Aggravate Insulin Resistance Research Articles

Association between periodontal disease and gestational diabetes: Systematic review and meta-analysis

AimPeriodontal disease (PD) can aggravate insulin resistance during pregnancy and trigger the development of gestational diabetes mellitus (GDM). MethodsA systematic review and meta-analysis was carried out. Two researchers carried out a literature search using internet databases. Studies that met the inclusion criteria were selected. OR was used as the measure of association. The fixed effects model was applied, and due to the presence of heterogeneity, the DerSimonian and Laird random effects model was applied. The level of significance was p < 0.05. The presence of biases was assessed using the Egger test and the funnel plot. ResultsOf the 176 articles found, 11 were included. 2032 pregnant women were analyzed, of which 572 developed GDM. It was found that PD was a risk factor for developing GDM when all studies were assessed (OR=1.83 95 % CI 1.25–2.69, p < 0.0017) and when analyzing only those that included an adjusted OR (OR= 1.83 95 % CI 1.31–2.56, p < 0.004). ConclusionsPD poses a high risk of suffering from GDM. The development of oral health programs in women who wish to conceive is essential to improve metabolic control and reduce obstetric and perinatal complications.

Trans, trans-2,4-decadienal, a lipid peroxidation product, aggravates insulin resistance in obese mice by promoting adipose inflammation.

Peroxidation of polyunsaturated fatty acids results in the creation of numerous α, β-unsaturated aldehydes, many of which are complicated by the development of diabetes. Trans, trans-2,4-decadienal (DDE) is a dietary α, β-unsaturated aldehyde that is commonly found in food and the environment. However, it is unknown whether DDE exposure has some negative effects on glucose homeostasis and insulin sensitivity. This study investigated the biological effects of long-term DDE exposure in normal chow diet (NCD)-fed non-obese mice and high-fat diet (HFD)-fed obese mice. Results showed that oral administration of DDE for 14 weeks did not cause severe toxicity in NCD-fed non-obese mice but had significant adverse effects in HFD-fed obese mice. It was found that DDE exposure caused significant increases in LDL and ALT levels and aggravated glucose intolerance and insulin resistance in obese mice. Moreover, DDE robustly accumulated in adipose tissue and promoted the impairment of the insulin signaling pathway in the adipose tissue of obese mice while not affecting the skeletal muscle or liver. Mechanistically, DDE aggravated adipose tissue inflammation by promoting M1 macrophage accumulation and increasing proinflammatory cytokines in the adipocytes of obese mice, thus leading to impaired systemic insulin resistance. These findings provide crucial insights into the potential health impacts of long-term DDE exposure.

Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Alleviative effects of the parthenolide derivative ACT001 on insulin resistance induced by sodium propionate combined with a high-fat diet and its potential mechanisms

The increasing side effects of traditional medications used to treat type II diabetes have made research into the development of safer and more effective natural medications necessary. ACT001, a derivative of parthenolide, has been shown to have good anti-inflammatory and antitumor effects; however, its role in diabetes is unclear. The short-chain fatty acid propionate is a common food preservative that has been found to cause disturbances in glucose metabolism in mice and humans. This study aimed to investigate whether sodium propionate could aggravate insulin resistance in obese mice and cause diabetes and to study the alleviative effects and potential mechanisms of action of ACT001 on insulin resistance in diabetic mice. Type II diabetic mice were adminietered sodium propionate combined with a high-fat diet (HFD + propionate) by gavage daily for four weeks. Biochemical analysis showed that ACT001 significantly affected blood glucose concentration in diabetic mice, mainly by downregulating the expression of phosphoenolpyruvate carboxykinase 2 and glucose-6-phosphatase. Meanwhile, the level of fatty acid-binding protein 4 in the liver was significantly decreased. ACT001 has a protective effect on the liver and adipose tissue of mice. In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.

