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Insulin resistance - Top 30 Publications

Association of matrix γ-carboxyglutamic acid protein levels with insulin resistance and Lp(a) in diabetes: A cross-sectional study.

The risk of cardiovascular disease (CVD) and mortality is increased in patients with chronic kidney disease (CKD), with a background role of vascular calcification in the development of CVD also reported. Studies have demonstrated that high lipoprotein(a) (Lp(a)) levels accelerate the development of atherosclerolsis and are potentially involved in the vascular calcification. Matrix Gla Protein (MGP) seems to play an important role in vascular calcification. The aim of the study was to examine the potential association of MGP concentrations with Lp(a) and insulin resistance.

Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study.

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor-1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = -0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis.

Effect of programmed exercise on insulin sensitivity in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials.

We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effect of programmed exercise for at least 12 weeks, in postmenopausal women on insulin sensitivity-related outcomes (ISROs), including fasting insulin, C-peptide, insulin growth factor (IGF-1) and IGF-binding protein (IGFBP-3), Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), and anthropometric variables.

Oral Insulin Delivery in a Physiologic Context.

Insulin remains indispensable to the treatment of diabetes, but its availability in injectable form only has hampered its timely and broader use. The development of an oral insulin remains an ultimate goal to both enhance ease of use, and to provide therapeutic advantages rooted in its direct delivery to the portal vein and liver. By mimicking the physiological path taken by pancreatic insulin, oral insulin is expected to have a distinct effect on the hepatic aspect of carbohydrate metabolism, hepatic insulin resistance, and, at the same time, avoid hyperinsulinemia and minimize the risk of hypoglycemia. With oral insulin approaching late stages of development, the goal of this review is to examine oral insulin in a physiological context and report on recent progress in its development.

A New Optimized Percutaneous Access System for CIPII.

In recent years, continuous intraperitoneal insulin infusion (CIPII) has become a favored treatment alternative for patients with subcutaneous insulin resistance, mainly due to its ability of mimicking physiological conditions of insulin absorption. CIPII has been shown to improve glycemic control as well as to reduce hypoglycemic events and to lead to increased patient satisfaction and quality of life (QoL). Among CIPII delivery systems, Diaport stands out due to its low side effects, its demonstrated clinical efficacy and the potential for integration into closed-loop systems.

Non-alcoholic fatty liver disease: An expanded review.

Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.

Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy.

Activation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy.

Association of keratin 8/18 variants with non-alcoholic fatty liver disease and insulin resistance in Chinese patients: A case-control study.

To test the hypothesis that K8/K18 variants predispose humans to non-alcoholic fatty liver disease (NAFLD) progression and its metabolic phenotypes.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Sex difference of hyperinsulinemia in the C57BL/6J-Daruma (obese) mouse.

The C57BL/6J-Daruma mouse is an animal model of obesity derived from the original genetically obese ICR-Daruma mouse by transfer of the phenotype into the C57BL/6J background by backcrossing into the C57BL/6J strain. Although, like the original ICR-Daruma mouse model, both male and female C57BL/6J-Daruma mice develop obesity, the latter strain shows sex differences in several phenotypes. A sex difference in plasma insulin levels was especially notable in C57BL/6J-Daruma mice; only males showed hyperinsulinemia. Orchiectomy suppressed this hyperinsulinemia completely, whereas testosterone supplementation restored it. Glucose administration increased the plasma glucose level in both male and female Daruma mice to a greater extent than in wild-type control mice. Orchiectomy, but not ovariectomy, decreased the plasma glucose level to that seen in wild-type controls. On the other hand, this effect of orchiectomy was abrogated by testosterone supplementation. The expression of mRNAs for several genes related to insulin resistance was significantly changed in white adipose tissue and liver of C57BL/6J-Daruma mice, especially males, as early as 4 weeks of age. The present results suggest that testosterone may be involved in the hyperinsulinemia shown by male C57BL/6J-Daruma mice and that this strain may be an appropriate animal model for examining the relationship between obesity and sex hormones.

Cardiometabolic Determinants of Carotid and Aortic Distensibility From Childhood to Early Adulthood.

