Regulation Of Insulin Sensitivity Research Articles

Association between the triglyceride–glucose index and serum soluble Klotho in middle-aged and older adults from NHANES 2007–2016

Klotho, an anti-aging protein, is believed to participate in metabolic diseases and play a potential protective role by regulating insulin sensitivity. This study aimed to explore the relationship between the triglyceride-glucose (TyG) index (a simple marker of insulin resistance) and serum soluble Klotho (S-Klotho) levels. The cross-sectional study comprised 5237 adults aged 40–79 years who participated in the National Health and Nutrition Examination Surveys (NHANES) 2007–2016. The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The serum levels of S-Klotho were measured by enzyme-linked immunosorbent assay. The association between the TyG index and S-Klotho levels was investigated by multiple linear regression models, smoothed curve fitting, segmented linear regression models, subgroup analyses, and interaction tests. The TyG index was inversely associated with serum S-Klotho level after full adjustment (β = − 45.11, 95% CI (− 79.53, − 10.69), P = 0.011). Furthermore, we also found a non-linear correlation and saturation phenomenon between the TyG index and serum S-Klotho levels, with a turning point of 9.56. In addition, a significant interaction effect of sex was found between the two (P for interaction < 0.001), with a more pronounced association observed in females. Further studies are required to explore the mechanisms and verify the correlation.

Combination of plant metabolites hinders starch digestion and glucose absorption while facilitating insulin sensitivity to diabetes.

Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately 90% of all DM cases. Current medicines used in the treatment of DM have some adverse or undesirable effects on patients, necessitating the use of alternative medications. To overcome the low bioavailability of plant metabolites, all entities were first screened through pharmacokinetic, network pharmacology, and molecular docking predictions. Experiments were further conducted on a combination of antidiabetic phytoactive molecules (rosmarinic acid, RA; luteolin, Lut; resveratrol, RS), along with in vitro evaluation (α-amylase inhibition assay) and diabetic mice tests (oral glucose tolerance test, OGTT; oral starch tolerance test, OSTT) for maximal responses to validate starch digestion and glucose absorption while facilitating insulin sensitivity. The results revealed that the combination of metabolites achieved all required criteria, including ADMET, drug likeness, and Lipinski rule. To determine the mechanisms underlying diabetic hyperglycemia and T2DM treatments, network pharmacology was used for regulatory network, PPI network, GO, and KEGG enrichment analyses. Furthermore, the combined metabolites showed adequate in silico predictions (α-amylase, α-glucosidase, and pancreatic lipase for improving starch digestion; SGLT-2, AMPK, glucokinase, aldose reductase, acetylcholinesterase, and acetylcholine M2 receptor for mediating glucose absorption; GLP-1R, DPP-IV, and PPAR-γ for regulating insulin sensitivity), in vitro α-amylase inhibition, and in vivo efficacy (OSTT versus acarbose; OGTT versus metformin and insulin) as nutraceuticals against T2DM. The results demonstrate that the combination of RA, Lut, and RS could be exploited for multitarget therapy as prospective antihyperglycemic phytopharmaceuticals that hinder starch digestion and glucose absorption while facilitating insulin sensitivity.

#770 Urinary PTM3 Fetuin-A in CKD patients with and without diabetic kidney disease

