NAFLD and Liver Fibrosis Are Not Associated With Reduced Femoral Bone Mineral Density in the General US Population.

CONTEXT: It is still debated whether nonalcoholic fatty liver disease (NAFLD) may be a risk factor for reduced bone mineral density (BMD), and it is not known whether liver fibrosis, the major predictor of future development of liver-related events in NAFLD, has an influence on BMD. OBJECTIVE: To assess whether liver steatosis and fibrosis are associated with reduced BMD in the general US population. METHODS: We performed a cross-sectional analysis of the population-based 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES), in which vibration-controlled transient elastography (VCTE) and dual-energy x-ray absorptiometry (DXA) of the femoral neck were simultaneously available. Controlled attenuation parameter (CAP) ≥ 274 dB/m was considered indicative of liver steatosis, while a median liver stiffness measurement (LSM) ≥ 8 kPa indicated the presence of significant liver fibrosis. We included all participants older than 50 years with reliable VCTE and femoral neck DXA results (925 men and 859 women). The main outcome measures were femoral neck BMD values indicative of osteopenia or osteoporosis. RESULTS: Steatosis and significant fibrosis were highly prevalent in the studied population, being present in 53.1% and 9.6% of men and 44.2% and 8.0% of women, respectively. In univariate analysis, liver steatosis was associated with a lower prevalence of osteoporosis in both men and women, while no difference was noted according to the degree of liver fibrosis. After adjustment for potential confounders, including age, BMI, race/ethnicity, cigarette smoking, and diabetes, neither CAP nor LSM were significantly associated with reduced BMD in both sexes. CONCLUSION: Liver steatosis and fibrosis are not associated with femoral DXA-based diagnosis of osteopenia or osteoporosis in the US population older than 50 years.

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.

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.

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.

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.

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.

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.

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.

Short-term evaluation of cardiac morphology, function, metabolism and structure following diagnosis of adult-onset growth hormone deficiency.

OBJECTIVE: The impact of growth hormone (GH) deficiency of the adult on cardiovascular function remains only partially elucidated. Purpose of this study was to test cardiac function in adult GH deficient patients using cardiac magnetic resonance (CMR). DESIGN: Cardiac magnetic resonance (CMR) techniques, including cardiac 31P MR spectroscopy and evaluation of gadolinium late-enhancement, were applied to assess simultaneously, in a cross-sectional fashion, morphological, functional, metabolic, and structural parameters of the left (LV) and right ventricle (RV) in 15 patients with adult onset GH deficiency. Fifteen healthy individuals served as controls. RESULTS: In GH deficient patients LV systolic function (EF%: 61 ±â€¯1.7 vs 62.1 ±â€¯0.8; p = .44) was not different in spite of a lower LV mass (83.2 ±â€¯5.3 vs 145.3 ±â€¯11.9 g; p = .001), a subclinical impairment of diastolic function (E/A peak ratio: 1.6 ±â€¯0.2 vs 2.1 ±â€¯0.2 p = .05), and a trend for lower PCr/ATP ratio (2.1 ±â€¯0.8 vs 2.3 ±â€¯0.1 p = .07). The RV showed reduced chamber size (end diastolic volume 123.8 ±â€¯9 vs 147.9 ±â€¯7.6 mL; p = .021) with preserved mass. No structural alterations of the LV and RV at late-enhancement were detected in these patients. CONCLUSIONS: GH deficient patients represent a unique model of reduced LV myocardial mass in which major structural and metabolic alterations are lacking. Mal-adaptive mechanisms developing in the long term in response to GH deficiency and more severely affecting the LV remain to be elucidated.

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.

Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats.

AIMS: Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling. METHODS: Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry. RESULTS: ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN. CONCLUSIONS: Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.

High prevalence of prolonged QT interval in obese hypogonadal males.

Obese subjects show several electrocardiographic alterations, including prolonged QT interval, a marker for fatal cardiac arrhythmias. Prolonged QT interval has recently been linked to low testosterone levels, a frequent occurrence in male obese patients but no study has yet assessed whether hypoandrogenism contributes to QT interval prolongation in this population. Aim of this study was to evaluate whether prolonged QT interval is linked to hypogonadism in male obese subjects. QT interval corrected for heart rate (QTc) was measured from standard electrocardiogram recordings in 136 obese men (BMI 30 >kg/m(2), range 30.1-75.4 kg/m(2)). Obese men were classified as eugonadal or hypogonadal according to serum total testosterone levels (i.e., greater or less than 9.9 nmol/l). Our study showed that QTc measurements corrected by either Bazett (419 ± 3.2 vs. 408 ± 3.4 ms, P < 0.05), Fridericia (406.3 ± 3.39 vs. 396.4 ± 3.03 ms, P < 0.05) or Hodges (407.0 ± 3.12 vs. 397.3 ± 2.84 ms, P < 0.05) were longer in hypogonadal compared with eugonadal obese men; further, prolonged QTc interval (i.e., >440 ms) was more frequent among hypogonadal compared with eugonadal obese men (23% vs. 10%, P < 0.05). The degree of weight excess, diabetes, sleep apnoea and potassium levels were not associated with prolonged QTc. In conclusion, obese hypogonadal men show a greater prevalence of prolonged QT interval compared with their eugonadal counterparts. It appears therefore that low levels of testosterone in obese men may contribute to the arrhythmogenic profile of these patients, a heretofore unknown link which warrants further clinical attention.