Mitochondrial Respiratory Supercomplex Assembly Factor COX7RP Contributes to Lifespan Extension in Mice

To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.

Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity

The relationship between excessive nutrient intake and hepatic endoplasmic reticulum stress (ER stress) is well stablished. However, mechanisms underlying the progression from adaptive to apoptotic pattern are still unclear. This study sought to investigate the effects of high‐sucrose diet on metabolic disorders associated to hepatic ER stress. Weaned Swiss mice received standard chow (CTR) or high‐sucrose diet (HSD; 25% sucrose) for distinct periods of 30 (CTR30 and HSD30) and 60 (CTR60 and HSD60) days. Weight gain, food intake, feed efficiency and Lee index (LI) were measured for obesity development assessment. At each treatment end, glucose (GTT) and insulin (ITT) tolerance tests were performed. Blood, white adipose tissue (WAT) depots and liver were collected upon euthanasia of anesthetized animals. Serum glucose (GL), triglycerides (TG), total cholesterol (TC) and free fatty acids (FFA) levels were determined. WAT depots were weighed and their lipolytic activity assessed. Hepatic tissue was used to determine the lipid profile and gene expression of ER stress (ATF6, IRE1α, PERK, GRP78, PDI, NRF2) and pro‐apoptotic (CHOP and caspase 2) markers. Only HSD60 showed higher weight gain (8%), LI (3%) and feed efficiency (31%), as compared to CTR60. WAT was 2‐fold higher in HSD60 than in HSD30, whereas both of them were significantly higher than their controls. Lipolytic activity under isoproterenol‐stimulation was 40% lower in HSD60. Serum GL and TC were increased in 20 and 40%, respectively, in both HSD groups. However, TG (43%) and FFA (25%) were increased only in HSD60. Area under the curve of GTT was augmented in both HSD30 (14%) and HSD60 (41%), as compared to their controls. Whereas only HSD60 presented reduced kITT (37%) and increase TyG (8%). Total fat liver content was increased in 22 and 61% for HSD30 and HSD60, respectively. On the other hand, hepatic TG was augmented only in HSD60 (69%). HSD30 presented increased hepatic gene expression of GRP78 (57%), PERK (83%), IRE1α (49%), ATF6 (70%), PDI (41%) and NRF2 (32%), and reduced expression of CHOP (39%). An opposite pattern was found in HSD60, with reduced expression of PERK (34%), IRE1α (52%), ATF6 (36%) and PDI (46%), and increase expression of CHOP (72%). Notwithstanding, caspase‐2 expression did not change in any group. Therefore, our data suggest the HSD intake for up to 60 days after weaning rapidly promotes metabolic disorders associate to early onset of hepatic ER stress, which promptly progress from an adaptive to a pro‐apoptotic pattern.Support or Funding InformationFAPEMA, CNPq, CAPES and UFMA.

