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Background: Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). Methods: Studies used various endothelial transgenic and deletion mutant ApoE −/− mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. Results: Enhancing insulin’s actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester ( L -NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE − /− mice. Conclusions: Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.

The sand bodies formed by braided fluvial fan deposits have a certain distinctiveness. They not only have the characteristics of fluvial facies sandbodies but also follow the distribution law of alluvial fan sand bodies. The variation law of sandbodies that are present along and perpendicular to a channel is relatively complex. Therefore, constraints in the modeling process of sand–mudstone facies of this type of reservoir are essential. This study selects the second member of the Shanxi Formation reservoir formed by a braided fluvial fan in the middle of Ordos Basin to perform sand–mudstone facies modeling. First, by studying the lithology and sedimentary structure of the area, the sedimentary characteristics and sand body distribution law of braided river fan are analyzed. Then, the original data points are analyzed, the variation function with high convergence is obtained, and the sand–mud facies model under the constraint of sedimentary facies is established using the random modeling method. Finally, the accuracy of the established random model is tested via single-well thinning, multi-well thinning, and random seed model similarity. The test results confirm that the distribution law of the sand and mudstone in the model is highly similar to that of the actual stratum. And it also conforms to the sedimentary model of braided fluvial fan. The accuracy of the model established by this method is reliable, and the method can be used to predict sand body distribution in areas with low well pattern density.

The particular characteristics of deaf-mutes make them more likely to have mental health problems. Due to their particular way of communication, it is more difficult for them to deal with mental health problems than ordinary people. Nowadays, those psychologists who are good at sign language are in short supply, and remote assistance cannot achieve satisfactory results. Therefore, a library of virtual emotional gestures based on electroencephalogram(EEG) was established and a prototype system for mental health examination of deaf-mutes was proposed, which help deaf-mutes identify their psychological problems in time and assist medical staff to examine the psychological problems encountered by deaf-mutes. In addition, the virtual library of emotional gestures is established with the assistance of the chief physician from a 3A hospital in Henan Province. More importantly, the later experiments demonstrate the applicability of this virtual system.

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by high fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared to their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β and IL-17A exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared to controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes.

The two monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), namely evolocumab and alirocumab, were first approved by the U.S. Food and Drug Administration (FDA) in 2015. PCSK9 inhibitor (PCSK9i) has served as a viable new therapeutic option to lower cholesterol levels and associated cardiovascular events. However, a better understanding of safety issue of PCSK9i is necessarily needed. We present here an increased risk of adverse pregnancy outcomes, including stillbirths and embryonic defects, particularly neural tube defects, following PCSK9i treatment harnessing a high-fat diet-based mouse model. Proteomics of PCSK9i-treated neural stem cells uncovered that PCSK9i may disrupt mitochondrial function via succinic dehydrogenase complex subunit A (SDHA), which is a key enzyme in the mitochondrial respiratory chain. Furthermore, PCSK9i-induced SDHA deficiency combines with high triglyceride to drive the production of reactive oxygen species and subsequent apoptosis during embryonic development, which may account for the occurrence of adverse pregnancy outcomes. Our findings reveal the existence of a hitherto unknown risk of PCSK9i in pregnant women, as well as novel gene-environment interaction.

Lithium–air batteries possess ultrahigh energy density compared to lithium-ion batteries because oxygen is applied as the reacting matter of the cathode without restrictions. However, they cannot b...

Nutritional deficiency is prevalent among the elderly, and it is associated with many adverse health consequences. China is rapidly moving toward an aging society with a large population; however, evidence on the epidemiological trends in nutritional deficiency among the Chinese elderly is limited. Data on the incidence of nutritional deficiency among Chinese adults aged 65 years or above from 1990 to 2019 were extracted from the Global Burden of Disease 2019 database. We used the joinpoint regression method to estimate the average annual percentage change (AAPC) and to describe trend patterns. Age, period, and cohort effects were determined using age–period–cohort models. From 1990 to 2019, the incidence of vitamin A deficiency and iodine deficiency among Chinese older adults decreased from 1784.12 and 8.20 to 304.27 and 7.26 per 100,000, with AAPCs of −0.41 (−0.44, −0.38)% and −5.86 (−6.29, −5.43)%, respectively. A continually increasing trend was seen for incidence rates of protein-energy malnutrition, from 1342.02 to 2275.87 per 100,000 person-years, with an AAPC of 1.70 (1.40, 2.01)%. These trends were more pronounced among men than women. A strong age effect and birth cohort effect were present. Specifically, the population that was older or born later had a lower incidence of deficiencies in vitamin A and iodine but a higher incidence of protein-energy malnutrition. The results show a substantial reduction in vitamin A and iodine deficiencies among the Chinese elderly, and health policies and public awareness are needed to address the burden of protein-energy malnutrition in this population.