Children who are obese or have familial hypercholesterolemia have stiffer arteries compared with lean, healthy peers. Limited data are, however, available on the association of cardiometabolic risk markers and arterial distensibility in healthy children, particularly in a longitudinal setting. Therefore, we studied in the prospective STRIP (Special Turku Coronary Risk Factor Intervention Project) comprising healthy, predominantly normal weight participants the association of several cardiometabolic and dietary risk markers with arterial distensibility from childhood to early adulthood. Carotid and aortic distensibility (cdist, adist) was assessed repeatedly with ultrasonography at the age of 11, 13, 15, 17, and 19 years in the longitudinal atherosclerosis prevention study (ncdist=420-503, nadist=407-476). Data on cardiometabolic risk markers and diet were available since early childhood. In multivariable analyses, body mass index (β=-0.0019 [SE 0.0085]; P=0.037), systolic blood pressure (β=-0.0025 [SE 0.00065]; P=0.0001), low-density lipoprotein cholesterol (β=-0.026 [SE 0.012]; P=0.034), and homeostasis model of insulin resistance (β=-0.048 [SE 0.018]; P=0.0071) were independently associated with carotid distensibility. Systolic blood pressure (β=-0.0069 [SE 0.00097]; P<0.0001) and low-density lipoprotein cholesterol (β=-0.039 [SE 0.018]; P=0.031) associated independently with aortic distensibility. Dietary variables were not independently associated with arterial distensibility. Participants with low arterial distensibility had higher body mass index (Pcdist=0.0090, Padist=0.098) and higher systolic (Pcdist<0.0001, Padist<0.0001) and diastolic blood pressures (Pcdist<0.0001, Padist=0.0002) already from early childhood. Body mass index, blood pressure, low-density lipoprotein cholesterol, and homeostasis model of insulin resistance identified since childhood associate with arterial distensibility in healthy children and adolescents. These data support the relevance of these factors as part of primordial prevention.

Tau deletion promotes brain insulin resistance.

The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.

Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux.

Obesity promotes the biogenesis of adipose tissue (AT) foam cells (FC), which contribute to AT insulin resistance. Autophagy, an evolutionarily-conserved house-keeping process, was implicated in cellular lipid handling by either feeding and/or degrading lipid-droplets (LDs). We hypothesized that beyond phagocytosis of dead adipocytes, AT-FC biogenesis is supported by the AT microenvironment by regulating autophagy. Non-polarized ("M0") RAW264.7 macrophages exposed to AT conditioned media (AT-CM) exhibited a markedly enhanced LDs biogenesis rate compared to control cells (8.3 Vs 0.3 LDs/cells/h, p<0.005). Autophagic flux was decreased by AT-CM, and fluorescently following autophagosomes over time revealed ~20% decline in new autophagic vesicles' formation rate, and 60-70% decrease in autophagosomal growth rate, without marked alternations in the acidic lysosomal compartment. Suppressing autophagy by either targeting autophagosome formation (pharmacologically, with 3-methyladenine or genetically, with Atg12±Atg7-siRNA), decreased the rate of LD formation induced by oleic acid. Conversely, interfering with late autophago-lysosomal function, either pharmacologically with bafilomycin-A1, chloroquine or leupeptin, enhanced LD formation in macrophages without affecting LD degradation rate. Similarly enhanced LD biogenesis rate was induced by siRNA targeting Lamp-1 or the V-ATPase. Collectively, we propose that secreted products from AT interrupt late autophagosome maturation in macrophages, supporting enhanced LDs biogenesis and AT-FC formation, thereby contributing to AT dysfunction in obesity.

Relationship between simple markers of insulin resistance and coronary artery calcification.

Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information.

Dietary Salba (Salvia hispanica L) improves the altered metabolic fate of glucose and reduces increased collagen deposition in the heart of insulin-resistant rats.

This study reports the effects of dietary Salba (chia) seeds on the mechanisms underlying impaired glucose metabolism in the heart of dyslipemic insulin-resistant rats fed a sucrose-rich diet (SRD). Wistar rats were fed a SRD for 3 months. Afterwards, half the animals continued with the SRD; in the other half's diet chia seeds replaced corn oil (CO) for three months (SRD+chia). In the control group, corn starch replaced sucrose. The replacement of CO by chia seeds in the SRD restored the activities of key enzymes involved in heart glucose metabolism decreasing fatty acid oxidation. Chia seeds normalized insulin stimulated GLUT-4 transporter, the abundance of IRS-1 and pAMPK, changed the profile of fatty acid phospholipids, reduced left-ventricle collagen deposition and normalized hypertension and dyslipidemia. New evidence is provided concerning the effects of dietary chia seeds in improving the altered metabolic fate of glucose in the heart of dyslipemic insulin-resistant rats.

Alterations in vitamin A/retinoic acid homeostasis in diet-induced obesity and insulin resistance.

Vitamin A is an essential micronutrient for life and the phytochemical β-carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator.

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study.

Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood.

Protein-Tyrosine Phosphatase-1B Mediates Sleep Fragmentation-Induced Insulin Resistance and Visceral Adipose Tissue Inflammation in Mice.

