Guido Lattuada

Prevalence, Metabolic Features, and Prognosis of Metabolically Healthy Obese Italian Individuals: The Cremona Study

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.

Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver.

Fatty liver is characterized by metabolic abnormalities at the liver, but also at skeletal muscle and adipose tissue sites. It is hypothesized that the heart may be suffering metabolic alterations, and this study was undertaken to ascertain whether individuals with fatty liver have left ventricular (LV) alterations of energy metabolism, structure, and function and abnormal amounts of epicardial fat as a specific marker of visceral fat accumulation. To this end we studied young, nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver by means of (1) cardiac magnetic resonance imaging (MRI); (2) cardiac 31P‐MR spectroscopy (MRS); and (3) hepatic 1H‐MRS to assess quantitatively the intrahepatic fat (IHF) content. Insulin sensitivity was determined by the updated HOMA‐2 computer model. Individuals with fatty liver showed reduced insulin sensitivity, increased serum free fatty acid (FFA), and E‐selectin, abnormal adipokine concentrations, and higher blood pressure. LV morphology and systolic and diastolic functions were not different; however, in the scanned intrathoracic region, the intrapericardial (7.8 ± 3.1 versus 5.9 ± 2.5 cm2; P < 0.05) and extrapericardial (11.7 ± 6.1 versus 7.8 ± 3.2 cm2; P < 0.03) fat was increased in men with fatty liver compared with those without fatty liver. The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, a recognized in vivo marker of myocardial energy metabolism, was reduced in men with fatty liver in comparison with normals (1.85 ± 0.35 versus 2.11 ± 0.31; P < 0.016). In conclusion, in newly found individuals with fatty liver, fat was accumulated in the epicardial area and despite normal LV morphological features and systolic and diastolic functions, they had abnormal LV energy metabolism. (HEPATOLOGY 2008.)

Fatty liver index and mortality: The cremona study in the 15th year of follow‐up

A fatty liver, which is a common feature in insulin‐resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non–hepatic‐related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ‐glutamyltransferase level, was associated with the prognosis in a population study. The 15‐year all‐cause, hepatic‐related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle‐aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15‐year observation period, 495 deaths were registered: 34 were hepatic‐related, 221 were CVD‐related, 180 were cancer‐related, and 60 were attributed to other causes. FLI was independently associated with the hepatic‐related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02‐1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all‐cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA‐IR), a surrogate marker of insulin resistance (Spearmans ρ = 0.57, P < 0.0001), and when HOMA‐IR was included in the multivariate analyses, FLI retained its association with hepatic‐related mortality but not with all‐cause, CVD, and cancer‐related mortality. Conclusion: FLI is independently associated with hepatic‐related mortality. It is also associated with all‐cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin‐resistant state. (HEPATOLOGY 2011;)

Association between plasma monocyte chemoattractant protein-1 concentration and cardiovascular disease mortality in middle-aged diabetic and nondiabetic individuals.

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.

Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure

Objective Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. Design Single blind randomised study. Setting University Hospital. Patients 44 patients with systolic heart failure receiving full medical treatment. Interventions Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. Main outcome measures Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. Results Trimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris–Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively). Conclusions In patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

Are genetic variants of the methyl group metabolism enzymes risk factors predisposing to obesity

Obesity, due to the combination of inherited genes and environmental factors, is continually increasing. We evaluated the relationship between polymorphisms of methylene-tetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), betaine:homocysteine methyltransferase (BHMT G742A) and cystathionine β-synthase (CBS 68-bp ins) genes and the risk of obesity. We studied these polymorphic variants in 54 normal and 82 obese subjects [body mass index (BMI)=22.4±1.8, 34.1±7.1; ages 35.2±10.7, 43.3±10.6 respectively]. Levels of total plasma homocysteine (t-Hcy), folates, and vitamins B6 and B12 were not significantly different, while leptin concentration was significantly higher (p=0.005) in the obese patients compared to the lean controls. The frequency of only (a) MTHFR (AC), (b) MTR (AG), and (c) MTRR (AG) heterozygous genotypes was statistically different in the obese compared to the control group (p=0.03, p=0.007, and p=0.01). Single (a), (b), and (c) heterozygous genotypes had a significant risk of developing obesity [p=0.02, 0.01, and 0.03; odds ratio (OR)=2.5, 3.0, and 2.4; 95% confidence interval (CI)=1.2–5.3, 1.3–7.1, and 1.2–5.1 respectively] and the risk remarkably increased for combined genotypes a+b, a+c, b+c, and a+b+c (p=0.002, 0.002, 0.016, 0.006; OR=7.7, 5.4, 5.8, 15.4; 95% CI=1.9–30.4, 1.7–16.8, 1.4–23.2, 1.6–152.3). These findings suggest that in obese subjects, Hcy cycle efficiency is impaired by MTHFR, MTR, and MTRR inability to supply methyl-group donors, providing evidence that MTHFR, MTR, and MTRR gene polymorphisms are genetic risk factors for obesity.