To study the levels of blood lipid among Chinese adults in 2010 and analyze the epidemiological features. Fasting serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C) were determined for 90 395 subjects aged 18 and over who were selected by multi stage cluster random sampling method from 162 surveillance sites of 31 provinces of China mainland in 2010. After complex weighting, the differences of levels of serum total TC, TG, HDL-C and LDL-C were analyzed in different age, gender and geographic regions. After complex weighting, the levels of serum TC in Chinese adults was (4.04 ± 1.08) mmol/L, with (3.86 ± 1.03), (4.29 ± 1.11) and (4.33 ± 1.09) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 177.56, P < 0.01), respectively. The level of serum TC was (4.06 ± 1.09) mmol/L and (4.03 ± 1.07) mmol/L in males and females (F = 2.38, P > 0.05), respectively; (4.08 ± 1.13) mmol/L and (4.03 ± 1.06) mmol/L in urban and rural areas (F = 0.51, P > 0.05), respectively, and (4.13 ± 1.11), (4.03 ± 1.01) and (3.93 ± 1.11) mmol/L in areas of east, middle and west respectively (F = 2.56, P > 0.05). The levels of serum TG was (1.33 ± 1.28) mmol/L, with(1.26 ± 1.24), (1.48 ± 1.46) and (1.35 ± 1.05) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 85.98, P < 0.01), respectively. The level of serum TG was (1.45 ± 1.48) mmol/L and (1.21 ± 1.01) mmol/L in males and females (F = 172.01, P < 0.01), respectively, (1.34 ± 1.26) mmol/L and (1.33 ± 1.28) mmol/L in urban and rural areas (F = 0.16, P > 0.05), respectively, and(1.30 ± 1.25), (1.35 ± 1.23) and (1.35 ± 1.36) mmol/L in areas of east, middle and west (F = 0.69, P > 0.05) respectively. The levels of serum HDL-C was (1.11 ± 0.31) mmol/L, with (1.09 ± 0.30), (1.13 ± 0.33) and (1.14 ± 0.33) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 27.81, P < 0.01), respectively. The level of serum HDL-C was (1.08 ± 0.32) mmol/L and (1.14 ± 0.30) mmol/L in males and females (F = 178.66, P < 0.01), respectively, (1.11 ± 0.31) mmol/L and (1.11 ± 0.32) mmol/L in urban and rural areas (F = 0.09, P > 0.05), respectively, and (1.12 ± 0.32), (1.12 ± 0.31) and (1.09 ± 0.32) mmol/L in areas of east, middle and west (F = 1.06, P > 0.05) respectively. The levels of serum LDL-C was (2.27 ± 0.78) mmol/L, with (2.15 ± 0.74), (2.42 ± 0.80) and (2.46 ± 0.81) mmol/L in the groups of 18 - 44, 45 - 59 and over 60 years old (F = 129.84, P < 0.01), respectively. The level of serum LDL-C was (2.30 ± 0.78) mmol/L and (2.24 ± 0.78) mmol/L in males and females (F = 25.06, P < 0.01), respectively, (2.33 ± 0.82) mmol/L and (2.24 ± 0.76) mmol/L in urban and rural areas (F = 3.48, P > 0.05), respectively, and (2.35 ± 0.80), (2.25 ± 0.74) and (2.17 ± 0.77) mmol/L in areas of east, middle and west (F = 4.58, P < 0.05) respectively. The levels of serum lipid of middle aged male, female after menopause and people living in eastern region were higher than other Chinese adults. Effective measures should be taken earlier to control serum lipid levels.

Obesity differentially affects serum levels of androstenedione and testosterone in polycystic ovary syndrome

Background: Both postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis, and to be a potent risk factor for cardiovascular event. Methods: To examine effects of glycemic state on postprandial hyperlipidemia and hyperinsulinemia in patients with coronary artery disease (CAD), a total of 146 consecutive male patients with angiographically confirmed CAD were loaded with a high-fat and high-glucose test meal. CAD patients were divided into three groups as “non-diabetic”, “prediabetic”, and “diabetic” CAD groups. 28 male normoglycemic patients without CAD matched on age were served as control subjects. Results: The serum triglyceride (TG) and remnant-like particle cholesterol (RLP-C) levels at the 6th hour in diabetic CAD group showed significantly higher than non-diabetic CAD group, and the area under the curves (AUCs) of these levels in diabetic CAD group were significantly greater than non-diabetic CAD group (TG, P = 0.0287; RLP-C, P = 0.0386). There were no significant differences in the AUCs of TG or RLP-C between prediabetic and non-diabetic CAD group. The AUCs of plasma insulin levels or insulin resistance index (IRI): (AUCs of insulin) x (AUCs of glucose) as the insulin resistance marker were greater in diabetic CAD group than non-diabetic CAD group (insulin, P = 0.0311; IRI, P = 0.0235). The AUCs of serum TG or RLP-C levels showed a correlation with the AUCs of plasma insulin (AUC-TG, r = 0.4381, P &lt;0.0001; AUC-RLC-P, r = 0.3953, P &lt;0.0001), and they correlated well with the insulin resistance index (AUC-TG, r = 0.7194, P &lt;0.0001; AUC-RLC-P, r = 0.6621, P &lt;0.0001). Conclusions: We found that the insulin resistance showed a close relationship with postprandial hyperlipidemia in CAD patients. Diabetic, but not prediabetic state, may be a risk for postprandial impaired lipid metabolism.

