Low 25 (OH) vitamin D levels are associated with increased prevalence of nonalcoholic fatty liver disease and significant liver fibrosis.

AIMS: Evidence on the role of 25-Hydroxyvitamin D (25(OH)D) in the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) is conflicting and population-based data are scarce. Here, we assess the association between 25(OH)D levels, NAFLD and liver fibrosis in the general population. MATERIALS AND METHODS: This is an analysis of data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey. We included adult participants with available data on vibration-controlled transient elastography (VCTE) and without viral hepatitis and significant alcohol consumption. Steatosis and fibrosis were diagnosed by the median values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. 25(OH)D was measured by high performance liquid chromatography-tandem mass spectrometry. RESULTS: A total of 3970 participants (1928 men and 2042 women) were included in the study. The prevalence of NAFLD (CAP ≥ 274 dB/m) and significant liver fibrosis (LSM ≥ 8 kPa) were 41.7% (95% CI 39.4-44.0) and 8.4% (95% CI 7.0-9.9), respectively, while 21.1% (95% CI 17.3-25.4) of participants had low 25(OH)D levels (<50 nmol/L). A multivariable logistic regression model adjusted for age, sex, race-ethnicity, body mass index, waist circumference, calendar period, diabetes, chronic kidney disease, and vitamin D supplementation showed that compared with participants with low 25(OH)D, those with optimal levels (≥75 nmol/L) had lower odds of both NAFLD (OR 0.73, 95% CI 0.55-0.98 p = 0.038) and significant liver fibrosis (OR 0.65, 95% CI 0.44-0.96, p = 0.033). CONCLUSIONS: An inverse relationship was found between 25(OH)D and NAFLD and fibrosis, suggesting a possible role of vitamin D in NAFLD occurrence and progression.

Baseline TSH levels and short-term weight loss after different procedures of bariatric surgery.

BACKGROUND: Bariatric surgery is a valuable therapeutic option in the treatment of obesity but the outcomes show a large subject-to-subject variability yet to be explained. Thyroid function may represent an involved factor and we have only few controversial data about its influence. SUBJECTS/METHODS: We retrospectively assessed using a longitudinal approach the relation between baseline TSH levels and short-term (6 and 12 months) weight loss in 387 euthyroid patients who underwent laparoscopic gastric banding (LAGB; n = 187) or sleeve gastrectomy (SG; n = 200). RESULTS: After LAGB, patients with low-normal TSH levels (0.40-1.40 mUI/L) had higher percent total weight loss, ∆BMI and percent excess weight loss when compared to patients with normal (1.41-2.48 mUI/L) and high-normal (2.49-4.00 mUI/L) TSH (p < 0.05). Conversely, no association was detected after SG (p = 0.17). The multivariable regression analysis showed that also baseline BMI (6-12 months) and HOMA2-IR (only at 6 months) were independently associated with the outcomes. CONCLUSIONS: TSH levels may influence the short-term weight loss response after LAGB. The lack of association after SG suggests that the influence of baseline endocrine and metabolic factors may not be relevant for procedures with greater and more immediate calorie intake restriction.

Hypercortisolism and altered glucose homeostasis in obese patients in the pre-bariatric surgery assessment.

AIMS: Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity was suggested to be associated with the metabolic syndrome (MS), obesity and diabetes. The aim of this study was to test whether hypercortisolism was associated with altered glucose homeostasis and insulin resistance, hypertension and dyslipidemia in a homogeneous population of obese patients. MATERIALS/METHODS: In retrospective analysis of a set of data about obese patients attending the outpatient service of a single obesity centre between January 2013 and January 2020, 884 patients with BMI >30 kg/m2 were segregated in two subgroups: patients with urinary free cortisol (UFC) higher than normal (UFC+; n = 129) or within the normal range (UFC-; n = 755). RESULTS: The overall prevalence of UFC+ was 14.6% and double test positivity (morning cortisol >1.8 mcg/dL following overnight dexamethasone suppression test, ODST) was detected in 1.0% of patients. Prediabetes (OR 1.74; 95%CI 1.13-2.69; p = 0.012) and diabetes (OR 2.03; 95%CI 1.21-3.42; p = 0.008) were associated with higher risk of UFC+ when analysis was adjusted for confounding variables. Conversely, hypertension and dyslipidemia were not related to UFC+. Within the individuals with normal FPG and HbA1c, those with higher estimated insulin resistance (HOMA2-IR) maintained a higher risk of UFC+ (OR 2.84, 95%CI 1.06-7.63; p = 0.039) and this relationship was weakened only when the body fat percentage was included into the model. CONCLUSIONS: In obese patients, hypercortisolism was more frequent across the entire spectrum of altered glucose homeostasis including the very early stages; this relation could not be detected for the other criteria of the MS, as waist, hypertension and atherogenic dyslipidemia.