Increased glycemic variability results in abnormal differentiation of T cell subpopulation in type 2 diabetes patients

AimsWe aimed to investigate the association between glycemic variability (GV) and the abnormal differentiation of T-cell subpopulations in patients with type 2 diabetes mellitus (T2DM). MethodsIn total, 108 hospitalized patients with T2DM were enrolled and divided into two subgroups (normal glycemic excursion (NGE) and high glycemic excursion (HGE)) according to their mean amplitude of glycemic excursion (MAGE) level. The MAGE was evaluated via continuous glucose monitoring for 72 h consecutively. Flow cytometry was used to determine the proportions of T cell subpopulations. ResultsThe T helper (Th) 1 cell/Th2 cell ratio was significantly higher, and the proportion of regulatory T cells (Tregs) was significantly lower in the NGE group than in the HGE group (all P < 0.05). After fully adjusting for confounders, the MAGE was positively associated with the Th1 cell/Th2 cell ratio (β = 0.370; P = 0.009) and negatively associated with the proportion of Tregs (β = −0.554; P = 0.001). ConclusionThe MAGE was an independent risk factor for abnormally high Th1 cell/Th2 cell ratio and proportion of Tregs. Abnormal differentiation of T cell subpopulations induced by GV may impair β-cell function, aggravate insulin resistance, and contribute to the development of diabetic complications.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Approach to Fatty Liver Disease in Patients with Type 2 Diabetes

Type 2 diabetes is a major risk factor for development and progression of non-alcoholic fatty liver disease (NAFLD). Fatty liver is prevalent in people with type 2 diabetes, and overweight or obesity in these patients aggravates insulin resistance and steatohepatitis, which appear to be drivers for the disease progression. The goal of screening is not to identify steatosis itself, but rather to identify patients at risk for adverse hepatic outcomes such as cirrhosis, hepatocellular carcinoma, and death from liver disease. The most important risk factors for disease progression are liver fibrosis and its severity. There is a consensus that the FIB-4 (fibrosis-4 index) is the most cost-effective strategy for initial screening of hepatic fibrosis in a clinical setting. At present, there are no approved drugs for the treatment of NAFLD. Clinically significant improvements in NAFLD are achieved with weight loss. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter 2 (SGLT2) inhibitors are effective for inducing weight loss in patients with type 2 diabetes, and some GLP-1 RAs and SGLT2 inhibitors have been shown to be effective for treating steatohepatitis. Therefore, GLP-1 RAs and SGLT2 inhibitors should be considered when choosing antidiabetic agents in patients with type 2 diabetes and NAFLD, especially in those who are overweight or obese.

Effect of Intestinal Flora on Hyperuricemia-Induced Chronic Kidney Injury in Type 2 Diabetic Patients and the Therapeutic Mechanism of New Anti-Diabetic Prescription Medications.

This article examined the current research on hyperuricemia (HUA) exacerbating diabetic kidney damage and novel anti-diabetic medications for treating these people. Hyperuricemia and type 2 diabetes (T2D), both of which are frequent metabolic disorders, are closely connected. Recent studies have shown that hyperuricemia can increase kidney injury in T2D patients by aggravating insulin resistance, by activating the renin-angiotensin-aldosterone system (RAAS), and by stimulating inflammatory factors, and the diversity, distribution, and metabolites of intestinal flora. Considering this, there are just a few of the research examining the effect of hyperuricemia on diabetic kidney injury via intestinal flora. Through the gut-kidney axis, intestinal flora primarily influences renal function. The primary mechanism is that variations in diversity, distribution, and metabolites of intestinal flora led to alterations in metabolites (such as short-chain fatty acids, Indoxyl sulfate and p-cresol sulfate, Trimethylamine N-oxide TMAO). This article reviewed the research and investigates the association between hyperuricemia and T2D, as well as the influence of hyperuricemia on diabetic kidney injury via intestinal flora. In addition, the current novel antidiabetic drugs are discussed, and their characteristics and mechanisms of action are reviewed. These novel antidiabetic drugs include SGLT2 inhibitors, GLP-1 receptor agonists, DDP-4 inhibitors, glucokinase (GK) enzyme activators (GK agonists), and mineralocorticoid receptor antagonists (MRA). Recent studies suggest that these new anti-diabetic medications may have a therapeutic effect on hyperuricemia-induced kidney impairment in diabetes patients via various mechanisms. Some of these medications may reduce blood uric acid levels, while others may improve kidney function by attenuating the overstimulation of RAAS or by decreasing insulin resistance and inflammation in the kidneys. These novel antidiabetic medicines may have a multifaceted approach to treating hyperuricemia-induced kidney impairment in diabetic patients; nevertheless, additional study is required to establish their efficacy and comprehend their specific mechanisms.