The sandstone of the third member of the Funing Formation (E1f3) in the northern slope zone of the Gaoyou Sag has the typical characteristics of high porosity and ultralow permeability, which makes it difficult for oil to flow. In this study, the lithological characteristics, sedimentary facies, diagenetic characteristics, pore structure, and seepage ability of this sandstone are characterized in detail. Correlation analysis is used to reveal the reason for the sandstone high porosity-low permeability phenomenon in the study area. The results indicate that this phenomenon is controlled mainly by the following three factors: 1) the sedimentary environment is the initial affecting factor, whereby the deposition of a large number of fine-grained materials reduces the primary pores of sandstone. 2) The Funing Formation has undergone strong compaction and cementation, which have led to the removal of most of the primary pores and a reduction in size of the throat channels. 3) Owing to fluid activity during the later stage of diagenesis, sandstone underwent intense dissolution and a large number of particles (feldspar and lithic debris) formed many dissolution pores (accounting for nearly 60% of the total pore space). Among these factors, dissolution has contributed the most to the development of high porosity-low permeability phenomenon. This is mainly attributed to the inhomogeneous dissolution process, whereby the degree of particle dissolution (e.g. feldspar) exceeds that of cementing minerals (clay and carbonate minerals). The secondary dissolution pores have increased the porosity of sandstone in the study area; however, the pore connectivity (permeability) has not been significantly improved, thus resulting in the special high porosity-low permeability characteristics of this sandstone.

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2) , were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR) , mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. Thus, these findings show that PKM2 activation in the podocyte can regulate mitochondrial metabolism of the entire glomeruli and prevent mitochondrial dysfunction induced by chronic diabetes and even reverse metabolic memory. PKM2 structures and enzymatic activities are necessary to mediate glomerular metabolism against toxicity of hyperglycemia via paracrine factors such as VEGF. Thus, PKM2 activation in podocyte is a potential therapeutic target to protect against DN. Disclosure J.Fu: None. T.Shinjo: None. Q.Li: None. K.Park: None. M.Yu: None. H.Yokomizo: None. Q.Huang: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of severe diabetic retinopathy (DR) , but significant subset of patients showed inadequate response to anti-VEGF. We have previously reported that retinol binding protein 3 (RBP3) prevented hyperglycemia induced retinal pathologies and progression to severe DR. Hypothesis: RBP3 and Anti-VEGF have differential protective profiles in preventing retinal dysfunctions induced by diabetes. Methods and Results: Recombinant human RBP3 (rhRBP3, 5ug/ml) and anti-VEGF (Avastin, 250mg/ml) inhibited VEGF-induced retinal vascular permeability (RVP) by 70% when intravitreal injections were given together in Lewis rats (P < 0.01) . After 2 months of diabetes induced by streptozotocin (STZ) , intravitreal injection of rhRBP3 and anti-VEGF for 3 days suppressed RVP by 64% and 53% (P < 0.01) in Lewis rats. This was accompanied by reductions of VEGF levels by both proteins. Electroretinogram (ERG) amplitudes of A wave, B wave, C wave were decreased in rats after 2 months of diabetes (P < 0.01) . rhRBP3 increased amplitudes of C wave (P < 0.01) , while anti-VEGF did not improve any waveforms. Furthermore, rhRBP3 decreased retinal mRNA expression of Cd11b and Tnfa (P =0.1) in diabetic rats. In cultured primary bovine Müller cells, rhRBP3 decreased mRNA expressions of Tnfa and Il-6 induced by high glucose (25mM) (P < 0.01) , whereas, anti-VEGF showed no effect. Metabolic function studies using Seahorse assays showed that isolated retina from intravitreal rhRBP3 treated rats exhibited reduced glycolysis rate in ECAR while anti-VEGF treatments had no effects. Conclusions: Both intravitreal anti-VEGF and RBP3 treatments normalized retinal vascular dysfunctions caused by diabetes. However, only RBP3 reversed abnormal neural-retinal dysfunctions and elevated inflammatory cytokines induced by hyperglycemia, possible by decreasing glucose uptake and glycolysis levels in retinal cells. Disclosure Q.Li: None. S.Onizuka: None. K.Park: None. H.Park: None. Q.Li: None. W.Fickweiler: None. J.Fu: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.