Seasonal variation in estimated cardiovascular risk in patients with type 2 diabetes.

BACKGROUND AND AIMS: Seasonal variations in several risk factors for cardiovascular events (CVD) were described. Here, we evaluate the impact of seasonal variations in blood pressure (BP), lipid profile and glycemic control on estimated CVD risk in patients with type 2 diabetes (T2D). METHODS AND RESULTS: Retrospective monocentric study of patients with T2D who were visited at least once in the winter period and once in the summer period, less than 8 months apart, for which data related to systolic (S) BP, diastolic (D) BP, body mass index, glycosylated hemoglobin (HbA1c), total cholesterol, HDL cholesterol and smoking habit were available on both occasions. The 10-year CVD risk was calculated using the UKPDS risk engine and the ASCVD risk estimator. As many as 411 patients were included in the study. Significant within-patient differences between summer and winter were found for the absolute risk of events assessed with both calculators (Δs-w UKPDS-CHD: -1.33%, Δs-w UKPDS-Stroke: -0.84%, Δs-w ASCVD: -2.21%). The seasonal change in SBP was the main responsible for the change in risk estimated with both the UKPDS-Stroke (r2 = 0.43) and the ASCVD (r2 = 0.50) scores, while the change in total cholesterol was the main determinant of the change in risk for the UKPDS-CHD (r2 = 0.34). A significant correlation was identified between changes in temperature and changes in SBP (ρ = 0.130, p = 0.008), but not in other risk factors. CONCLUSIONS: Seasonal variations in the classic CVD risk factors influence the risk estimated using validated calculators.

Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.

UNLABELLED: 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 (Spearman's 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.

Resting cardiac energy metabolism is inversely associated with heart rate in healthy young adult men.

BACKGROUND: 31-Phosphorus-magnetic resonance spectroscopy may provide pathophysiological insights into the high-energy phosphate metabolism of the myocardium as measured by phosphocreatine to adenosine triphosphate (PCr/ATP) ratio. Aim of the present study was to determine in vivo the relation between cardiac PCr/ATP ratio and heart rate in normal male subjects. METHODS: One hundred twelve apparently healthy, young male individuals (age 34 ± 10 years) were prospectively evaluated. They underwent cardiac cine magnetic resonance imaging to assess left ventricular (LV) function and morphology and 3D-ISIS (31)P-magnetic resonance spectroscopy of the LV to assess the PCr/ATP ratio (a recognized in vivo marker of myocardial energy metabolism). Data were analyzed after segregation by tertiles of the resting PCr/ATP ratio. RESULTS: A significant inverse association between PCr/ATP ratios and resting heart rate was observed (Spearman ρ: r=-0.37; P < .0001). PCr/ATP ratios were also inversely associated with body mass index, diastolic blood pressure, wall mass and with insulin resistance, but in multiple regression analysis heart rate was found to be independently related to PCr/ATP. CONCLUSIONS: The present study shows that resting heart rate is proportionally lower across tertiles of increasing PCr/ATP ratio of the LV in apparently healthy young male individuals, supporting the hypothesis that heart rate is a major determinant of cardiac energy stores. These findings may explain the prognostic role of heart rate in the general population as evidenced by previous large epidemiological studies.

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 ß-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.

Metabolic and Psychological Features are Associated with Weight Loss 12 Months After Sleeve Gastrectomy.

CONTEXT: Laparoscopic sleeve gastrectomy (LSG) is a recognized effective procedure of bariatric surgery, but a poor response in weight loss may still represent a clinical problem. To date there are no validated predictors useful to better perform patient selection. OBJECTIVE: To establish the association of baseline anthropometric, metabolic, and psychologic features with the percent total weight loss (%TWL) and percent excess weight loss (%EWL) 12 months after surgery. DESIGN: Retrospective longitudinal analysis of a set of data about obese patients attending the outpatient service of a single obesity center from June 2016 to June 2019. PATIENTS: A total of 106 obese patients underwent LSG with presurgery evaluation and follow-up at 12 months after surgery. MAIN OUTCOME: Weight loss 12 months after LSG. RESULTS: Patients who achieved a %TWL higher than the observed median (≥34%) were younger, with a lower fasting plasma glucose and glycated hemoglobin, with a lower prevalence of hypertension and with a lower score in the impulsiveness scale, compared with patients with a %TWL < 34%. Similar findings were found when %EWL was considered. Multivariable stepwise regression analysis showed that younger age, lower impulsiveness, higher-than-normal urinary free cortisol, and lower HbA1c were associated with higher %TWL, explaining about 31.5% of the weight loss. CONCLUSION: Metabolic and psychologic features at baseline were independently associated with weight loss and explained a non-negligible effect on the response to LSG. These data suggest that careful metabolic and psychologic profiling could help in sharper indications and personalized pre- and postsurgical follow-up protocols in candidates for LSG.