Increased serum resistin in elite endurance athletes with high insulin sensitivity

Aims/hypothesisResistin is an adipokine associated with obesity and type 2 diabetes in animal models, but in humans its role remains uncertain. This study was undertaken to test whether serum resistin is related to insulin resistance and markers of low-grade inflammation in elite athletes taken as a model of extreme insulin sensitivity.Subjects materials and methodsIn 23 elite athletes (sprinters, middle-distance and marathon runners) and in 72 sedentary men including lean and obese individuals with NGT, and obese individuals with IGT or new-onset type 2 diabetes, we assessed insulin sensitivity using a whole-body insulin-sensitivity index (WBISI) derived from a 3-h OGTT; energy homeostasis was also assessed by means of indirect calorimetry, along with circulating adipokines and low-grade pro-inflammatory cyto-chemokines.ResultsProfessional athletes had increased WBISIs (p<0.001) and lipid oxidation (p<0.03); they also showed higher serum resistin concentrations (p<0.001), although the pro-inflammatory chemokines were not increased in comparison with the other study groups. Resistin was independently associated only with fasting plasma NEFA. Increased resistin was detected in the middle-distance and marathon runners, but not in the sprinters when compared with the lean, young, sedentary individuals.Conclusions/interpretationSerum resistin concentration is increased in elite athletes, providing evidence against the notion that resistin levels reflect insulin resistance in humans, as seen in animal studies. Increased resistin was observed in aerobic-endurance, but not sustained-power athletes and this feature appeared to be independently associated with parameters of fatty acid metabolism.

Why Does NAFLD Predict Type 2 Diabetes

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.

Left ventricular function and energy metabolism in middle-aged men undergoing long-lasting sustained aerobic oxidative training

Objective: Ageing of the human heart is characterised by morphological, functional and metabolic changes. Short-term interventions and cross-sectional studies in older individuals questioned the possibility that physical exercise may reverse these alterations. In this study we aimed to assess whether in middle-aged men involved in regular and long lasting physical activity these alterations were attenuated. Design: Left ventricular (LV) magnetic resonance imaging (MRI) and three-dimensional image selected in-vivo spectroscopy (3D-ISIS) 31P magnetic resonance spectroscopy (MRS) were performed using a 1.5T scanner in 20 healthy, young and 25 healthy middle-aged non-obese men with a sedentary lifestyle (11 young and 14 middle-aged) or undergoing regular aerobic oxidative training (9 young and 11 middle-aged). Insulin sensitivity was estimated by the homeostatic model assessment 2 (HOMA-2) model. Results: Sedentary young and middle-aged men were not different with respect to LV morphological parameters and systolic function. The phosphocreatine/ATP (PCr/ATP) ratio (marker of high energy phosphates metabolism) and the LV E-peak filling rate/A-peak filling rate ratio (E/A ratio) were lower in sedentary middle-aged than physically active subjects. Parameters of LV systolic function and the PCr/ATP ratio were not different in the middle-aged compared with the young trained men; the E/A peak flow ratio was higher in the middle-aged trained men than in the middle-aged sedentary men. Within the entire population, the PCr/ATP ratio and the E/A peak flow ratio were associated with insulin sensitivity. Conclusions: Trained middle-aged subjects showed a better pattern of LV energy metabolism and of diastolic function than their sedentary counterparts. At this age the exercise-related cardiac benefits were detectable when physical exercise was performed regularly and for a long period of time.

Assessment of insulin sensitivity based on a fasting blood sample in men with liver cirrhosis before and after liver transplantation.

Background. Insulin resistance is a key factor in the pathogenesis of hepatogenous diabetes and influences the prognosis of chronic liver diseases. In vivo assessment of insulin resistance in humans is expensive; therefore, surrogate indices based on a fasting plasma glucose and insulin concentrations (HOMA-IS, QUICKI) were proposed. This study aimed to test whether these simple indices are reliable measures of insulin sensitivity in patients with liver cirrhosis before and after liver transplantation (LTx). Methods. HOMA-IS and QUICKI were compared with insulin sensitivity as assessed with the gold standard technique (insulin clamp) in 20 patients with liver cirrhosis, in 36 patients after LTx, and in 25 matched healthy subjects (predominantly men). To test whether these indices may be applied also in prospective studies, 10 patients with liver cirrhosis were studied longitudinally before and 2 years after LTx. Results. Both HOMA-IS and QUICKI were associated with insulin sensitivity in patients with liver cirrhosis (r =0.63, P =0.005 and r =0.60, P =0.009) and in LTx patients (r =0.41, P =0.02 and r =0.46, P =0.05). Both were able to detect the improvement of insulin sensitivity after LTx in the patients studied prospectively. Conclusions. HOMA-IS and QUICKI are simple reliable tools to assess insulin sensitivity in clinical and epidemiologic investigations of chronic liver disease before and after LTx.