Abstract Background and Aims Fetuin-A is a member of the cystatins superfamily, primarily synthesized in the liver, which is involved in multiple physiological processes including calcium homeostasis, cell signaling, calcification inhibition and the regulation of insulin sensitivity. Diabetes mellitus may impact upon Fetuin-A regulation and kidney tubular cells produce Fetuin-A as part of stress and inflammatory response and release it in urine in case of kidney damage. A novel post-translational modification (PTM) fragment derived from the cleavage of Fetuin-A (PTM3) has recently emerged as a very sensitive biomarker for early kidney damage, but its usefulness in the context of CKD has not been assessed yet. In this study, we aimed at evaluating the clinical significance of urinary PTM3 fetuin A in a pilot cohort of CKD patients with or without diabetic kidney disease (DKD). Method We enrolled 47 adult patients with CKD (mean CKD-Epi 40.10 ± 16.5 mL/min/1.73 m2) due to DKD (n = 34) or other causes (n = 13). PTM3 levels were measured in the urine (uPTM3) using a commercially available ELISA kit. 15 healthy individuals served as controls. Clinical, anthropometric and laboratory parameters were also recorded. Results Collectively, all CKD patients displayed higher levels of uPTM3 than the ones of control group (0.84 [0.10-1.15] vs 29.68 [2.50-55.16] ng/mL p = 0.0005). Moreover, uPTM3 values were higher in DKD patients than in non-DKD CKD patients (39.4 [4.20-28.2] vs. 4.15 [0.29-1.38] p &amp;lt; 0.01). uPTM3 had a remarkable diagnostic capacity at ROC analysis to discriminate CKD patients from controls (AUC 0.776; p &amp;lt; 0.001; Fig. 1) and, within CKD patients, to discriminate between DKD and non-DKD patients (AUC 0.673; p = 0.02; Fig. 2). At multivariate correlation analyses, only proteinuria (β = 0.442; p = 0.02) and BMI (β = 0.334; p = 0.04) values remained significantly associated with uPTM3 Fetuin-A in the whole cohort, thus indicating that renal damage following metabolic syndrome may play a significant impact on the overall balance of this protein. Conclusion uPTM3 could be a novel sensitive biomarker reflecting renal damage in CKD patients and could also represent an additional tool for assessing the renal involvement in diabetic patients. Further studies are needed to evaluate whether uPTM3 measurement may predict different disease evolution in these patients.

Гідроген сульфід: біологічні та патохімічні ефекти

Hydrogen sulfide (H2S) belongs to the family of «gasotransmitters» can by synthesized by enzymatic systems and also formed non-enzymatically. At physiological concentrations, it regulates a range of biological functions in various organs and tissues. H2 S is involved in biochemical changes that play an important role in the pathogenesis of diseases such as cancer, COVID-19, diabetes mellitus, and neurodegenerative pathologies. In carcinogenesis, H2S influences cancer cell proliferation, inhibits cancer cell apoptosis, regulates the cell cycle, intracellular signaling pathways, stimulates angiogenesis, and autophagy of cancer cells. In lung inflammation caused by COVID-19, H2S disrupts disulfide bonds in mucus, reducing its viscosity, blocks NF-κB pathway activation, preventing the onset of a «cytokine storm», promotes Nrf2 activation, increasing the expression of antioxidant molecules and enzymes, activates potassium channels, and blocks Na+/K+-ATPase, promoting electrolyte absorption. In the pancreas, H 2 S regulates insulin secretion and plays a significant role in insulin sensitivity regulation in insulin-responsive tissues. It inhibits glucose uptake and glycogen accumulation, which is crucial in diabetes mellitus. In adipose tissue, H 2 S promotes adipogenesis, inhibits lipolysis, and regulates the secretion of adiponectin and MCP-1 in type 2 diabetes. In neural tissue, H2S acts as a neuromodulator, increases GABA expression, induces Ca2+ concentration increase, participates in long-term potentiation, neurotransmitter modulation, affects NADPH levels, and exerts epigenetic effects. Understanding the role of H2 S may be crucial in developing effective therapy strategies for various diseases.

New Mediators in the Crosstalk between Different Adipose Tissues.

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

The Association between the Plasma Phospholipid Profile and Insulin Resistance: A Population-Based Cross-Section Study from the China Adult Chronic Disease and Nutrition Surveillance.

The dysfunction of phospholipid metabolism enzymes and the change in membrane phospholipid composition are associated with insulin resistance, indicating that phospholipids play an important role in the regulation of insulin sensitivity. The reflection of phospholipid changes in blood might provide clues for both mechanism understanding and intervention. Using a targeted phospholipidomic approach, 199 phospholipid molecular species were identified and quantified in the plasma of 1053 middle-aged participants from a national investigation. The associations of the phospholipid matrix, clusters, and molecular species with insulin resistance were investigated. A significant association was confirmed between the phospholipid matrix and the homeostatic-model assessment of insulin resistance (HOMA-IR) by a distance-based linear model. Furthermore, three clustered phospholipid modules and 32 phospholipid molecular species were associated with HOMA-IR with the strict control of demographic and lifestyle parameters, family history of diabetes, BMI, WC, and blood lipid parameters. The overall decline in lysophosphatidylcholines (LPCs), the decrease in saturated lysophosphatidylethanolamines (LPEs), the decrease in polyunsaturated/plasmenyl phosphatidylcholines (PCs), and the increase in polyunsaturated phatidylethanolamines (PEs) were the prominent characters of plasma phospholipid perturbation associated with insulin resistance. This suggested that PC- and PE-related metabolic pathways were widely involved in the process of insulin resistance, especially the disorder of LPC acylation to diacyl-PC.