Resting Whole Body Energy Metabolism in Class 3 Obesity; from Preserved Insulin Sensitivity to Overt Type 2 Diabetes.

CONTEXT: Insulin resistance and diabetes may influence separately or in combination whole body energy metabolism. OBJECTIVE: To assess the impact of insulin resistance and/or overt type 2 diabetes on resting energy expenditure (REE) in class 3 obese individuals. DESIGN AND SETTING: Retrospective, cross-sectional analysis of a set of data about individuals attending the outpatients service of a single center of bariatric surgery between January 2015 and December 2017. PATIENTS: We screened 382 patients in which abnormal thyroid function was excluded, and segregated them in three groups of subjects: patients with type 2 diabetes (T2DM; n=70), non-diabetic insulin-resistant patients with HOMA-IR ≥ 3 (n=236), non-diabetic insulin-sensitive patients with HOMA-IR < 3 (n=75). MAIN OUTCOME MEASURE: Resting energy expenditure (REE), body composition and insulin resistance assessed using indirect calorimetry, bioimpedance and HOMA-IR. RESULTS: Non-diabetic insulin-sensitive patients resulted to be younger, with lower BMI and higher prevalence of female subjects; meanwhile, non-diabetic but insulin-resistant patients and T2DM patients were not different in terms of anthropometric parameters. REE was higher in T2DM than in non-diabetic insulin-resistant and insulin-sensitive individuals when expressed as percent of the predicted REE (based on Harris Benedict equation) (p<0.0001) or when adjusted for kg of free fat mass (p<0.0001) and was found to be higher also in insulin-resistant vs insulin-sensitive patients (p<0.001). The respiratory quotient was different between groups (0.87±0.11, 0.86±0.12 and 0.91±0.14 in T2DM, insulin-resistant and insulin-sensitive patients, respectively; p<0.03). Regression analysis confirmed that HOMA-IR was independently associated with the REE (R2=0.110, p<0.001). CONCLUSION: Class 3 obese patients with normal insulin sensitivity are characterized by reduced fasting REE in comparison to insulin-resistant obese patients and obese patients with short duration of diabetes supporting the hypothesis that down-regulation of nutrients' oxidative disposal may represent an adaptation of energy metabolism in obese individuals with preserved insulin sensitivity.

Resting Energy Expenditure in Obese Women with Primary Hypothyroidism and Appropriate Levothyroxine Replacement Therapy.

CONTEXT: Growing evidence suggests that appropriate levothyroxine (LT4) replacement therapy may not correct the full set of metabolic defects afflicting individuals with hypothyroidism. OBJECTIVE: To assess whether obese subjects with primary hypothyroidism are characterized by alterations of the resting energy expenditure (REE). DESIGN: Retrospective analysis of a set of data about obese women attending the outpatients service of a single obesity center from January 2013 to July 2019. PATIENTS: A total of 649 nondiabetic women with body mass index (BMI) > 30 kg/m2 and thyrotropin (TSH) level 0.4-4.0 mU/L were segregated into 2 groups: patients with primary hypothyroidism taking LT4 therapy (n = 85) and patients with normal thyroid function (n = 564). MAIN OUTCOMES: REE and body composition assessed using indirect calorimetry and bioimpedance. RESULTS: REE was reduced in women with hypothyroidism in LT4 therapy when compared with controls (28.59 ±â€…3.26 vs 29.91 ±â€…3.59 kcal/kg fat-free mass (FFM)/day), including when adjusted for age, BMI, body composition, and level of physical activity (P = 0.008). This metabolic difference was attenuated only when adjustment for homeostatic model assessment of insulin resistance (HOMA-IR) was performed. CONCLUSIONS: This study demonstrated that obese hypothyroid women in LT4 therapy, with normal serum TSH level compared with euthyroid controls, are characterized by reduced REE, in line with the hypothesis that standard LT4 replacement therapy may not fully correct metabolic alterations related to hypothyroidism. We are not able to exclude that this feature may be influenced by the modulation of insulin sensitivity at the liver site, induced by LT4 oral administration.

