Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome, with a clinical spectrum ranging from simple fatty liver to steatohepatitis, cirrhosis, and hepatocellular carcinoma. The primary event of NAFLD is the accumulation of triacylglycerols (TAGs) in hepatocytes. In this issue of the JCI, Donnelly et al. report on their use of stable isotope methodology to show that fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis are the major sources of TAGs in the liver and are secreted as lipoproteins in NAFLD

Clinical significance of visceral fat reduction through health education in preventing atherosclerotic cardiovascular disease - Lesson from the Amagasaki Visceral Fat Study: A Japanese perspective

The metabolic syndrome has received worldwide recognition and is useful clinical aid in early-preventing atherosclerosis. Visceral adiposity is the main component of the metabolic syndrome in Japan, based on ethnic and racial difference in the pattern of adiposity. In the Amagasaki Visceral Fat Study, subjects had undergone annual health check-ups and then received health education by medical personnel. Visceral fat reduction improved hypoadiponectinemia and the number of obesity-related cardiovascular risk factors, and effectively prevented cardiovascular events. The health education that includes voluntary lifestyle modification aimed at reducing visceral fat could be useful in preventing cardiovascular events in the metabolic syndrome

Metabolic syndrome, adiponectin and fat ROS

The metabolic syndrome, a cluster of insulin resistance, elevated blood pressure, and atherogenic dyslipidemia, is a common basis of atherosclerosis. Accumulation of intra-abdominal visceral fat stands upstream of the metabolic syndrome. Adipose tissue expresses a variety of genes for bioactive secretory proteins conceptualized as adipocytokines. We discovered a novel adipose-specific protein named adiponectin from human fat cDNAs. Adiponectin circulates in the plasma and its serum level is decreased in visceral fat accumulation. Results of experimental and clinical researches have demonstrated that hypoadiponectinemia underlies the pathogenesis of multiple diseases related to visceral fat accumulation, including atherosclerosis, hypertension, cardiac failure, insulin resistance, diabetes, hepatic steatosis, inflammatory bowel disease, and cancers. Recently, we revealed fat-derived reactive oxygen species (fat ROS) as an upstream factor in the development of hypoadiponectinemia and metabolic syndrome. Intervention targeting visceral fat accumulation, hypoadiponectinemia and fat ROS should be the way to therapeutically tackle the metabolic syndrome.Biomedical Reviews 2006; 17: 1-10

Hyperinsulinemia correlates with low levels of plasma B-type natriuretic peptide in Japanese men irrespective of fat distribution

<p>Abstract</p> <p>Background</p> <p>B-type natriuretic peptide (BNP), a member of the natriuretic peptide family, is a cardiac-derived secretory hormone with natriuretic, diuretic, and vasorelaxant activities. Intraabdominal fat accumulation is associated with atherosclerotic cardiovascular diseases and cardiac dysfunction. Circulating BNP levels are relatively low (within the normal limits) in obesity and the metabolic syndrome. However, the relationship between plasma BNP levels and visceral fat accumulation in general population has not been reported. The present study analyzed the relationships between plasma BNP levels and various clinical variables, including insulin, visceral and subcutaneous fat area (VFA and SFA, respectively), in normal Japanese men.</p> <p>Methods</p> <p>The study (Victor-J study) subjects were consecutive 500 Japanese male workers, who underwent a health checkup and were measured VFA and SFA by computed tomography.</p> <p>Results</p> <p>Age-adjusted simple linear regression analysis showed that log-BNP correlated positively with HDL-cholesterol, and negatively with VFA, log-immunoreactive insulin (IRI), log-triglyceride, and LDL-cholesterol, but not body mass index or SFA. Stepwise multiple regression analysis identified log-IRI and HDL-cholesterol as significant determinants of log-BNP. Subjects with IRI ≥5.5 μIU/mL had lower plasma BNP levels than those with IRI < 5.5 μIU/mL, irrespective of obesity (body mass index, cutoff value 25 kg/m²), visceral fat accumulation (VFA, cutoff value 100 cm²) and subcutaneous fat accumulation (SFA, cutoff value 128 cm²).</p> <p>Conclusions</p> <p>Our study showed that hyperinsulinemia correlated with low levels of plasma BNP in general men, irrespective of fat distribution.</p> <p>Trial registration</p> <p>UMIN 000004318.</p

T1DM complication in continuous insulin

To evaluate whether continuous subcutaneous insulin infusion attenuates the progression of diabetic complications, we retrospectively extracted data from 35 individuals who had developed type 1 diabetes mellitus aged ≤20 years and whose treatment had been changed from multiple daily injections to continuous subcutaneous insulin infusion. The annual changes in estimated glomerular filtration rate, urinary albumin excretion rate, carotid intima-media thickness and brachial-ankle pulse wave velocity during each treatment period were calculated. Although mean glycated hemoglobin under the continuous subcutaneous insulin infusion treatment was lower than that under the multiple daily injection treatment, there were no significant differences in annual changes in diabetic nephropathy and atherosclerosis between the two treatment periods. This pilot study showed that, in Japanese patients with juvenile-onset type 1 diabetes mellitus, there was no significant difference in the progression of diabetic nephropathy and atherosclerosis, at least in the early stage, between the two treatments