Physical inactivity induces insulin resistance in plantaris muscle through protein tyrosine phosphatase 1B activation in mice.

Inactivity causes insulin resistance in skeletal muscle and exacerbates various lifestyle-related diseases. We previously found that 24-h hindlimb cast immobilization (HCI) of the predominantly slow-twitch soleus muscle increased intramyocellular diacylglycerol (IMDG) and insulin resistance by activation of lipin1, and HCI after a high-fat diet (HFD) further aggravated insulin resistance. Here, we investigated the effects of HCI on the fast-twitch-predominant plantaris muscle. HCI reduced the insulin sensitivity of plantaris muscle by approximately 30%, and HCI following HFD dramatically reduced insulin sensitivity by approximately 70% without significant changes in the amount of IMDG. Insulin-stimulated phosphorylation levels of insulin receptor (IR), IR substrate-1, and Akt were reduced in parallel with the decrease in insulin sensitivity. Furthermore, tyrosine phosphatase 1B (PTP1B), a protein known to inhibit insulin action by dephosphorylating IR, was activated, and PTP1B inhibition canceled HCI-induced insulin resistance. In conclusion, HCI causes insulin resistance in the fast-twitch-predominant plantaris muscle as well as in the slow-twitch-predominant soleus muscle, and HFD potentiates these effects in both muscle types. However, the mechanism differed between soleus and plantaris muscles, since insulin resistance was mediated by the PTP1B inhibition at IR in plantaris muscle.

PP1γ regulates neuronal insulin signaling and aggravates insulin resistance leading to AD-like phenotypes

BackgroundPP1γ is one of the isoforms of catalytic subunit of a Ser/Thr phosphatase PP1. The role of PP1γ in cellular regulation is largely unknown. The present study investigated the role of PP1γ in regulating neuronal insulin signaling and insulin resistance in neuronal cells. PP1 was inhibited in mouse neuroblastoma cells (N2a) and human neuroblastoma cells (SH-SY5Y). The expression of PP1α and PP1γ was determined in insulin resistant N2a, SH-SY5Y cells and in high-fat-diet-fed-diabetic mice whole-brain-lysates. PP1α and PP1γ were silenced by siRNA in N2a and SH-SY5Y cells and effect was tested on AKT isoforms, AS160 and GSK3 isoforms using western immunoblot, GLUT4 translocation by confocal microscopy and glucose uptake by fluorescence-based assay.ResultsResults showed that, in one hand PP1γ, and not PP1α, regulates neuronal insulin signaling and insulin resistance by regulating phosphorylation of AKT2 via AKT2-AS160-GLUT4 axis. On the other hand, PP1γ regulates phosphorylation of GSK3β via AKT2 while phosphorylation of GSK3α via MLK3. Imbalance in this regulation results into AD-like phenotype.ConclusionPP1γ acts as a linker, regulating two pathophysiological conditions, neuronal insulin resistance and AD.9kZE1HTKkUH8PMrXCf3pWdVideo

PTEN, MMP2, and NF-κB and Regulating MicroRNA-181 Aggravate Insulin Resistance and Progression of Diabetic Nephropathy: A Case-Control Study