Visit-to-visit blood pressure variability in patients with type 2 diabetes with and without previous history of cardiovascular disease.

OBJECTIVE: Visit-to-visit variability in SBP is a risk factor for cardiovascular disease (CVD) in type 2 diabetes (T2DM) but little is known on whether in T2DM this differs according to presence or absence of previous CVD. METHODS: We retrospectively assessed the coefficient of variation (standard deviation/mean) of mean SBP (SBP-CV) in 970 patients (44% with established CVD) attending at least four times our secondary care diabetes clinic in 2015-2016 to estimate their risk of CVD-related events using the 10-year UKPDS Risk Engine. RESULTS: Patients with established CVD had a higher SBP-CV (10.3 ±â€Š4.8%) than patients without CVD (8.9 ±â€Š4.3%; P < 0.001) as confirmed by the progressively higher prevalence of established CVD in tertiles of SBP-CV (36.6, 46.1, and 52.0%; P < 0.001), in association with more aggressive and complex drug regimens. On the basis of the 10-year UKPDS Risk Engine, higher SBP-CV values were associated with increased risks of the CVD outcomes regardless of the previous history of CVD in multivariate models. CONCLUSION: Visit-to-visit variability of SBP was greater in T2DM patients with that in those without previous history of CVD, and maintained an independent association with higher estimated risk of CVD-related events regardless of the history of CVD, suggesting that its prognostic significance is relevant in the entire CVD continuum of patients with T2DM.

Screening for non-alcoholic fatty liver disease in type 2 diabetes using non-invasive scores and association with diabetic complications.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is prevalent in patients with type 2 diabetes. Here, we estimate the proportion of patients with type 2 diabetes that should be referred to hepatologists according to the European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) Guidelines and evaluate the association between non-invasive biomarkers of steatosis and fibrosis and diabetic complications. RESEARCH DESIGN AND METHODS: This is a retrospective analysis of type 2 diabetes patients who attended on a regular basis our diabetes clinic between 2013 and 2018 (n=2770). Steatosis was assessed using Fatty Liver Index (FLI), Hepatic Steatosis Index and NAFLD Ridge Score and fibrosis using NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI) and AST/alanine aminotransferase (ALT) ratio. Outcome measures were altered albumin excretion rate (AER), chronic kidney disease (CKD) and cardiovascular disease (CVD). RESULTS: The prevalence of advanced fibrosis varied from 1% (APRI) to 33% (NFS). The application of the guidelines using a sequential combination of FLI and FIB-4 would lead to referral of 28.3% of patients when using standard FIB-4 cut-offs, while this number dropped to 13.4% when age-adjusted FIB-4 thresholds were applied. A higher prevalence of altered AER was associated with liver steatosis (FLI: OR: 3.49; 95% CI 2.05 to 5.94, p<0.01), whereas liver fibrosis was associated with CKD (FIB-4: OR: 6.39; 95% CI 4.05 to 10.08, p<0.01) and CVD (FIB-4: OR: 2.62; 95% CI 1.69 to 4.04, p<0.01). CONCLUSIONS: While specific fibrosis scores identify different proportion of patients with advanced fibrosis, the use of age-adjusted FIB-4 cut-offs leads to a drop in gray-zone results, making referrals to hepatologists more sustainable. Interestingly non-invasive biomarkers were consistently associated with a different pattern of diabetic complications.

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 (31)P-MR spectroscopy (MRS); and (3) hepatic (1)H-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 cm(2); P < 0.05) and extrapericardial (11.7 +/- 6.1 versus 7.8 +/- 3.2 cm(2); 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.

Fasting Whole-Body Energy Homeostasis and Hepatic Energy Metabolism in Nondiabetic Humans with Fatty Liver.