This study aimed to investigate the associations between social jetlag (SJL), dietary behavior, physical activity, and weight status in Chinese youth. Data were derived from a cross-sectional survey in Wuhan, China in 2019. Information on SJL, the frequency of food and beverage consumption, physical activity, and BMI category were collected via a self-reported questionnaire. The Kruskal-Wallis test and ANOVA were conducted to determine differences in daily consumption frequency of food and beverage groups, BMI category, and physical activity among SJL groups. Logistic regressions and restricted cubic splines were performed to test the association between SJL and the incidence of overweight or obesity. A final sample of 3567 Chinese adolescents [mean (SD) age, 14.67 (1.72) years; 47.41% (1691) female] were included. Our findings demonstrated that adolescents with SJL may consume more unhealthy foods and fewer beneficial foods, while engaging in less moderate to vigorous physical activity (MVPA) and reporting higher BMIs. In addition, adolescents who experience more than 2 h of SJL had significant greater risk of overweight or obesity. Our findings on SJL of Chinese adolescents confirm the harmful effects of SJL and also provide insights into the etiology of obesity in Chinese adolescents.

This study aimed to investigate the associations between perceived parental control, perceived parental modeling and parent–teen co-decision making, and fruit and vegetable (F&V) and sugar-sweetened beverage and junk food (S&J) consumption among Chinese adolescents, and examine whether self-efficacy mediates the associations. Data were collected in a cross-sectional survey of Chinese adolescents carried out in the fall of 2019. The questionnaires were adapted from the Family Life, Activity, Sun, Health, and Eating (FLASHE) Study. Ordinary least-squares regressions and a path analysis were performed to evaluate the hypothesized associations. The final sample included 3595 Chinese adolescents (mean (SD) age, 14.67 (1.73) years; 52.82% (n = 1899) males). Perceived parental control was positively associated with adolescents’ F&V consumption, and was negatively associated with adolescents’ S&J consumption. Perceived parental modeling and parent–teen co-decision making were both positively associated with adolescents’ F&V consumption and negatively associated with their S&J consumption. Adolescents’ self-efficacy was positively associated with F&V consumption and negatively associated with S&J consumption. These results suggest that serving as a positive role model, having adolescents participate in the decision-making process, and increasing adolescents’ self-efficacy can be feasible and efficacious strategies to improve the nutritional quality of Chinese adolescents’ diets.

Type II diabetes mellitus (T2DM) is a metabolic disorder that occurs in the body because of decreased insulin activity and/or insulin secretion. The incidence of T2DM has rapidly increased over recent decades. The relation between consumption of different types of red meats and risk of T2DM remains uncertain. This meta-analysis was conducted to quantitatively assess the associations of processed red meat (PRM) and unprocessed red meat (URM) consumption with T2DM. We searched PubMed, Embase, Web of Science and The Cochrane Library for English-language cohort studies published before January 2021. Summary relative risks (RR) with 95% confidence interval (CI) were estimated using fixed effects and random effects. Additionally, dose–response relationships were explored using meta-regression. Fifteen studies (n = 682,963 participants, cases = 50,675) were identified. Compared with the lowest intake group, high consumption of PRM and URM increased T2DM risk by 27% (95% CI 1.15–1.40) and 15% (95% CI 1.08–1.23), respectively. These relationships were consistently strongest for U.S-based studies, though the effects of sex are inconclusive. In conclusion, PRM and URM are both positively associated with T2DM incidence, and these relationships are strongest in the U.S. reduction of red meat consumption should be explored as a target for T2DM prevention initiatives.