Diabetic nephropathy (DN) is characterized by an increase in urinary albumin excretion, diabetic glomerular lesions, and a decline in glomerular filtration rate (GFR). We assessed the expression of phosphatase and tensin homolog (PTEN), nuclear factor kappa-β (NF-κB), matrix metalloproteinase-2 (MMP2), and microRNA-181 in healthy controls (HC), individuals with type 2 diabetes mellitus (T2DM) without nephropathy, and those with DN. Our study investigated the association between these genes, insulin resistance (IR), and eGFR to gain insight into their roles in the pathogenesis and progression of DN. Anthropometric measurements and biochemical tests were conducted on HC (N = 36), T2DM (N = 38) patients, and DN (N = 35) patients. We used real-time polymerase chain reaction (RT-PCR) for whole blood gene expression analysis and performed bioinformatics analyses, including protein–protein interaction, gene ontology, and co-expression networks. We compared our expression data with other GEO-Microarray datasets. Our study highlights the role of IR in the progression of nephropathy in T2DM via the PTEN-Akt-mTOR signalling pathway. We also observed a decreasing trend in the expression of MMP2 and PTEN and an increasing trend in the expression of NF-κB and miR-181b-5p with the progression of nephropathy to the severe stage. The dysregulated expression of MMP2, PTEN, NF-κB, and miR-181b-5p in patients with T2DM contributes to the progression of T2DM to DN by aggravating IR, inflammation, accelerating basement membrane thickening, mesangial matrix expansion, and renal fibrosis.

Gryllus bimaculatus-containing diets protect against dexamethasone-induced muscle atrophy, but not high-fat diet-induced obesity.

Sarcopenia and obesity are emerging as major social problems. In this study, we examined whether Gryllus bimaculatus (GB), an edible insect, prevents dexamethasone-induced muscle atrophy (sarcopenia) or high-fat diet (HFD)-induced obesity in mice. We generated a standard chow diet (SCD) + GB (85% SCD and 15% GB powder) and HFD + GB (85% HFD and 15% GB powder). SCD + GB feeding increased gains in body weight and white adipose tissue (WAT). Despite no difference in weight change between HFD + GB- and HFD-fed mice, HFD + GB feeding aggravated insulin resistance compared with HFD feeding. SCD + GB or HFD + GB feeding did not change most gene expressions in the liver and WAT but did increase MyHC1 expression in the muscle, meaning that GB increased muscle generation. Therefore, we fed SCD + GB with dexamethasone, which induces muscle degeneration. As a result, muscle fiber size increased, as did grip strength compared with dexamethasone-injected mice. In addition, SCD + GB reduced the expression of muscle degradation factors, such as atrogin1 and muscle RING-finger protein 1 (MuRF1). Furthermore, SCD + GB feeding increased Akt, mTOR, and p70S6K phosphorylation and MyHC1 expression, meaning that it may have increased protein synthesis. In conclusion, GB has great potential for inhibiting dexamethasone-induced muscle mass loss by increasing muscle protein synthesis and inhibiting muscle protein degradation.

Plasma microRNA expression profiles associated with zinc exposure and type 2 diabetes mellitus: Exploring potential role of miR-144-3p in zinc-induced insulin resistance

Zinc exposure has been linked with disordered glucose metabolism and type 2 diabetes mellitus (T2DM) development. However, the underlying mechanism remains unclear. We conducted population-based studies and in vitro experiments to explore potential role of microRNAs (miRNAs) in zinc-related hyperglycemia and T2DM. In the discovery stage, we identified plasma miRNAs expression profile for zinc exposure based on 87 community residents from the Wuhan-Zhuhai cohort through next-generation sequencing. MiRNAs profiling for T2DM was also performed among 9 pairs newly diagnosed T2DM-healthy controls. In the validating stage, plasma miRNA related to both of zinc exposure and T2DM among the discovery population was measured by qRT-PCR in 161 general individuals derived from the same cohort. Furthermore, zinc treated HepG2 cells with mimic or inhibitor were used to verify the regulating role of miR-144-3p. Based on the discovery and validating populations, we observed that miR-144-3p was positively associated with urinary zinc, hyperglycemia, and risk of T2DM. In vitro experiments confirmed that zinc-induced increase in miR-144-3p expression suppressed the target gene Nrf2 and downstream antioxidant enzymes, and aggravated insulin resistance. Our findings provided a novel clue for mechanism underlying zinc-induced glucose dysmetabolism and T2DM development, emphasizing the important role of miR-144-3p dysregulation.