BACKGROUND: Fatty liver is believed to be sustained by a higher than normal adipose-derived NEFA flux to the liver. Also, hepatic energy metabolism may be a rate-limiting step of intrahepatic fat (IHF) accumulation. AIMS: To assess whole-body energy metabolism and hepatic high-energy phosphates (HEPs) in individuals with fatty liver. METHODS: We studied 22 individuals with fatty liver and 22 control individuals matched for anthropometric features by means of (1) hepatic 1H-magnetic resonance spectroscopy (MRS) to measure the IHF content, (2) hepatic 31P-MRS to assess the relative content of HEPs (phosphomonoesters, phosphodiesters, inorganic phosphorus, and ATP), and (3) indirect calorimetry to assess whole-body resting energy expenditure and substrate oxidation. RESULTS: Patients with newly diagnosed fatty liver and controls were not different for anthropometric parameters. Based on HOMA2%-S, individuals with fatty liver were more insulin resistant than controls. Resting energy expenditure and the pattern of substrate oxidation were not different between groups. Relative content of HEPs was not different between groups; in particular, the Pi/γ-ATP ratio, the most important signals in terms of monitoring energy homeostasis, was not different even if it was associated with indirect calorimetry-derived parameters of oxidative substrate disposal. CONCLUSIONS: These data demonstrate that fasting whole-body energy metabolism and the relative content of HEPs in nondiabetic patients with fatty liver are not different than those in controls when they are matched for anthropometric features.

Serum retinol-binding protein-4, leptin, and adiponectin concentrations are related to ectopic fat accumulation.

CONTEXT: Serum retinol-binding protein 4 (RBP-4), leptin, and adiponectin concentrations identify insulin resistance in varied conditions, but their relationships with insulin sensitivity and ectopic fat accumulation are unclear. OBJECTIVE: Our objective was to establish how these adipokines are related with intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content. DESIGN AND SETTING: We assessed retrospectively serum fasting RBP-4 concentrations in 1) 53 nondiabetic individuals in which insulin sensitivity and IMCL content were assessed by means of the insulin clamp and of 1H magnetic resonance spectroscopy of the calf muscles, and 2) 140 nondiabetic individuals in which insulin sensitivity and the IHL content were assessed by means of the updated homeostasis model assessment and of 1H magnetic resonance spectroscopy. In both experiments, serum leptin and adiponectin concentrations were measured. RESULTS: Fasting serum RBP-4, adiponectin, and leptin were associated with peripheral insulin sensitivity, were abnormal in the first-degree relatives of type 2 diabetic parents, and correlated with the soleus IMCL content and with the IHL content. The association of RBP-4 and adiponectin with insulin sensitivity was age, sex, and body mass index independent, but stepwise regression analysis suggested that RBP-4, but not adiponectin and leptin, was independently associated with insulin sensitivity. Adiponectin was independently associated with the IHL content, RBP-4, and leptin with the soleus IMCL content. CONCLUSION: Serum RBP-4 was a robust marker of insulin resistance. Serum RBP-4, leptin, and adiponectin concentrations reflected ectopic fat accumulation in humans.

Effect of the sporting discipline on the right and left ventricular morphology and function of elite male track runners: a magnetic resonance imaging and phosphorus 31 spectroscopy study.

BACKGROUND: Professional, long-term physical training is often associated with morphological and metabolic changes in the heart. This study was undertaken to assess the left ventricular (LV) and right ventricular (RV) morphology and function and the LV high-energy phosphates of athletes trained to a sustained power or aerobic exercise. METHODS: Magnetic resonance imaging (MRI) of the LV and RV and phosphorous 31 magnetic resonance spectroscopy of the LV were performed by means of a 1.5-T clinical scanner in 23 elite track sprinters (sustained power or anaerobic power sprint training, 100-400 m) or marathon runners (sustained aerobic endurance training) and in 10 sedentary, young, lean men. RESULTS: Athletes had LV hypertrophy and unaffected chamber size, systolic and diastolic functions, and high-energy phosphates metabolism. Also, the RV of the athletes was hypertrophied in comparison with that of the nonathletic controls, and the systolic and diastolic functions were unaffected; the chamber volume was higher in the sprinters (end-diastolic volume 190 +/- 15 mL) in comparison with that of the marathon runners (174 +/- 19 mL, P < .05) and controls (168 +/- 19 mL, P < .01) even if this difference, when adjusted for body surface area, was maintained only when compared with that of controls (P < .02). CONCLUSIONS: Left ventricular and RV hypertrophy in athletes is associated with normal systolic and diastolic functions and resting cardiac energy metabolism, supporting its benign nature. A more pronounced RV dilatation was found in the anaerobic power athletes and further investigation is warranted to establish the clinical significance of this training effect.

Serum resistin and hepatic fat content in nondiabetic individuals.