Investigate, in healthy sedentary rats, the potential mechanisms involved on the effects of beta hydroxy beta methylbutyrate (HMB) supplementation upon the glycaemic homeostasis, by evaluating the insulin sensitivity in liver, skeletal muscle, and white adipose tissue. Rats were supplemented with either beta hydroxy beta methylbutyrate (320mgkg(-1) BW) or saline by gavage for 4weeks. After the experimental period, the animals were subjected to the glucose tolerance test (GTT) and plasma non-esterified fatty acids (NEFA) concentration measurements. The soleus skeletal muscle, liver and white adipose tissue were removed for molecular (western blotting and RT-PCR) and histological analysis. The beta hydroxy beta methylbutyrate supplemented rats presented: (i) higher ratio between the area under the curve (AUC) of insulinaemia and glycaemia during glucose tolerance test; (ii) impairment of insulin sensitivity on liver and soleus skeletal muscle after insulin overload; (iii) reduction of glucose transporter 4 (GLUT 4) total and plasma membrane content on soleus; (iv) increased hormone-sensitive lipase (HSL) mRNA and protein expression on white adipose tissue and plasma NEFA levels and (v) reduction of fibre cross-sectional area of soleus muscle. The data altogether indicate that beta hydroxy beta methylbutyrate supplementation impairs insulin sensitivity in healthy sedentary rats, which, in the long-term, could lead to an increased risk of developing type 2 diabetes.

To observe the effect of acupuncture on the expressions of transforming growth factor β(TGF-β)/Smad homolog 3(Smad 3)signaling pathway and autophagy-related factors in obese rats induced by a high-fat diet, so as to explore its possible mechanisms in improving obesity. Male SD rats were randomly divided into normal, model, medication and acupuncture groups, with 10 rats in each group.The obesity model was established by feeding the rats with a high-fat diet.Rats of the acupuncture group received acupuncture at "Guanyuan"(CV4) "Zhongwan"(CV12) and bilateral "Tianshu"(ST25) etc., for 30 min, once daily for 4 weeks. Rats in the medication group received gavage of orlistat solution (32.4 mg·kg-1·d-1), once daily for 4 weeks.The rat's body weight was measured for calculating the Lee's index.The weights of epididymal fat and perirenal fat were measured.The fasting blood glucose (FBG) and insulin levels were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) index was calculated. Additionally, intraperitoneal glucose tolerance and insulin tolerance tests were performed.The serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured. HE staining was used to observe the morphology and structure of liver and epididymal adipose tissue, and oil red O staining was used to observe the lipid droplets in liver tissue.The mRNA and protein expression levels of TGF-β, TGF-β receptor 1 (TGF-βR1), Smad3, autophagy related protein Beclin-1, ubiquitin binding protein p62, and microtubule-associated protein 1 light chain 3(LC3) in epididymal adipose tissue were detected by real-time fluorescence quantitative PCR and Western blot, respectively. Compared with the normal group, the body weight, Lee's index, perirenal and epididymal fat mass, serum TC, TG and LDL content, fasting insulin level, and HOMA-IR of rats in the model group were increased (P<0.01), the blood glucose levels were also increased at 30, 60, and 120 min after glucose and insulin injection (P<0.01, P<0.05), while the HDL content was decreased (P<0.01). Compared with the model group, the body weight, Lee's index, perirenal and epididymal fat mass, serum TC, TG and LDL content, and HOMA-IR of the medication and acupuncture groups were decreased (P<0.01, P<0.05), and the serum HDL content of the acupuncture group was increased (P<0.01). Compared with the normal group, the mRNA expression levels of TGF-β, TGF-βR1, Smad3, LC3, and Beclin-1, the protein expression levels of TGF-β, TGF-βR1, p-Smad3/Smad3, LC3-Ⅱ/LC3- Ⅰ, and Beclin-1 in the epididymal adipose tissue of rats in the model group were significantly increased (P<0.01, P<0.05), while the mRNA and protein expression levels of p62 were decreased (P<0.01). Compared with the model group, the mRNA expression levels of TGF-β, LC3, and Beclin-1, the protein expression levels of TGF-β, p-Smad3/Smad3, and Beclin-1 in the medication and acupuncture groups were decreased (P<0.01), while the mRNA and protein expression levels of p62 were increased (P<0.01). Additionally, the mRNA expression of TGF-βR1, the protein expression of TGF-βR1 and LC3-Ⅱ/LC3- Ⅰ in the acupuncture group was decreased (P<0.05, P<0.01). Compared with the medication group, the serum HDL content and the expression of p62 protein in adipose tissue were significantly increased in the acupuncture group (P<0.01), while the protein expression level of TGF-βR1, the ratio of p-Smad3/Smad3, and the expression of Beclin-1 protein in adipose tissue were significantly decreased (P<0.01). Compared with the normal group, the adipocytes in the model group exhibited significantly enlarged lipid droplets with disordered arrangement, and hepatic lipid deposition was markedly increased;whereas compared with the model group, both the acupuncture and medication groups showed reduced lipid droplet size. Acupuncture may induce weight loss by inhibiting the TGF-β/Smad3 signaling pathway and excessive autophagy of adipose tissue, thereby improving the metabolic state of obese rats and reducing the volume of adipocytes.

