Liver fat and lipid oxidation in humans

Background: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole‐body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. Aims: We examined whether whole‐body and hepatic lipid oxidation are altered in subjects with non‐alcoholic fatty liver disease (NAFLD) compared with controls. Methods: In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3‐³H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5–20.5%), n=29] and in control subjects [1.6% (1.0–3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3‐hydroxybutyrate (3‐OHB) were measured as markers of hepatic lipid oxidation. Results: In the basal state, substrate oxidation rates and serum 3‐OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3‐OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole‐body lipid oxidation was inversely correlated with insulin‐stimulated glucose disposal (r=?0.48, P<0.0001), which was lower in subjects with NAFLD [3.7±0.2 mg/(kg fat‐free mass min)] than in the control subjects [5.0±0.3 mg/(kg fat‐free mass min), P=0.0008]. Conclusions: Hepatic lipid oxidation is unchanged in NAFLD. Whole‐body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans.     

No effect of resveratrol on VLDL‐TG kinetics and insulin sensitivity in obese men with nonalcoholic fatty liver disease

The present study (NCT01446276, ClinicalTrials.gov ) assessed long‐term effects of high‐dose Resveratrol (RSV) on basal and insulin‐mediated very low‐density lipoprotein triglyceride (VLDL‐TG), palmitate and glucose kinetics, and liver fat content in men with nonalcoholic fatty liver disease (NAFLD). Participants (n = 16) were non‐diabetic, upper‐body obese (BMI > 28 kg/m², WHR > 0.9) men with NAFLD who were randomized (1:1) in a double‐blinded, placebo‐controlled clinical trial to either RSV or placebo (500 mg 3 times daily) for 6 months. Magnetic resonance (MR) spectroscopy, dual‐X‐ray absorptiometry and MR imaging assessed liver fat content and body composition, respectively. ¹⁴C‐labeled VLDL‐TG and ³H‐labeled glucose and palmitate tracers, in combination with indirect calorimetry and breath samples, were used to assess kinetics and substrate oxidations during basal and hyperinsulinaemic euglycaemic clamp conditions. RSV did not improve either basal or insulin‐mediated VLDL‐TG secretion, oxidation or clearance rates, nor did it affect palmitate or glucose turnover. Likewise, no changes in body composition or liver fat content occurred following RSV compared with placebo treatment. Therefore, RSV cannot be recommended for treatment of metabolic abnormalities in NAFLD.     

Pancreatic fat and β-cell function in overweight/obese children with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease (NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction (HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue (VAT), pancreatic fat fraction (PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance (HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index (WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either: (1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/dL to < 126 mg/dL; (2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/dL and < 200 mg/dL; or (3) hemoglobin A1c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index (BMI)-SD score, and VAT. In multiple regression analysis with WBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI (standardized coefficient B, -0.398; P = 0.001) as well as HOMA-IR (0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes (OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.     

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight,liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial

We compared the effects of weight loss induced by the glucagon‐like peptide 1‐agonist liraglutide with a structured lifestyle intervention in obese adults with non‐alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m², mean weight 96.0 ± 16.3 kg) non‐diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate‐intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (?3.5 ± 3.3 vs ?3.5 ± 2.1 kg, respectively, P = .72), LFF (?8.9 ± 13.4 vs ?7.2% ± 7.1%, P = .70), serum alanine aminotransferase (?42 ± 46 vs ?34 ± 27 U/L, P = .52) and aspartate aminotransferase (?23 ± 24 vs ?18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight‐loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.     

Long‐term high‐physiological‐dose growth hormone reduces intra‐abdominal fat in HIV‐infected patients with a neutral effect on glucose metabolism

Objectives

The aim of the study was to investigate the effect of long‐term high‐physiological‐dose recombinant human growth hormone (rhGH) therapy on fat distribution and glucose metabolism in HIV‐infected patients.

Methods

Forty‐six HIV‐infected Caucasian men on highly active antiretroviral therapy (HAART), with an age range of 21–60 years and no significant comorbidity, were included in this randomized, placebo‐controlled, double‐blind, single‐centre trial. Twenty‐eight subjects were randomized to 0.7 mg/day rhGH, and 18 subjects to placebo, administered as daily subcutaneous injections between 1 and 3 pm for 40 weeks. Endpoints included changes in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), limb fat mass, percentage of limb fat, plasma lipids, insulin resistance and glucose tolerance.

Results

VAT and trunk fat mass decreased significantly in the GH group compared with the placebo group [−19 cm² (−11%) vs. 12 cm² (6%), P=0.03, and −548 g (−9%) vs. 353 g (6%), P<0.01, respectively]. The beneficial fat redistribution in the GH group occurred without concomitant changes in subcutaneous fat at the abdomen or extremities. rhGH therapy was well tolerated. Insulin resistance, glucose tolerance, and total plasma cholesterol and triglycerides did not significantly change during intervention.