Sleep fragmentation (SF) is highly prevalent and has emerged as an important contributing factor to obesity and metabolic syndrome. We hypothesized that SF-induced increases in protein tyrosine phosphatase-1B (PTP-1B) expression and activity underlie increased food intake, inflammation, and leptin and insulin resistance.

Rosiglitazone improves insulin resistance mediated by 10,12 conjugated linoleic acid in a male mouse model of metabolic syndrome.

Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a dietary fatty acid that promotes weight loss and disproportionate fat loss. Obese mice fed a high fat high sucrose (HFHS) diet containing 10,12 CLA are resistant to weight gain and contain markedly reduced subcutaneous fat and adiponectin, with a concurrent lack of improvement in insulin sensitivity despite significant weight loss. Taken together, 10,12 CLA promotes a phenotype resembling PPARγ antagonism. Since thiazolidinediones such as rosiglitazone (Rosi) are used clinically to improve insulin sensitivity by activating PPARγ, with particular efficacy in subcutaneous white adipose tissue, we hypothesized that Rosi would improve glucose metabolism in mice losing weight with 10,12 CLA. Obese Ldlr-/- mice were fed a HFHS control diet, or supplemented with 1% 10,12 CLA with or without Rosi (10 mg/kg) for 8 weeks. Body composition, glucose and insulin tolerance tests, tissue gene expression, and plasma lipid analyses were performed. Mice consuming 10,12 CLA with Rosi lost weight and body fat compared to control groups, but with a healthier redistribution of body fat towards more subcutaneous adipose tissue than with 10,12 CLA alone. Further, Rosi improved 10,12 CLA-mediated insulin resistance parameters and increased plasma and subcutaneous adipose tissue adiponectin levels without adverse effects on plasma or hepatic lipids. We conclude that co-treatment of mice with 10,12 CLA and Rosi promotes fat loss with a healthier fat distribution that leads to improved insulin sensitivity, suggesting that the combination treatment strategy of 10,12 CLA with Rosi could have therapeutic potential for obesity treatment.

Tanshinone I alleviates insulin resistance in type 2 diabetes mellitus rats through IRS-1 pathway.

Tanshinone I from tanshen has been used in traditional Chinese medicine for treating cardiovascular diseases and inflammatory diseases. Given the link between inflammation and Type 2 diabetes mellitus (T2DM), we suspect that tanshinone I may have a beneficial effect on T2DM. This study was to investigate the potential effects of tanshinone I on T2DM and its underlying mechanism. T2DM was thus induced in Sprague-Dawley (SD) rats using streptozotocin (STZ) and high-fat diet. It was observed that T2DM rats had higher levels of total cholesterol (TC), nonesterified fatty acids (NEFAs), total triglyceride (TG) and total low density lipoprotein cholesterol (LDL-C) compared with normal, healthy SD rats. Treatment with tanshinone I decreased these levels and lowered blood glucose level in T2DM rats. In addition, enzyme-linked immunosorbent assay (ELISA) analysis showed that T2DM rats had elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, Western blot analysis revealed that T2DM rats had enhanced nuclear translocation of NF-κB as well as elevated phosphorylation of Ser307 in IRS-1(insulin receptor substrate 1). Treatment by tanshinone I lowered the levels of IL-6 and TNF-α, decreased nuclear translocation of NF-κB as well as phosphorylation of Ser307 in IRS-1. These results demonstrated that tanshinone I could alleviate T2DM syndrome in rats.

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects.

Progranulin as a biomarker and potential therapeutic agent.

Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases.

Iron elevation and adipose tissue remodeling in the epididymal depot of a mouse model of polygenic obesity.

Iron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications. KK/HIJ (KK) mice, a polygenic obese mouse model, have elevated serum iron levels. A subset of KK male mice display a bronzing of epididymal adipose tissue (eAT) associated with >100-fold (p<0.001) higher iron concentration.

Alteration of ghrelin/obestatin ratio in adolescence with polycystic ovarian syndrome.

Ghrelin, an endoggenous for the growth hormone secretagogue receptor, has been shown to participate in the regulation of energy homeostasis and pituitary hormone secretion. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. Ghrelin and obestatin are altered in polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and pituitary hormone secretion disorder. The aim of this study was to evaluate ghrelin/obestatin imbalance in relation to insulin resistance and pituitary hormone in adolescence with PCOS. This restrospective case-control study included 33 adolescence with PCOS and 38 control adolescence. Ghrelin and obestatin concentrations in serum were determined by RIA, and the serum fasting glucose and Insulin were determined by the glucose oxidase color method and INS-EASIA. The serum LH and FSH were measured by highly specific hemiluminescence immunoassays. We found that the serum ghrelin levels and ghrelin/obestatin ratio were significant lower in PCOS group than in control group, and the serum obestatin levels were significant higher in PCOS group than in control group. The ghrelin/obestatin ratios were negatively correlation with LH/FSH ratio and insulin resistant index in PCOS group. The findings of this study suggest that ghrelin/obestatin imbalance may play a role in pathogenesis of adolescent PCOS.