This study aimed to determine ANGPTL3 serum levels in healthy young lean and obese non-diabetic men during an oral glucose tolerance test (OGTT) and correlate them with anthropometric, biochemical and hormonal parameters. A case–control study was carried out and 30 young obese non-diabetic (23.90 ± 3.84 years and BMI 37.92 ± 4.85 kg/m2) and 28 age-matched healthy lean (24.56 ± 3.50 years and BMI of 22.10 ± 1.72 kg/m2) men were included in this study. The primary outcome measures were serum basal ANGPTL3 and ANGPTL3–area under the curve (AUC) levels. The percentage of body fat was measured by dual-energy X-ray absorptiometry and biochemical, hormonal and insulin resistance indices were determined. Basal ANGPTL3 and ANGPTL3–AUC levels were significantly elevated (p < 0.05) in young obese subjects compared with lean subjects and were positively and significantly associated with different anthropometric measurements. Fasting ANGPTL3 serum levels were positively correlated with fasting insulin, leptin, Leptin/Adiponectin index and triglyceride—glucose index. Moreover, ANGPTL3–AUC was negatively correlated with Matsuda index. In this regard, chronically high ANGPTL3 levels in young obese subjects might favor triglyceride-rich lipoprotein clearance to replenish triglyceride stores by white adipose tissue rather than oxidative tissues.

To examine the significance of apolipoprotein E (apo E) polymorphism in the hypolipidemic effect of bezafibrate, we evaluated the influence of different apo E phenotypes on serum lipid response to bezafibrate treatment in 58 dyslipidemic patients with WHO phenotypes of IIb, IV, or isolated hypo HDL cholesterolemia. Patients were categorized into one of three groups according to apo E phenotypes of E2 (E2/3, n=5), E3 (E3/3, n=35), and E4 (E3/4 and E4/4, n=18). After 3 months daily administration of 400 mg bezafibrate, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels changed on average in the E3 group [-8.0%; p<0.05 and +1.1%; not significant (ns), respectively], the E2 group (-18.3%; p<0.005 and -26.9%; p<0.05, respectively) and the E4 group (+3.8%; ns and +10.1%; ns, respectively). The changes in TC and LDLC levels in the E4 group was significantly less effective compared with those in the E3 (p<0.05) and E2 groups (p<0.01). Bezafibrate induced a reduction in serum triglyceride (TG) levels in the E3 group (-50.1%; p<0.0001), the E2 group (-46.9%; p<0.05) and the E4 group (-44.8%; p<0.005). An increase in high-density lipoprotein cholesterol (HDLC) levels was also observed in the E3 group (+27.5%; p<0.0001), the E2 group (+35.0%; ns) and the E4 group (+38.8%; p<0.005). However, there was no significant difference in the changes of TG and HDLC levels between the groups. These results suggest an important role of apo E polymorphism in modulating serum lipid response to bezafibrate, and phenotyping of apo E helps predict the therapeutic effect of bezafibrate treatment.