Dose-Dependent Effect of Sitagliptin on Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus Receiving Insulin Treatment: A Post Hoc Analysis

IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors reduce blood glucose in a dose-dependent manner, but the dose-dependent effect relationship between DPP-4 inhibitors and atherosclerosis has not been investigated.MethodsPatients with type 2 diabetes mellitus (T2DM) treated with insulin were randomized to the sitagliptin (n = 137) or conventional treatment group (n = 137). In the sitagliptin group, each investigator was allowed to adjust the sitagliptin dose to avoid hypoglycemia. In this post hoc analysis, subjects in the sitagliptin group were divided into two groups based on the average dose of sitagliptin during the study period: greater than or equal to median (higher sitagliptin dose group) or less than median (lower sitagliptin dose group).ResultsIn this study, subjects were divided into three groups: the conventional treatment group (n = 137), lower sitagliptin dose group (n = 42), and higher sitagliptin dose group (n = 95). The higher sitagliptin dose group had a significantly larger reduction in HbA1c (−0.62 ± 1.05%) than the conventional treatment group (−0.20 ± 0.91%, P = 0.007). Over 104 weeks, the higher sitagliptin dose significantly reduced the mean intima media thickness-common carotid artery (IMT-CCA) and left max-IMT-CCA relative to baseline. In addition, the higher sitagliptin dose significantly inhibited the progression in mean-IMT-CCA compared with conventional treatment. Multiple linear regression analysis showed that changes in mean-IMT-CCA and left max-IMT-CCA decreased with higher sitagliptin dose.ConclusionsAddition of sitagliptin to insulin therapy might attenuate the progression of atherosclerosis in patients with T2DM in a dose-dependent manner

Changes in carotid intima-media thickening in patients with type 2 diabetes mellitus: Subanalysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Type 2 diabetes mellitus is a risk factor for cardiovascular disease. Both the absolute value and progression of carotid artery intima‐media thickness (IMT) are considered a marker of progression of atherosclerosis. We reported recently that treatment with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, attenuated the progression of carotid IMT in insulin‐treated patients with type 2 diabetes mellitus compared with conventional therapy1. Here, we compared the efficacy of treatment with sitagliptin with that of other modalities on the progression of carotid IMT in prespecified subgroups of the Sitagliptin Preventive Study of Intima‐Media Thickness Evaluation (SPIKE) registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)1, 2. The aim of the comparison was to identify the characteristics of patients who benefited most from the sitagliptin treatment in terms of decrease in IMT.The recruits in the original study included 282 insulin‐treated Japanese type 2 diabetes mellitus patients free of past history of apparent cardiovascular disease. They were randomly allocated to either the sitagliptin group (n = 142) or the conventional treatment group (using drugs other than sitagliptin; n = 140). After the exclusion of eight patients, data of 137 patients of the sitagliptin group and 137 of the conventional treatment group were subjected to analysis. The mean‐IMT of the common carotid arteries (mean‐IMT‐CCA) and right and left max‐IMT‐CCA were measured by expert sonographers at the start of the study, and the procedure was repeated after 52 and 104 weeks, as reported previously1, 2. Figure 1 shows differences in treatment‐induced delta change in carotid IMT, relative to baseline in 243 patients whose IMT data were available at baseline and 104 weeks, according to various predefined risk factors for atherosclerosis. The results showed consistent reductions in mean IMT‐CCA and left max IMT‐CCA, but not right max IMT‐CCA, in the sitagliptin group (Figure 1). In particular, a greater reduction in carotid IMT was noted after treatment with sitagliptin in patients with risk factors for cardiovascular disease, such as higher glycated hemoglobin, higher body mass index, longer duration of type 2 diabetes mellitus, use of angiotensin‐converting enzyme inhibitors/angiotensin II receptor blocker, use of statins, worse hypertension and/or hyperlipidemia at baseline, compared with conventional treatment. These data suggest that treatment with dipeptidyl peptidase‐4 inhibitors seems to prevent the progression of carotid atherosclerosis regardless of disease burden. Previous studies showed that treatment with statins and angiotensin‐converting enzyme inhibitors reduces the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus3, 4. In this subgroup analysis, sitagliptin still attenuated the progression of carotid IMT, even in patients who were receiving those therapies. Thus, dipeptidyl peptidase‐4 inhibitors seem to have unique and/or additive anti‐atherosclerotic effects as add‐on therapy to statins and/or angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers

The Effect of Sitagliptin on the Regression of Carotid Intima-Media Thickening in Patients with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Background. The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on the regression of carotid IMT remains largely unknown. The present study aimed to clarify whether sitagliptin, DPP-4 inhibitor, could regress carotid intima-media thickness (IMT) in insulin-treated patients with type 2 diabetes mellitus (T2DM). Methods. This is an exploratory analysis of a randomized trial in which we investigated the effect of sitagliptin on the progression of carotid IMT in insulin-treated patients with T2DM. Here, we compared the efficacy of sitagliptin treatment on the number of patients who showed regression of carotid IMT of ≥0.10 mm in a post hoc analysis. Results. The percentages of the number of the patients who showed regression of mean-IMT-CCA (28.9% in the sitagliptin group versus 16.4% in the conventional group, P = 0.022) and left max-IMT-CCA (43.0% in the sitagliptin group versus 26.2% in the conventional group, P = 0.007), but not right max-IMT-CCA, were higher in the sitagliptin treatment group compared with those in the non-DPP-4 inhibitor treatment group. In multiple logistic regression analysis, sitagliptin treatment significantly achieved higher target attainment of mean-IMT-CCA ≥0.10 mm and right and left max-IMT-CCA ≥0.10 mm compared to conventional treatment. Conclusions. Our data suggested that DPP-4 inhibitors were associated with the regression of carotid atherosclerosis in insulin-treated T2DM patients. This study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)

Metabolic syndrome correlates intracoronary stenosis detected by multislice computed tomography in male subjects with sleep-disordered breathing

<p>Abstract</p> <p>Background</p> <p>Sleep-disordered breathing (SDB), especially obstructive sleep apnea (OSA), has frequent complications include hypertension, dyslipidemia and insulin resistance based on abdominal obesity or excess visceral fat (called Syndrome Z). OSA is a potential risk factor for cardiovascular diseases. The clinical characteristics of Japanese OSA subjects with OSA remain unclear. The present study investigated prevalence and predictive factors of intracoronary stenosis detected by multislice computed tomography (MSCT) in Japanese male subjects with SDB/OSA.</p> <p>Findings</p> <p>The study (O-VFStudy) subjects were 39 Japanese men with SDB/OSA who underwent all-night cardiorespiratory monitoring with fully attended polysomnography, and moreover both fat computed tomography (CT) scan and 64-row MSCT coronary angiography. The prevalence of coronary stenosis in this selected population with SDB/OSA was 15%. Logistic regression analysis showed a significant relationship between age-adjusted CAD and metabolic syndrome (<it>p </it>< 0.05), but not serum adiponectin levels and nocturnal fall in adiponectin. Subjects with the metabolic syndrome had significantly higher prevalence of CAD (31.3 versus 4.3%, <it>p </it>= 0.033), and lower levels of serum adiponectin (4.5 ± 0.6 versus 6.4 ± 0.6 μg/mL, <it>p </it>= 0.014), compared with groups without the metabolic syndrome.</p> <p>Conclusions</p> <p>The present study describes that the prevalence of greater than 50% intracoronary stenotic lesions detected by MSCT was 15% and the metabolic syndrome was correlated with intracoronary stenosis detected by MSCT in Japanese SDB/OSA subjects.</p> <p>Trial Registration</p> <p>UMIN 000002997</p> <p><url>https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000003633&language=E</url>.</p

The Effect of Sitagliptin on the Regression of Carotid Intima-Media Thickening in Patients with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Background. The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on the regression of carotid IMT remains largely unknown. The present study aimed to clarify whether sitagliptin, DPP-4 inhibitor, could regress carotid intima-media thickness (IMT) in insulin-treated patients with type 2 diabetes mellitus (T2DM). Methods. This is an exploratory analysis of a randomized trial in which we investigated the effect of sitagliptin on the progression of carotid IMT in insulin-treated patients with T2DM. Here, we compared the efficacy of sitagliptin treatment on the number of patients who showed regression of carotid IMT of ≥0.10 mm in a post hoc analysis. Results. The percentages of the number of the patients who showed regression of mean-IMT-CCA (28.9% in the sitagliptin group versus 16.4% in the conventional group, P = 0.022) and left max-IMT-CCA (43.0% in the sitagliptin group versus 26.2% in the conventional group, P = 0.007), but not right max-IMT-CCA, were higher in the sitagliptin treatment group compared with those in the non-DPP-4 inhibitor treatment group. In multiple logistic regression analysis, sitagliptin treatment significantly achieved higher target attainment of mean-IMT-CCA ≥0.10 mm and right and left max-IMT-CCA ≥0.10 mm compared to conventional treatment. Conclusions. Our data suggested that DPP-4 inhibitors were associated with the regression of carotid atherosclerosis in insulin-treated T2DM patients. This study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)