C1q and Tumor Necrosis Factor Related Protein 9 Protects from Diabetic Cardiomyopathy by Alleviating Cardiac Insulin Resistance and Inflammation.

(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target.

Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice.

Chronic unpredictable mild stress (CUMS) has been shown to exacerbate atherosclerosis, but the underlying mechanism remains unknown. Adipose tissue is an energy storage organ and the largest endocrine organ in the human body, playing a key role in the development of cardiovascular disease. In this research, it was hypothesized that CUMS may exacerbate the development of atherosclerosis by inducing the hypertrophy and dysfunction of white adipocytes. The CUMS-induced atherosclerosis model was developed in Western diet-fed apolipoprotein E (ApoE)-/- mice. White adipose tissue (WAT), serum, aortic root, and the brachiocephalic trunk were collected and tested after 12 weeks of CUMS development. The mouse model of CUMS was evaluated for depression-like behavior using the open field test (OFT) and the elevated plus maze (EPM) test. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect serum noradrenaline and urine adrenaline protein levels. Serological assays were used to detect serum low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and free fatty acid (FFA) concentrations. Hematoxylin and eosin (H&E) staining and oil red O were used to detect atherosclerotic plaque area, lipid deposition, and adipocyte size. The mRNA levels of genes related to aberrant adipose tissue function were determined using real-time PCR. Immunofluorescence assay and western blotting were conducted to examine the expression of proteins in the adipose tissue samples. CUMS aggravated vascular atherosclerotic lesions in ApoE-/- mice. It decreased body weight while increasing the percentage of WAT. The serological results indicated that the concentration of HDL decreased in CUMS mice. Notably, adipocyte hypertrophy increased, whereas the mRNA levels of Pparg and its target genes (Slc2a4 (encodes for GLUT4), Adipoq, and Plin1) decreased. Further investigation revealed that CUMS increased subcutaneous inguinal WAT (iWAT) lipid synthesis and adipocyte inflammation while decreasing lipid hydrolysis and the expression of HDL-associated protein ApoA-I. Moreover, CUMS aggravated insulin resistance in mice and inhibited the insulin pathway in iWAT. These findings indicated that CUMS induces adipose tissue dysfunction via a mechanism that leads to dyslipidemia, increased inflammation, and insulin resistance in the body, thereby exacerbating atherosclerosis. Notably, CUMS that is involved in decreasing the expression of HDL-associated proteins in adipose tissue may be a crucial link between adipose hypertrophy and advanced atherosclerosis. This study reveals a novel mechanism via which CUMS exacerbates atherosclerosis from the novel perspective of abnormal adipose function and identifies a novel potential therapeutic target for this disease.

High-fat diet and palmitate inhibits FNDC5 expression via AMPK-Zfp57 pathway in mouse muscle cells

Irisin, a muscle-secreted cytokine involved in maintaining glucose homeostasis and improving insulin resistance, is generated from the precursor fibronectin type Ⅲ domain-containing protein 5 (FNDC5) by specific proteases. Zinc-finger protein Zfp57, a transcription factor that maintains the methylation during early embryonic development, is also reported to be associated with diabetes mellitus. However, the association between Zfp57 and FNDC5 is still unclear. In our study, we explored the detailed regulatory effect of Zfp57 on FNDC5 expression. In this study, we found that high-fat diet or saturated fatty acid palmitate increased the Zfp57 expression and decreased FNDC5 expression in muscle tissue or C2C12 myotubes. RNA sequencing analysis disclosed effects of the high-fat diet on genes associated with insulin resistance and the AMP-activated protein kinase (AMPK) signaling pathway in muscle tissue of mice. Chromatin immunoprecipitation experiments revealed that Zfp57 binds the FNDC5 gene promoter at positions −308 to −188. Moreover, Zfp57 overexpression inhibited FNDC5 expression, and Zfp57 knockdown alleviated the inhibitory effect of palmitate on FNDC5 expression in C2C12 myotubes. In addition, in vivo and in vitro studies demonstrated that activation of the AMPK pathway by 5-Aminoimidazole-4-carboxamide riboside (AICAR) or metformin mitigated the inhibitory effect of Zfp57 on FNDC5 expression and improved insulin resistance. These findings collectively suggest that high-fat diet and palmitate inhibit the AMPK pathway to increase Zfp57 expression, which in turn induces FNDC5 inhibition, to further aggravate insulin resistance.