Can the source of hyperandrogenism in adolescents with polycystic ovary syndrome predict metabolic phenotype?

In this study, we demonstrated an association between adrenal hyperandrogenism, as determined by dehydroepiandrostenedione-to-free testosterone (DHEA-S/FT) ratio, and metabolic phenotype in obese and lean adolescents with polycystic ovary syndrome (PCOS). We compared 64 overweight/obese adolescents with PCOS (PCOS-O) with 18 lean (PCOS-L) adolescents. We analyzed the association between DHEA-S/FT ratios and metabolic parameters. Patients in the PCOS-O group were younger (median [interquartile range]) than those in the PCOS-L group (15 [15-17] vs. 16 [16-17] years; p = .04). The median DHEA-S/FT ratio and total testosterone concentrations did not differ. However, androstenedione concentrations were higher in the PCOS-L group (p = .02) and free testosterone levels lower in the PCOS-L group compared with the PCOS-O group (p = .02). Insulin resistance was present in 30 of 64 (46.9%) adolescents with PCOS-O compared with 1 of 18 (5.6%) with PCOS-L (p = .001). A significant negative correlation between DHEA-S/FT ratios and insulin concentrations in PCOS-O (p = .03) and PCOS-L (p = .04) groups was noted. In the PCOS-O group, the DHEA-S/FT ratio was negatively associated with serum triglyceride (p = .03) and total cholesterol concentrations (p = .02). We conclude that in adolescents with PCOS, a higher ratio of adrenal to ovarian androgens, signified by DHEA-S/FT, may be associated with a more favorable metabolic phenotype.

Combined immunotherapy with "anti-insulin resistance" therapy as a novel therapeutic strategy against neurodegenerative diseases.

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid β monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "anti-insulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy.

Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans.

Mucoid structures that coat the epithelium play an essential role in keeping the intestinal microbiota at a safe distance from host cells. Encroachment of bacteria into the normally almost-sterile inner mucus layer has been observed in inflammatory bowel disease and in mouse models of colitis. Moreover, such microbiota encroachment has also been observed in mouse models of metabolic syndrome, which are associated low-grade intestinal inflammation. Hence, we investigated if microbiota encroachment might correlate with indices of metabolic syndrome in humans.

Asymmetric paternal effect on offspring size linked to parent-of-origin expression of an insulin-like growth factor.

Sexual reproduction brings together reproductive partners whose long-term interests often differ, raising the possibility of conflict over their reproductive investment. Males that enhance maternal investment in their offspring gain fitness benefits, even if this compromises future reproductive investment by iteroparous females. When the conflict occurs at a genomic level, it may be uncovered by crossing divergent populations, as a mismatch in the coevolved patterns of paternal manipulation and maternal resistance may generate asymmetric embryonic growth. We report such an asymmetry in reciprocal crosses between populations of the fish Girardinichthys multiradiatus. We also show that a fragment of a gene which can influence embryonic growth (Insulin-Like Growth Factor 2; igf2) exhibits a parent-of-origin methylation pattern, where the maternally inherited igf2 allele has much more 5' cytosine methylation than the paternally inherited allele. Our findings suggest that male manipulation of maternal investment may have evolved in fish, while the parent-of-origin methylation pattern appears to be a potential candidate mechanism modulating this antagonistic coevolution process. However, disruption of other coadaptive processes cannot be ruled out, as these can lead to similar effects as conflict.

Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).

Sirtuins are NAD(+)-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD(+) decline during the aging process, the approach to regulating aging using NAD(+) precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD(+) through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed.

Aging and homeostasis. Aging of skeletal muscle.

With aging, insulin resistance and sarcopenia in skeletal muscle are induced, resulting in skeletal muscle aging. It is suggested that the former is one of the reasons that mitochondrial function decreases with aging, and the latter is due to endocrinologic dysfunction, neurological mechanism, nutritional deficiency and inactivity such as waste are complicatedly involved. Also, as sarcopenia progresses, the amount of physical activity further decreases, and it is also assumed that insulin resistance and sarcopenia progress synergistically. It is suggested that exercise enhances the activity and amount of mitochondria and works preventively against insulin resistance in skeletal muscle accompanying aging and it also works for prevention and amelioration of sarcopenia. On the other hand, as for nutritional supplementation, it has been reported that it works for improving sarcopenia by amino acid ingestion.