This study aimed to use path analysis to determine the association between perceived parental attitudes toward restricting junk food (JF)/sugar-sweetened beverage (SSB) intake and JF/SSB consumption among Chinese adolescents, and whether JF/SSB availability in the home environment and autonomous motivation of adolescents mediated the association. A cross-sectional survey was conducted using questionnaires adapted from the Family Life, Activity, Sun, Health, and Eating (FLASHE) Study to collect data on 3819 participants with an average age of 14.7 years (SD = 1.7). Spearman correlations and path analysis were performed. It was found that perceived parental attitudes were not directly associated with adolescents’ JF/SSB consumption frequency, but indirectly related to them through JF/SSB availability in the home environment and autonomous motivation of adolescents. When parents held a less positive attitude toward JF/SSB consumption and kept less JFs/SSBs at home, youth displayed more autonomous motivation for restricting JF/SSB intake and consumed fewer JFs/SSBs.

Background Extensive research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety. The immunomodulating effects of antidepressants on depression have been reported, however, there is no evidence of the similar effects of antidepressants on anxiety. The aim of the study was to investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on peripheral inflammatory cytokines in patients with first episode generalized anxiety disorder (GAD). Methods A prospective cohort design was employed: 42 patients with first episode GAD were treated with either escitalopram or sertraline for 12 weeks. Anxiety was measured by the Generalized Anxiety Disorder Scale and the State Trait Anxiety Inventory, serum pro-inflammatory cytokine levels were measured by the enzyme-linked immunosorbent assay (ELISA), and CRP determined by an immunoturbidimetric method before and after SSRIs treatment Results Baseline levels of anxiety and pro-inflammatory cytokines including IL-1α, IL-6, IL-8, IL-12, IFN-γ, and CRP were significantly reduced after treatment of SSRIs (p

Hyperglycemia has been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the effects of the autoantibody on atherosclerosis and immunogenic trigger are not well understood in T1D. Using the generated several mice models of atherosclerosis including NOD, congenic ApoE-/-/NOD (NDM and no- autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, NDM) and ApoE-/-/NOD autoimmune DM mice, we analyzed immune cells composition of aorta and have observed the increasing numbers of CD3+(CD3+/CD25-), Th1 and Th17 subset of T cells and B cells and decreased Treg (CD3+/CD25+/Foxp3+) in the ApoE-/-/NOD and ApoE-/-/NOD-DM mice vs. control. In addition, we postulate that the identification of specific autoantibody(s) which induce dysregulaton of T-cells, resulting in enhancing its infiltration and accumulation at the plaques could aid new immunotherapies for atherosclerosis. Here we performed autoantigen microarrays to profile and identify specific autoantibodies, enhancing the severe atherosclerosis in subgroups of Medalist patients with chronic duration of T1D due to autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and compared to the people with monogenic diabetes lacking HLA DR3/4 risk alleles for T1D and autoantibodies. Autoantigen microarrays from the plasma of T1D patients with positive DR3/4 risk and CVD identified 8 autoantibodies changed in the context of atherosclerosis, compared to the people with monogenic diabetes. To confirm the autoantibody profiling data from the patients, we analyzed the autoantibody profiles in the T1D mice models of atherosclerosis described above. Autoantigen microarrays analysis of the plasma of T1D patients and mice showed several common findings that reached significance anti-Nucleolin Ab, p=0.005. These findings indicate autoimmunity may contribute to the progression of atherosclerosis in T1D. Further studies are in progress to replicate these findings in other cohorts of T1D. Disclosure K. Park: None. Q. Li: None. H. Park: None. J. Fu: None. S. Kissler: None. E. Maddaloni: Research Support; Self; European Foundation for the Study of Diabetes, Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck KGaA. I. Wu: None. A. H. Lichtman: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding DK036836, DK036836, EY026080