Conclusions

Daily 0.7 mg rhGH treatment for 40 weeks reduced abdominal visceral fat and trunk fat mass in HIV‐infected patients. This treatment appeared to be safe with respect to glucose tolerance and insulin sensitivity.

     

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes

We investigated the short‐term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m²) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24‐week double‐blinded, placebo‐controlled trial. At baseline and after 24 weeks of treatment, 24‐hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima‐media thickness were evaluated. Compared with placebo, liraglutide increased 24‐hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night‐time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long‐standing type 1 diabetes, liraglutide as add‐on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.     

Visceral adipose tissue quality was associated with nonalcoholic fatty liver disease,independent of its quantity

Background and aimsNonalcoholic fatty liver disease (NAFLD) is a serious liver disease. Recent studies have shown that both visceral adipose tissue (VAT) quantity and density (as an indirect measure of quality) are associated with metabolic profiles. Therefore, we investigated the association between VAT quantity and quality, and the prevalence and incidence of NAFLD.Methods and resultsIn this cross-sectional, retrospective cohort study, the prevalence and incidence of NAFLD were analyzed in 627 and 360 middle-aged subjects, respectively. VAT was evaluated using an unenhanced computed tomography scan, while NAFLD was evaluated using ultrasonography. The VAT area was normalized to the square value of the subjects’ height in meters, the visceral fat area (VFA) index. The VAT density was described as the visceral fat density (VFD). The VFA index and VFD had an interaction effect on the prevalence of NAFLD (P = 0.0059). The VFA index (adjusted odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01–1.07; P = 0.0145, per 1.0 cm²/m²) and the VFD (OR, 0.90; 95% CI, 0.84–0.96; P = 0.0026, per 1.0 Hounsfield unit [HU]) were independently associated with the prevalence of NAFLD. In our cohort, 36 subjects developed NAFLD. The VFD (adjusted hazards ratio [HR], 0.84; 95% CI, 0.77–0.91; P < 0.0001, per 1.0 HU) was independently associated with the incidence of NAFLD, whereas the VFA index was not.ConclusionBoth the VFA index and VFD were independently associated with NAFLD prevalence. The VFD might be more related to the incidence of NAFLD than the VFA index.     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

Non-alcoholic fatty liver disease and obesity: Biochemical,metabolic and clinical presentations

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m². However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m²) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.     

Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease

Background and Aim: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T‐455C at rs2854116 and C‐482T at rs2854117) to contribute to non‐alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort. Methods: A total of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) influencing liver fat. Plasma apoC3 concentration was measured enzymatically, and liver fat by proton magnetic resonance spectroscopy. Results: APOC3 wild‐type homozygotes and variant allele (T‐455C or C‐482T or both) carriers did not differ with regard to liver fat, apoC3 concentrations, triglyceride‐, high density lipoprotein‐, fasting plasma glucose, insulin‐, alanine aminotransferase‐ and aspartate aminotransferase‐concentrations, nor was there a difference in prevalence of NAFLD. In contrast, carriers of the PNPLA3 GG genotype at rs738409 had a 2.7‐fold (median 11.3%) higher liver fat than those with the CC (median 4.2%) genotype. The PNPLA3 rs738409 was also an independent predictor of liver fat, together with age, gender, and body mass index. Conclusion: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD.     

Insulin resistance and hyperandrogenemia independently predict nonalcoholic fatty liver disease in women with polycystic ovary syndrome

AimsTo find the prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in Asian Indian polycystic ovary syndrome (PCOS) women.Materials and methodsThis is a prospective, cross-sectional study conducted at a tertiary care hospital from South India. Sixty women fulfilling the Rotterdam (2003) criteria for PCOS were recruited for the study. All participants were evaluated with ultrasound abdomen for fatty liver and additional biochemical investigations including fasting plasma glucose, postprandial plasma glucose, serum insulin, lipid profile and liver function tests.ResultsThe mean age of the study population was 24.06 ± 5.9 (range: 15–39) years. Oligomenorrhea, hirsutism and acne were present in 58 (96.7%), 37 (61.7%) and 33 (55%) women. Mean BMI of the study population was 29.5 ± 5.28 (range: 19.95 to 45.44) kg/m². Fifty (83.3%) women were obese (BMI: ≥ 25 kg/m²). Twenty-three (38.3%) women with PCOS had NAFLD. Three women each had isolated elevation of alanine transaminase (ALT) and aspartate transaminases (AST) whereas three women had elevation of both. All women with elevated transaminases had NAFLD. By univariate analysis, factors associated with NAFLD were serum total cholesterol, serum insulin, HOMA-IR, hyperandrogenism, ALT and AST. On multiple regression analysis using linear regression, HOMA-IR and hyperandrogenemia were the only significant predictors of NAFLD.ConclusionOur study reports NAFLD in more than one third of Asian Indian women with PCOS. In addition to insulin resistance (HOMA-IR), hyperandrogenemia is an independent predictor of NAFLD in women with PCOS.     