CONTEXT: Serum resistin concentration is increased in patients with nonalcoholic fatty liver disease in proportion with the histological severity of the disease, but the relevance of the contribution of fatty liver per se is undetermined. OBJECTIVE: The objective of the study was to assess the relationship between serum resistin and the degree of ectopic fat accumulation in vivo in humans. DESIGN AND SETTING: The hepatic fat (IHF) content, measured quantitatively by means of 1H magnetic resonance spectroscopy, serum resistin, and biochemical and hormonal metabolic correlates of fatty liver and insulin resistance were assessed in 28 affected patients, and 47 individuals with comparable anthropometric features served as controls. Insulin sensitivity was estimated using the computer homeostatic model assessment (HOMA)-2. A subset of volunteers (n = 18) also underwent 1H magnetic resonance spectroscopy of the calf muscles to assess the intramyocellular lipid content (IMCL). RESULTS: In patients with fatty liver, the IHF content (13 +/- 8 vs. 2 +/- 1% wet weight; P < 0.0001) and also the soleus IMCL content (P < 0.05) were increased in comparison with the controls. Patients with fatty liver had lower insulin sensitivity (HOMA2 insulin sensitivity: 59 +/- 24 vs. 72 +/- 29%; P < 0.04), serum resistin (3.4 +/- 0.8 vs. 3.9 +/- 1.0 ng/ml; P < 0.02), and adiponectin (P < 0.01) concentrations. Serum resistin was inversely correlated with the IHF content (r = -0.35; P < 0.003) and the soleus IMCL content (r = -0.51; P < 0.05) but not HOMA2 insulin sensitivity. CONCLUSION: This study demonstrates that excessive ectopic fat accumulation in the liver and skeletal muscle of insulin-resistant subjects is associated with lower serum resistin concentration and not with hyperresistinemia.

The anti-ischemic effect of trimetazidine in patients with postprandial myocardial ischemia is unrelated to meal composition.

BACKGROUND: Previous studies provide evidence for a significant reduction of coronary flow reserve after ingestion of meals of different compositions. A possible role of hyperinsulinemia and increased free fatty acid levels, which are deleterious during acute myocardial ischemia and reperfusion, has been hypothesized. We assessed in patients with stable coronary disease the effects of high-fat meals (HFMs) and high-carbohydrate meals (HCMs) on ischemic threshold and stress left ventricular function on placebo and after partial fatty acid inhibition by trimetazidine (TMZ). METHODS: Ten patients (9 men, age 68 +/- 7 years) were allocated to placebo and TMZ (40 mg TID), both administered in the 24 hours preceding testing, according to a randomized double-blind study design. All patients underwent stress (treadmill exercise testing according to the Bruce protocol) echocardiography after fasting (8 hours) and after an HFM and HCM (2 hours) either on placebo or on TMZ. Time to 1-mm ST-segment depression (time to 1 mm) and stress wall motion score index (WMSI) were evaluated. RESULTS: An HFM did not affect exercise variables compared with fasting, whereas an HCM resulted in a reduction of the ischemic threshold (time to 1 mm from 402 +/- 141 to 292 +/- 123 seconds, P = .025). Compared with placebo, TMZ improved time to 1 mm after fasting, HFM, and HCM (432 +/- 153 vs 402 +/- 141, 439 +/- 118 vs 380 +/- 107, 377 +/- 123 vs 292 +/- 123, F(1,9) = 26.91, P = .0006). Compared with placebo, on TMZ, stress WMSI decreased from 1.55 +/- 0.25 to 1.29 +/- 0.14 after fasting, from 1.57 +/- 0.10 to 1.39 +/- 0.28 after HFM, and from 1.64 +/- 0.21 to 1.39 +/- 0.21 after HCM (F(1,9) = 37.04, P = .0002). Interestingly, stress WMSI on TMZ was never different from rest WMSI on placebo. CONCLUSIONS: In patients with coronary disease, exercise testing after an HCM results in more severe myocardial ischemia compared with that after an HFM. The observed beneficial effects of the partial fatty acid inhibitor TMZ seem to be unrelated to meal composition and are possibly caused by the better glucose use induced by the drug.

Postabsorptive and insulin-stimulated energy homeostasis and leucine turnover in offspring of type 2 diabetic patients.

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 x m(-2) x 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 micromol x kg lean body mass(-1) x 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 x kg lean body mass(-1) x 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.

Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality.

OBJECTIVE: Leptin and tumor necrosis factor (TNF)-alpha are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS: In this study, fasting plasma leptin, soluble TNF-alpha receptor 2 (TNF-alpha-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2)), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS: At baseline, leptin and TNF-alpha-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02). CONCLUSIONS: In middle-aged women, MCP-1/CCL2, leptin, and TNF-alpha-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-alpha-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.