Risks of unstable arterial plaques are increased in diabetes or insulin resistance. We hypothesized that insulin resistance in VSMCs contributes to reduced plaque stability since we have reported that insulin receptors (IR) on VSMCs are potent regulators of its proliferation and apoptosis. Further, insulin induced Akt phosphorylation was decreased in the aorta of diabetic mice. Lipid deposition were increased in the aortas of ApoE-/- and VSMCs IR double knockout (SMIRKO/ApoE-/-) mice vs. control mice. Pathological analysis of the atherosclerotic plaques of SMIRKO/ApoE-/- mice demonstrated features of unstable plaques, including reduced VSMCs proliferation and reduced cap thickness and collagen, but increased VSMCs apoptosis and more macrophages and necrosis area. VSMCs from SMIRKO/ApoE-/- mice exhibited less insulin induced proliferation and more apoptosis which were not inhibited by insulin compared to VSMCs from ApoE-/- mice. Artery relaxation induced by sodium nitroprusside (SNP) (NO donor) was impaired in artery from SMIRKO/ApoE-/- mice vs. control mice. Insulin and SNP induced VASP phosphorylation, a downstream signaling protein of NO in VSMCs, were reduced in SMIRKO/ApoE-/- mice vs. control mice. Expressions of MMP2, THBS1, sFRP3, and COMP were increased in the aorta of SMIRKO/ApoE-/- mice vs. ApoE-/- mice, which were also observed in the aorta of diabetic mice fed with high fat diet or diabetes induced by STZ. Insulin induced Akt and Foxo1 phosphorylation were impaired in cultured VSMCs from SMIRKO/ApoE-/- mice vs. control mice. Overexpression of constitutively activated Akt increased VASP phosphorylation and downregulated THBS1 expression in cultured VSMCs, whereas overexpression of FoxO1 increased THBS1 expression. This is the first report that selective inhibition of IR activation of pAkt in VSMCs is partially causing the elevated risk of unstable atherosclerotic plaques found in insulin resistance or diabetes. Disclosure Q. Li: None. J. Fu: None. K. Park: None. I. Wu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105)

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2), were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. After 7 months of STZ induced diabetes, mice with PKM2 specific overexpression in podocytes (PPKM2Tg) with podocin promoter, exhibited lower albumin-creatinine ratio (ACR), kidney-body weight ratio, mesangial expansion, basement membrane thickness and podocyte foot process effacement vs. WT diabetic littermates. PPKM2Tg mice exhibited lower expression of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes and improvement in endothelial function with increased eNOS and VEGF expressions in the glomeruli, compared to diabetic WT mice. Glycolytic and mitochondrial metabolisms as measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using Seahorse showed striking improvement of impaired mitochondrial maximal respiration capacity and glycolytic rate in isolated glomeruli of diabetic PPKM2Tg mice, in concordance with elevated expressions of mitochondrial related-genes, such as PGC1α. Knocking-down PKM by shRNA in podocyte cell line (pPKMKD) replicated metabolic findings induced by diabetes with dramatic decline of both OCR and glycolytic rate. Re-expressing human PKM1 or PKM2 in pPKMKD cell line reversed impaired mitochondrial function and glycolysis, which were not improved in pPKMKD cells re-expressing with enzymatically inactive human PKM2 gene. These results indicate that PKM2 and its enzymatical function are both necessary in podocytes to improve glomerular mitochondrial abnormalities and delay the progression of DN. Disclosure J. Fu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. T. Shinjo: None. Q. Li: None. R. St-louis: None. K. Park: None. H. Yokomizo: None. M. Yu: None. H. Shah: None. I. Wu: None. Funding Iacocca Family Foundation

Background Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. Scope of review In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. Major conclusions Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes., Highlights • Insulin's actions in vascular cells have a significant influence on systemic metabolism. • Insulin exerts its vascular effects through its receptors and signaling cascades. • Inhibition or enhancement of different insulin signaling leads to selective insulin resistance. • Loss of insulin's actions causes endothelial dysfunction and vascular complications in diabetes.