Visceral adiposity is closely correlated with neck circumference and represents a significant indicator of insulin resistance in WHO grade III obesity

Objective Although associations between visceral adiposity (intra‐abdominal fat mass) and insulin resistance are well established, previous data include few subjects with WHO grade III obesity [body mass index (BMI) > 40 kg/m²]. We have investigated the relationship between visceral adiposity and insulin resistance using computed tomography (CT)‐quantified fat mass and the homeostasis model assessment for insulin resistance (HOMA‐IR) in patients with severe obesity. Patients and methods Eighteen nondiabetic subjects with BMI > 40 kg/m² were recruited. BMI, and waist, hip and neck circumferences were measured. Fasting plasma insulin and glucose were measured to calculate HOMA‐IR. A single slice CT scan was taken at L4 and visceral and abdominal subcutaneous adipose tissue (VAT and ASAT, respectively) quantified using ‘SliceOmatic’ image analysis software. Results A close correlation was demonstrated between VAT and HOMA‐IR (r² = 0·46, P = 0·002), whereas ASAT showed no relationship. Neck circumference correlated with both VAT (r² = 0·67, P < 0·0001) and HOMA‐IR (r² = 0·35, P = 0·01). Waist circumference only correlated significantly with VAT (r² = 0·25, P = 0·03). Conclusions Visceral adiposity remains a strongly significant indicator of insulin resistance in WHO grade III obesity. Neck circumference surpasses other anthropometric measurements as a powerful marker of both VAT and insulin resistance.     

Elevated fasting plasma C‐peptide occurs in non‐diabetic individuals with fatty liver,irrespective of insulin resistance

Aims Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B‐cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C‐peptide, an index of fasting B‐cell function, was related to intra‐hepatic fat (IHF) content in non‐diabetic humans. Methods We assessed, retrospectively, fasting plasma C‐peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy (¹H‐MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. Results Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C‐peptide (P < 0.005) and lower insulin sensitivity (HOMA2‐%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C‐peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2‐%S. These data were analysed by conditional logistic regression which showed that, when HOMA2‐%S was matched between groups, fasting C‐peptide remained the only significant predictor of fatty liver. Conclusions Non‐diabetic individuals with fatty liver are characterized by increased fasting plasma C‐peptide concentration, irrespective of their insulin resistant state.     

Effects of resveratrol supplementation on liver fat content in overweight and insulin‐resistant subjects: A randomized,double‐blind,placebo‐controlled clinical trial

We performed the largest randomized, placebo‐controlled clinical trial to date (N = 112, 12‐week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin‐resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%‐12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (?0.7%) but not in the resveratrol group (?0.03%) (differences between groups: P = .018 for the intention‐to‐treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans.     

Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes

Aim: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. Methods: Twenty‐five insulin‐treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks. Dual‐energy X‐ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre‐/posttreatment (a ratio <1 represents fatty liver). Results: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm², p < 0.01) compared to a non‐significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm²). VAT decreased non‐significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm² with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm² with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. Conclusions: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.     

Femoral–gluteal adiposity is not associated with insulin sensitivity in Type 1 diabetes

Aims To quantify and compare associations between femoral–gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance. Methods Individuals with Type 1 diabetes (n = 28) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study, a 24‐year prospective study of childhood‐onset diabetes, and compared cross‐sectionally with individuals with normal glucose tolerance (n = 56) of similar age, sex and BMI. Insulin sensitivity was defined as whole‐body glucose disposal measured by hyperinsulinaemic–euglycaemic clamps. Adiposity was quantified by dual energy X‐ray absorptiometry. Results Individuals with Type 1 diabetes exhibited lower insulin sensitivity (5.8 vs. 8.2 mg min^?1 kg fat‐free mass^?1, P < 0.01), lower total fat mass (20.1 vs. 29.0 kg, P < 0.001) and lower proportional leg fat mass (36.0 vs.37.7%, P = 0.03), but similar proportional trunk fat (% trunk fat mass) compared with individuals with normal glucose tolerance. Overall, results from linear regression demonstrated that higher % leg fat mass (P < 0.01) and lower % trunk fat mass (P < 0.01) were independently associated with lower insulin sensitivity after adjustments for age, sex, height, total fat mass (kg) and diabetes status. Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance (P < 0.01) after similar adjustment; significant associations were not observed in Type 1 diabetes. Conclusions Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity. Compared with adults with normal glucose tolerance, leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes.     