Upregulation of Klotho Aggravates Insulin Resistance in Gestational Diabetes Mellitus Trophoblast Cells.

Insulin resistance (IR) plays a key role in gestational diabetes mellitus (GDM) pathogenesis. The antiaging protein klotho has been proven to be closely related to IR. The purpose of this study was to investigate the effect of klotho on IR in GDM trophoblast cells. The GDM cell model of HTR-8/SVneo cells was induced by high glucose (HG). Plasmid transfection was used to mediate the overexpression or silencing of klotho. The effects of klotho on cell viability, IR, and the IGF-1/PI3K pathways were observed by RT-qPCR, western blot, Cell Counting Kit-8 detection, glucose uptake assay, and immunofluorescence detection. Klotho expression was up-regulated in HG-induced cells. Overexpression of klotho could reduce the cell viability, insulin signaling molecules (INSR-α, INSR-β, IRS1, IRS2, and GLUT4), and glucose uptake in HTR-8/SVneo cells of the HG group. In addition, the overexpression of klotho inhibited the levels of IGF-1, IGF-1R/p-IGF-1R, and the phosphorylation and activation of the signal transduction molecules PI3K/Akt/mTOR. On the contrary, klotho deletions could reverse these changes of HTR-8/SVneo cells induced by HG. Conclusion. In a word, the results of this study showed that the regulation of klotho played an important role in the IR of trophoblast cells induced by HG, which was mediated at least in part by the IGF-1/PI3K/Akt/mTOR pathway.

Maternal Low-Protein Diet during Puberty and Adulthood Aggravates Lipid Metabolism of Their Offspring Fed a High-Fat Diet in Mice.

A maternal low-protein (LP) diet during gestation and/or lactation results in metabolic syndrome in their offspring. Here, we investigated the effect of maternal LP diet during puberty and adulthood on the metabolic homeostasis of glucose and lipids in offspring. Female mice were fed with normal-protein (NP) diet or a LP diet for 11 weeks. Male offspring were then fed with a high-fat diet (NP-HFD and LP-HFD groups) or standard chow diet (NP-Chow and LP-Chow groups) for 4 months. Results showed that maternal LP diet during puberty and adulthood did not alter the insulin sensitivity and hepatic lipid homeostasis of their offspring under chow diet, but aggravated insulin resistance, hepatic steatosis, and hypercholesterolemia of offspring in response to a post-weaning HFD. Accordingly, transcriptomics study with offspring’s liver indicated that several genes related to glucose and lipid metabolism, including lipoprotein lipase (Lpl), long-chain acyl-CoA synthetase 1 (Acsl1), Apoprotein A1 (Apoa1), major urinary protein 19 (Mup19), cholesterol 7α hydroxylase (Cyp7a1) and fibroblast growth factor 1 (Fgf1), were changed by maternal LP diet. Taken together, maternal LP diet during puberty and adulthood could disarrange the expression of metabolic genes in the liver of offspring and aggravate insulin resistance and hepatic steatosis in offspring fed a HFD.

Therapeutic Investigation of Standardized Aqueous Methanolic Extract of Bitter Melon (Momordica charantia L.) for Its Potential against Polycystic Ovarian Syndrome in Experimental Animals' Model: In Vitro and In Vivo Studies.