Coronary computed tomography angiography (CCTA) can be used to investigate the relationship between white adipose tissue (WAT) and brown adipose tissue (BAT) in pericardial fat (PF) and high-risk plaques (HRP) in patients with coronary artery disease (CAD). This study aimed to explore the association between specific components of PF and HRP/culprit ischemic plaques, as well as their mediating role in overall metabolic status, providing new imaging evidence for predicting adverse events in CAD. The clinical risk factors and imaging images of 107 CAD patients were retrospectively analyzed. Quantification of coronary artery calcium scores (CACS), PF, WAT, BAT, and pericardial fat attenuation (PFatt) were performed on non-contrast CT images. CCTA was used to evaluate myocardial ischemia and the presence of HRP. Fractional flow reserve derived from CCTA (CT-FFR) was performed in three major coronary arteries, with a threshold of ≤0.80 considered indicative of the presence of lesion-specific ischemia. HRP was defined as the presence of at least two of the four HRP features including positive remodeling (PR), low attenuation, napkin-ring sign (NRS), and spotty calcification. Mediator analysis was performed using Hayes (2018) Model-4. A total of 107 CAD patients aged 65±8 years were included in this study. There were 49 patients (45.79%) with HRP and 57 patients (53.27%) with lesion-specific ischemia (CT-FFR ≤0.80). PF including WAT and BAT in the HRP group was significantly higher than that in the non-HRP group (PF: 241.28 vs. 204.94 cm3, P=0.005, WAT: 91.78 vs. 78.40 cm3, P=0.002, BAT: 56.25 vs. 46.71 cm3, P=0.008). Adding WAT to meaningful clinical risk factors and CACS increases the area under the curve (AUC) for HRP prediction {AUC [95% confidence interval (95% CI)]: 0.789 (0.692-0.887) vs. 0.655 (0.535-0.775), P<0.05}. Interestingly, adding PF to clinical risk factors and CACS decreased the AUC for the prediction of lesion-specific ischemia with no significant difference (P=0.083) [AUC (95% CI): 0.705 (0.592-0.817) vs. 0.796 (0.696-0.897), P<0.05]. Additionally, the mediation effect of PF accounted for 95.19% of the total effect of clinical risk factors on HRP (P<0.05). PF is associated with HRP, and clinical risk factors increase the risk of plaque rupture by promoting PF volume accumulation, especially WAT, which may be a potential predictor of HRP.

Few studies have described the metabolic phenotype of AbPos individuals who remain T1D free for an extended period of time. We aimed to compare C-peptide and glucose (Glu) data from oral glucose tolerance tests (OGTTs) performed longitudinally in 646 AbPos TrialNet Pathway to Prevention (PTP) participants who remained T1D free for ≥5.0 yrs (LTNPs; mean follow-up: 7.8±2.3 yrs) versus 405 Rapid Progressor (RP) PTP participants who progressed to T1D within &amp;lt;2 yrs of study entry (mean follow-up 0.97±0.54 yrs) and 150 Ab negative (AbNeg) controls. At study entry, 48% of LTNPs were single AbPos and 52% were multiple AbPos; 45.8% of single AbPos LTNPs became multiple AbPos during follow-up. LTNPs were older (mean age 18.8 ± 14.1 yrs) compared to RPs (11.8 ± 9.3 yrs) and AbNeg individuals (16 ± 10 yrs) (p&amp;lt;0.001). LTNPS exhibited an intermediate metabolic phenotype, with age and BMIZ-adjusted C-peptide area under the curve (AUC) and 30-0 min C-peptide values that were lower than AbNegs but higher than RPs (p&amp;lt;0.001), and Index60 levels (a composite of glucose and C-peptide values from OGTTs) that were higher than AbNegs but lower than RPs (p&amp;lt;0.001). Longitudinal trends in LTNPs were analyzed using fitted linear mixed models. Multiple AbPos LTNPs had higher Glu AUC (p=0.01) and Index60 values (p=0.032) compared to single AbPos LTNPs. However within both AbPos groups, metabolic patterns were remarkably stable over extended follow-up. When measures were evaluated for non-linear interactions using a regression tree analysis, the combination of Index60&amp;lt;1.06 + Glu AUC&amp;lt;137.7 at baseline was associated with an odds ratio of 8.55 (p&amp;lt;0.001) of being a LTNP. These data suggest that, while β cell function is reduced in LTNPs at the time of AbPos identification, longitudinal Glu and C-peptide patterns are largely stable without evidence of a relapsing or remitting course. Baseline OGTT measures (here, Index 60 and Glu AUC) may be able to predict AbPos individuals with lower risk of progression to T1D. Disclosure C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. Z.I. Saeed: None. J. Sosenko: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. H.M. Ismail: None. H. Elding Larsson: None. M. Lundgren: None. A. Moran: Research Support; Self; Abbott, Intrexon, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Provention Bio, Inc. Other Relationship; Self; Novo Nordisk Inc. D.J. Moore: None. B.M. Nathan: None. J.P. Palmer: None. E.K. Sims: None. A. Steck: None. D.K. Wherrett: None. M.J. Redondo: None. Funding National Institutes of Health (U01107014, U01DK106993)