Postprandial insulin secretion pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior known diabetes mellitus

Background and Aim: Insulin resistance and diabetes mellitus (DM) are known to contribute to the progression of non‐alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolism and NAFLD is not well known. In this study, we investigated whether secretion patterns of glucose and insulin could influence the histological severity in NAFLD patients without prior known type 2 DM. Methods: A 75‐g glucose tolerance test was performed on 173 biopsy‐proven NAFLD patients without prior known type 2 DM. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Results: Of the 173 NAFLD patients, 168 had non‐alcoholic steatohepatitis, whereas no patient had cirrhosis. Irrespective of the hemoglobin A1c levels, impaired glucose tolerance, including DM, was detected in 60% of the NAFLD patients. While the secretion pattern of glucose after glucose loading was similar among the NAFLD patients, postprandial insulin levels increased and delayed insulin secretion increased in severity in parallel with the aggravation of histological findings (fibrosis stages). Factors associated with advanced fibrosis were higher insulin levels at 120 min after oral glucose loading (P = 0.0001; odds ratio [OR], 3.56; 95% confidence interval [CI], 1.61–7.86), aspartate aminotransferase (P = 0.003; OR, 2.70; 95% CI: 1.19–6.12), and age (P = 0.02; OR, 2.49; 95% CI: 1.15–5.37) as determined by multivariate analysis. Conclusions: Postprandial hyperinsulinemia (but not glucose levels) was associated with advanced fibrosis. The oral glucose tolerance test should be considered in NAFLD patients without prior known type 2 DM in order to facilitate early therapeutic intervention.     

Effect of longitudinal changes of body fat on the incidence and regression of nonalcoholic fatty liver disease

AimsTo investigate the longitudinal association between changes in body fat amount and the incidence and regression of nonalcoholic fatty liver disease (NAFLD).MethodsWe performed a cohort study of 2017 subjects without liver disease or significant alcohol consumption from 2007 to 2008 and participated in a voluntary follow-up between 2011 and 2013. Of the 2017 subjects, we enrolled 956 (47.4%) subjects who had available abdominal fat data in both 2007–2008 and 2011–2013. NAFLD was diagnosed on the basis of ultrasonographic findings. Adipose tissue area was evaluated by computed tomography.ResultsWe observed 145 incident cases of NAFLD (22.6% of 642), and 79 subjects experienced a regression of NAFLD (25.2% of 314) during a median of 4.64 years. An increasing change in visceral adipose tissue (VAT) area was associated with a higher incidence of NAFLD (highest tertile vs. lowest tertile of VAT hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.56–3.85, P for trend <0.001) in the multivariable analysis. An increasing change in VAT area was inversely associated with the regression of NAFLD (highest tertile vs. lowest tertile of VAT HR 0.40, 95% CI 0.20–0.80, P for trend = 0.008).ConclusionsAn increasing change in VAT area was longitudinally associated with a higher risk of incident NAFLD and inversely associated with the regression of NAFLD.     

Effects of combined low‐dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance,non‐invasive indices of steatosis and fibrosis,and adipokine levels in non‐alcoholic fatty liver disease: a randomized controlled trial

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non‐alcoholic fatty liver disease (NAFLD). The aim of the present 52‐week randomized controlled trial was to compare the effects of low‐dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non‐invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA‐IR) and non‐invasive indices of steatosis and fibrosis were calculated. Analysis was intention‐to‐treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase‐to‐platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA‐IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low‐dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger‐scale trials are needed to clarify the effect of low‐dose spironolactone on hepatic histology.     

Predictors and correlates of systolic blood pressure reduction with liraglutide treatment in patients with type 2 diabetes

Liraglutide is associated with blood pressure reduction in patients with type 2 diabetes. However, it is not known whether this blood pressure reduction can be predicted prior to treatment initiation, and to what extent it correlates with weight loss and with improved glycemic control during follow‐up. We analyzed data from a double‐blind, placebo‐controlled trial, in which 124 insulin‐treated patients with type 2 diabetes were randomized to liraglutide or placebo. We evaluated various baseline variables as potential predictors of systolic blood pressure (SBP) reduction, and evaluated whether changes in SBP correlated with weight loss and with improved glycemic control. A greater reduction in SBP among liraglutide‐treated patients was predicted by higher baseline values of SBP (P < 0.0001) and diastolic blood pressure (P = 0.012), and by lower baseline values of mean glucose measured by continuous glucose monitoring (CGM; P = 0.044), and serum fasting C‐peptide (P = 0.015). The regression coefficients differed significantly between the liraglutide group and the placebo group only for diastolic blood pressure (P = 0.037) and mean CGM (P = 0.021). During the trial period, SBP reduction correlated directly with change in body weight and BMI, but not with change in HbA1c. We conclude that patients with lower mean CGM values at baseline responded to liraglutide with a larger reduction in SBP, and that improved HbA1c during follow‐up was not associated with reductions of SBP. Our data suggest that some patients with type 2 diabetes may benefit from liraglutide in terms of weight and SBP reduction.