Polycystic ovarian syndrome (PCOS) is an heterogenous, endocrine, metabolic, and multidisciplinary disorder of reproductive-aged females that aggravates insulin resistance, hyperandrogenism, obesity, menstrual irregularities, and infertility. Bitter melon is consumed as vegetable in various parts of the world. The purpose of this study was to provide the rationale for the folkloric uses of bitter melon (Momordica charantia L.) in reproductive abnormalities. HPLC analysis of standardized aqueous methanolic extract of bitter melon revealed the presence of various phytochemicals such as quercetin, gallic acid, benzoic acid, chlorogenic acid, syringic acid, p-coumaric acid, ferulic acid, and cinnamic acid. Twenty-five Swiss albino adult female rats (120–130 g) were acquired and divided into two groups (5 + 20). Letrozole (1 mg/kg p.o.) was used for four weeks to induce PCOS in twenty rats. Disease induction was confirmed by vaginal smear cytology analysis under the microscope. Animals were further divided into four groups, with one group as PCOS group, and the remaining three are treated with standardized extract of bitter melon (500 mg/kg p.o.), bitter melon plus metformin (500 mg/kg p.o.), and metformin alone for the period of next four weeks. After four weeks, the rats were euthanized at diestrus stage. Ovaries of the experimental animals were removed and fixed in 10% buffered formalin, and blood samples were obtained from direct cardiac puncture and stored. Ovaries histopathological analysis showed cystic follicles (9–10) in PCOS group, while, in all the treatment groups, we found developing and mature follicles. Similarly, hormone analysis showed significant (p < 0.001) reduction of LH surge, insulin, and testosterone levels and improvement in FSH levels. Lipid profile and antioxidant enzymes status were also significantly (p < 0.001) improved. In conclusion, the study validates the bitter melon potential as an insulin sensitizer and ovulation enhancer and authenticates its potential in PCOS management.

Expansion of the Inguinal Adipose Tissue Depot Correlates With Systemic Insulin Resistance in C57BL/6J Mice.

To accommodate surplus energy, the adipose tissue expands by increasing adipocyte size (hypertrophy) and number (hyperplasia). The presence of hypertrophic adipocytes is a key characteristic of adipose tissue dysfunction. High-fat diet (HFD) fed C57BL/6J mice are a commonly used model to study obesity and obesity-related complications. In the present study, we have characterized adipose plasticity, at both the cellular and tissue level, by examining the temporal development of systemic insulin resistance and adiposity in response to HFD-feeding for 4, 8, and 12 weeks (4w, 8w, and 12w). Within the same time frame, we examined systemic metabolic flexibility and adipose plasticity when switching from HFD- to chow-diet during the last 2 weeks of diet intervention (referred to as the reverse (REV) group: 4wREV (2w HFD+2w chow), 8wREV (6w HFD+2w chow), 12wREV (10w HFD+2w chow)). In response to HFD-feeding over time, the 12w group had impaired systemic insulin sensitivity compared to both the 4w and 8w groups, accompanied by an increase in hypertrophic inguinal adipocytes and liver triglycerides. After reversing from HFD- to chow-feeding, most parameters were completely restored to chow control levels for 4wREV and 8wREV groups. In contrast, the 12wREV group had a significantly increased number of hypertrophic adipocytes, liver triglycerides accumulation, and impaired systemic insulin sensitivity compared to chow-fed mice. Further, image analysis at the single-cell level revealed a cell-size dependent organization of actin filaments for all feeding conditions. Indeed, the impaired adipocyte size plasticity in the 12wREV group was accompanied by increased actin filamentation and reduced insulin-stimulated glucose uptake compared with chow-fed mice. In summary, these results demonstrate that the C57BL/6J HFD-feeding model has a large capacity to restore adipocyte cell size and systemic insulin sensitivity, and that a metabolic tipping point occurs between 8 and 12w of HFD-feeding where this plasticity deteriorates. We believe these findings provide substantial understanding of C57BL/6J mice as an obesity model, and that an increased pool of hypertrophic ING adipocytes could contribute to aggravated insulin resistance.