Associations of arterial stiffness with glucose, insulin, and proinsulin dynamics during the oral glucose tolerance test (OGTT) remain under debate. The aim of this study was to investigate whether plasma glucose (PG), insulin, and proinsulin (Pro) contribute to arterial stiffness, measured by pulse wave velocity (PWV), in young Japanese persons. PG, immunoreactive insulin (IRI), and Pro levels were determined in 1193 young Japanese subjects (<40 years of age) with normal glucose tolerance or nondiabetic hyperglycemia before and at 30, 60, and 120 min during a 75-g OGTT. Participants were divided into two groups according to the median PWV. Background factors, PG, IRI, and Pro levels during the OGTT, and insulin sensitivity (SI) indices in each group were compared. Several multiple regression analysis models were used to evaluate factors contributing to PWV. All IRI and Pro levels before and after glucose loading and the area under the curve (AUC) values for IRI and Pro increased with higher PWV. 1/HOMA-IR and ISI-Matsuda as measures of SI decreased with higher PWV. The IRI AUC and Pro level before glucose loading (Pro0) were independently associated with PWV, in addition to male sex, heart rate, and mean blood pressure. The IRI AUC had a stronger relationship with PWV than Pro0. The IRI AUC had an independent relationship with PWV, whereas both SI indices did not. Postloading insulinemia, but not reduced SI, was independently associated with arterial stiffness in young Japanese persons.

PurposeTo determine the associations between apolipoprotein E (APOE) genotypes and serum levels of glucose, total cholesterol, and triglycerides in a cognitively normal aging Han Chinese population.MethodsThere were 1,003 cognitively normal aging subjects included in this study. APOE genotypes were analyzed and biochemical parameters were tested. All the subjects were divided into three groups according to APOE genotypes: (1) E2/2 or E2/3 (APOE E2); (2) E3/3 (APOE E3); and (3) E2/4, E3/4, or E4/4 (APOE E4). Correlations of serum levels of glucose, total cholesterol, and triglycerides with APOE genotypes were assessed.ResultsE2, E3, and E4 allele frequencies were found to be 6.2%, 82.1%, and 11.7%, respectively. Serum levels of total cholesterol were higher in the APOE E4 group (P<0.05). A higher level of total cholesterol was associated with the E4 allele (adjusted odds ratio 1.689, 95% confidence interval 1.223–2.334, P<0.01). However, no association was found between APOE status and serum levels of glucose (adjusted odds ratio 0.981, 95% confidence interval 0.720–1.336, P=0.903) or total triglycerides (adjusted odds ratio 1.042, 95% confidence interval 0.759–1.429, P=0.800).ConclusionA higher serum level of total cholesterol was significantly correlated with APOE E4 status in a cognitively normal, nondiabetic aging population. However, there was no correlation between APOE genotypes and serum levels of glucose or total triglycerides.

An intact genotoxic stress response appears to be atheroprotective and insulin sensitizing. ATM, mutated in ataxia telangiectasia, is critical for the genotoxic stress response, and its deficiency is associated with accelerated atherosclerosis and insulin resistance in humans and mice. The antimalarial drug chloroquine activates ATM signaling and improves metabolic phenotypes in mice. p53 is a major effector of ATM signaling, but it is unknown if p53 is required for the beneficial effects of chloroquine. We tested the hypothesis that the cardiometabolic effects of chloroquine are p53-dependent. ApoE-null mice with or without p53 were treated with low-dose chloroquine or saline in the setting of a Western diet. After 8 weeks, there was no p53-dependent or chloroquine-specific effect on serum lipids or body weight. Chloroquine reduced plaque burden in mice wild-type for p53, but it did not decrease lesion extent in p53-null mice. However, chloroquine improved glucose tolerance, enhanced insulin sensitivity, and increased hepatic Akt signaling regardless of the p53 genotype. These results indicate that atheroprotection induced by chloroquine is p53-dependent but the insulin-sensitizing effects of this agent are not. Discrete components of the genotoxic stress response might be targeted to treat lipid-driven disorders, such as diabetes and atherosclerosis.