistant offspring of type 2 diabetic patients were characterized by an impairment of insulin-dependent suppression of protein breakdown, which was proportional to the impairment of glucose metabolism. These results demonstrate that in humans, a primary in vivo impairment of insulin action affects glucose and fatty acid metabolism as previously shown and also protein/amino acid metabolism. ELF, endogenous leucine flux FFA, free fatty acid REE, resting energy expenditure α-TNF-R2, α-tumor necrosis factor receptor-2 Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted August 8, 2004. Received June 18, 2004. DIABETES CARE

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19–2.20; P  < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73–3.94; P  < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome.

Based on the “lipotoxic” hypothesis, the free fatty acid flux from the excessive amount of adipose tissue toward the peripheral tissues would induce the development of insulin resistance especially when the triglyceride storage or the concentration of intermediate fat metabolites (diacylglycerides, ceramides) within the cytoplasm of these cells become excessive. Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis and advanced fibrosis. NAFLD is associated with general and intra-abdominal obesity and with a reduced ability of insulin to stimulate metabolic pathways in the liver itself and in other tissues. There are animal models and models in human diseases sustaining the hypothesis that a primary hepatic disease may determine the development of type 2 diabetes (T2DM). Epidemiologic data generated on surrogate markers of NAFLD (transaminases and γ-glutamyltransferase), semiquantitative assessment of fatty liver (ultrasound), and surrogate algorithms of NAFLD also support a causative effect of NAFLD on the risk to develop T2DM. In spite of the presence of these indirect associations, a clear-cut link between NAFLD and abnormal β-cell function is yet to be reported. Therefore, more data are warranted to prove what is considered a likely causative relationship between NAFLD and T2DM.