The goal of this study was to investigate the associations of midday nap duration and change in midday nap duration with hypertension in a retrospective cohort using a nationwide representative sample of middle-aged and older Chinese adults. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS) database during 2011–2015. Information on midday nap duration was collected via a self-reported questionnaire and blood pressure was objectively measured. Hazard ratios (HR) with 95% confidence interval (CI) were estimated using Cox proportional hazards regression models to quantify the associations. A sample of 5729 Chinese adults (≥45 years old) were included in the longitudinal analysis. Relative to non-nappers, participants who napping for ≥90 min/day was associated with significantly larger HR for hypertension at four-year follow-up (HR = 1.18, 95% CI = 1.01–1.40, p = 0.048). Compared with people who napped ≥90 min/day both at baseline (2011) and follow-up (2013), hypertension risk at four-year follow-up declined in individuals whose midday nap durations decreased in the 2-year study period from ≥ 90 min/day to 1–59 min/day (HR = 0.59, 95% CI = 0.36–0.97, p = 0.037) and 60–89 min/day (HR = 0.68, 95% CI = 0.47–0.99, p = 0.044). Among middle-aged and older Chinese adults, relative to non-nappers, people who had longer midday nap duration (≥90 min/day) were associated with significantly larger HR for hypertension and decreased napping duration may confer benefit for hypertension prevention.

This study examined the cross-sectional and longitudinal association of sleep timing with weight status in 14- to 19-year-old adolescents in Wuhan, China. A prospective school-based study was conducted in Wuhan, China between 28 May and 29 September 2019. Data on sociodemographic information, academic performance, diet, mental health status, physical activity, sleep characteristics, body weight, and height were collected. A linear regression model and binary logistic regression model were performed. A total of 1194 adolescents were included in the analysis. Adolescents who woke up before 05:45 had higher body mass index (BMI) Z-score (odds ratio (OR) with 95% confidence interval (CI) = 1.28 (1.05, 1.57), p = 0.02) and higher odds of overweight/obesity (odds ratio (OR) with 95% confidence interval (CI) = 1.74 (1.10, 2.76), p = 0.02) at baseline after fully adjustment for covariates, compared with those who woke up after 05:45. Longitudinal data showed a nonsignificant association between waking up time and change in BMI Z-score (p = 0.18). No association of bedtime with weight status was observed in this sample after full adjustment (p &gt, 0.1). Earlier waking up time might contribute to overweight and obesity in adolescents, however, more data are needed to test and elucidate this relationship.

This study examined the independent associations between psychosocial factors, perceived neighborhood characteristics, and physical activity (PA) in Chinese adolescents. A cross-sectional study using a convenience sample was conducted in fall 2019 at a high school in Wuhan, China. Sociodemographic data, body weight, height, psychosocial factors, perceptions of neighborhood environment, and PA were collected using questionnaires. Hierarchical linear regression analyses were performed in 4 steps, where step 1 included demographic covariates, step 2 added psychosocial factors into the model, step 3 added perceived neighborhood environmental factors, and step 4 added interaction terms between significant psychosocial and environmental factors. A total of 4027 adolescents were included in analysis. The results of the third model indicated that friends’ support (b = 4.58), friends’ norms (b = 7.16), barriers to PA (b = −10.19), autonomous motivation (b = 4.75), self-efficacy (b = 8.86), the presence of shops/stores nearby (b = 5.79), and the availability of PA resources (b = 6.02) were significant predictors (P

Vascular smooth muscle cells (VSMCs) play an important role in the development of the stability of atherosclerotic plaque. We reported that knockout of insulin receptor (IR), but not IGF1 receptor, in VSMCs reduced intimal hyperplasia of femoral artery after wire injury. To investigate the role of IR in VSMCs on atherosclerotic plaque, ApoE and smooth muscle cells IR double knockout (SMIRKO/ApoE-/-) mice were generated. Extent of lipid deposition and atherosclerosis were increased in the aorta of SMIRKO/ApoE-/- mice compared to control mice (p Disclosure Q. Li: None. J. Fu: None. K. Park: None. Y. Zaitsu: Employee; Self; Sunstar Group. R. St-Louis: None. C. Rask-Madsen: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105)

Mitochondrial abnormalities induced by diabetes have been postulated to cause several complications including nephropathy. Elevated expressions of enzymes for glycolysis and mitochondrial functions in the glomeruli have been associated with protection against the development of diabetic nephropathy of chronic duration. Activation of a glycolytic enzyme, pyruvate kinase M2 (PKM2), by a small molecule selective activator (TEPP-46) or its targeted overexpression to the podocytes in mice reversed glomerular mitochondrial dysfunction and pathology in insulin deficient diabetic mice. However, the effects of PKM2 activation to stop glomerular dysfunction and pathology have not been studied in animal models of type 2 diabetes (T2D). Thus, we studied the effect of activating glycolysis and mitochondrial metabolism with PKM2 activator, TEPP-46, in db/db mice (with obesity and hyperglycemia) and BLKS mice on regular diet (RD) or high fat diet (HFD). HFD feeding induced obesity in BLKS but did not cause changes in glomerular PKM activities or functions as measured by urinary albumin to creatinine ratio (ACR). Oral feeding with TEPP-46 did not affect body weight (BW), glucose tolerance, lipids, ACR, glomerular pathology in BLKS mice on RD or HFD. In contrast, db/db mice on RD had elevated BW and hyperglycemia that were significantly increased by HFD, which also induced loss of glomerular PKM2 protein expression and activities, elevations of gene expression for fibrosis (fibronectin, TGF-b), mesangial expansion and ACR after 3 months. Intervention with oral TEPP-46 treatment for 3 months, but not 1 month, after 3 months of diabetes and HFD, (total of 6 months of diabetes), improved significantly both glomerular PK activities and ACR, without lowering hyperglycemia and hyperlipidemia of the db/db mice. These findings support the idea that systemic activation of PKM2 can improve renal functions in both T1D and T2D. Disclosure R. St-Louis: None. J. Fu: None. K. Park: None. T. Shinjo: None. J. Ludeke: None. H. Yokomizo: None. Q. Li: None. E. Wolfson: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Diabetic nephropathy (DN) is the result of systemic and local changes in metabolism and hemodynamics. We have found that the elevation of glycolytic enzymes, such as pyruvate kinase M2 (PKM2) in the renal glomeruli is correlated with preservation of renal function in human type 1 and type 2 diabetes. A small-molecule PKM2 activator, TEPP46, prevented or reversed glomerular pathology in diabetic mice of chronic duration. Mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated, which after 7 months of diabetes induced by streptozotocin, exhibited significantly lower albumin-creatinine ratio (ACR), kidney weight-body weight ratio, and glomeruli pathology such as reduced glomeruli size, mesangial expansion, and basement membrane thickness compared to diabetic WT mice. Furthermore, the glomeruli of diabetic PPKM2Tg mice exhibited lower expressions of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes compared to WT diabetic mice. Interestingly, the decreased expression of endothelial-trophic genes and mitochondrial-related genes were improved in the whole glomeruli of diabetic PPKM2Tg mice. Oxygen consumption rate (OCR) of glomeruli as measured by Seahorse showed significant improvement in diabetic PPKM2Tg mice versus WT mice (p < 0.05). In vitro studies showed that the activation of PKM2 in mouse podocyte cell line by TEPP-46 decreased high glucose-induced ROS production, improved mitochondrial membrane potential (MMP) by increased the level of mitochondrial OCR and enhanced glycolytic rate. Furthermore, PKM-knockdown stable podocyte cell line, mimicking diabetic conditions, showed dramatical decline of OCR and glycolytic rate. These results showed that PKM2 specific overexpression in podocytes can significantly reduce diabetes-induced mitochondrial abnormalities and oxidative stress in the whole glomeruli, and delay the progression of diabetic nephropathy. Disclosure J. Fu: None. T. Shinjo: None. R. St-Louis: None. Q. Li: None. K. Park: None. H. Yokomizo: None. Y. Zaitsu: Employee; Self; Sunstar Group. M. Yu: None. I. Wu: None. H. Shah: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Hyperglycemia, hyperlipidemia and hypertension have been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the impact of autoimmunity in T1DM on CVD has not been determined. We have generated several mice models of atherosclerosis including ApoE-/-/NOD, ApoE-/-/NOD (congenic non diabetes and non-autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, nondiabetes) and ApoE-/-/NOD autoimmune diabetic mice. All groups of mice have high plasma lipids but only ApoE-/-/NOD diabetic mice had hyperglycemia. However, ApoE-/-/NOD (insulitis and nondiabetes) and ApoE-/-/NOD (insulitis and diabetes) had high titers of autoantibodies to IA2 compared to control CongApoE-/-/NOD mice or nondiabetic ApoE-/-/NOD mice (P Disclosure K. Park: None. Q. Li: None. H. Park: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. H. Yokomizo: None. S. Kissler: None. A.H. Lichtman: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK053105); Thomas J. Beatson, Jr. Foundation