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment.

Circadian misalignment due to night work has been associated with an elevated risk for chronic diseases. We investigated the effects of circadian misalignment using shotgun protein profiling of peripheral blood mononuclear cells taken from healthy humans during a constant routine protocol, which was conducted immediately after participants had been subjected to a 3-day simulated night shift schedule or a 3-day simulated day shift schedule. By comparing proteomic profiles between the simulated shift conditions, we identified proteins and pathways that are associated with the effects of circadian misalignment and observed that insulin regulation pathways and inflammation-related proteins displayed markedly different temporal patterns after simulated night shift. Further, by integrating the proteomic profiles with previously assessed metabolomic profiles in a network-based approach, we found key associations between circadian dysregulation of protein-level pathways and metabolites of interest in the context of chronic metabolic diseases. Endogenous circadian rhythms in circulating glucose and insulin differed between the simulated shift conditions. Overall, our results suggest that circadian misalignment is associated with a tug of war between central clock mechanisms controlling insulin secretion and peripheral clock mechanisms regulating insulin sensitivity, which may lead to adverse long-term outcomes such as diabetes and obesity. Our study provides a molecular-level mechanism linking circadian misalignment and adverse long-term health consequences of night work.

Associations of adupocutokine and metaboliv hormone level in young people aged 25-44 years with type 2 diabetes mellitus and abdominal obesity

BACKGROUND: Diabetes mellitus and obesity are two closely related diseases that are a global public health problem. Obesity is characterized by an increase in the volume of adipose tissue and a change in the production and function of adipocytokines, which leads to a violation of the regulation of insulin sensitivity and glucose metabolism, contributing to the development of insulin resistance and diabetic pathology.AIM: The aim of this study was to evaluate the concentrations of individual adipocytokines and metabolic hormones in patients with DM2 and without diabetes, depending on the presence/absence of abdominal obesity (AO).MATERIALS AND METHODS: A single-center observational cross-sectional study was conducted. A population subsample of men and women aged 25–44 years was examined. Socio-demographic data were collected, anthropometric measurements were performed. The levels of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, were determined in blood serum by multiplex analysis using a set of reagents Human Metabolic Hormone V3 (USA) and Human Adipokine Panel 1 (USA) on a Luminex MAGPIX flow fluorimeter (USA). interleukin 6, insulin, leptin, monocytic chemotactic factor 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor-1 (PAI-1) and resistin.RESULTS: The study included 105 people. The main group consisted of 35 people with diabetes mellitus, 11 of them without AO and 24 with AO, the control group consisted of 70 people without diabetes mellitus (35 people with AO and 35 without AO), comparable in gender and age with the main group. In individuals with abdominal obesity, regardless of the presence of type 2 diabetes mellitus, the levels of C-peptide, GLP-1, insulin, leptin and TNF-alpha are higher than in individuals without abdominal obesity. The chance of having diabetes mellitus and AO is associated with an increase in leptin levels (OR=1.367, 95% CI: 1.050–1.779, p=0.020).CONCLUSION: The results of our study show that the indicators of the adipocytokine profile differ significantly in individuals with the presence/absence of abdominal obesity. According to our data, leptin makes the greatest contribution to the development of SD2 against the background of AO. Further research is needed to identify causal relationships and determine whether treatment that regulates adipocytokine levels can help in personalized approaches to the prevention and treatment of type 2 diabetes mellitus.

Liver ChREBP deficiency inhibits fructose-induced insulin resistance in pregnant mice and female offspring

High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.

Plasma proteome profiling reveals the therapeutic effects of the PPAR pan-agonist chiglitazar on insulin sensitivity, lipid metabolism, and inflammation in type 2 diabetes

Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist, which passed phase III clinical trials and was newly approved in China for use as an adjunct to diet and exercise in glycemic control in adult patients with Type 2 Diabetes (T2D). To explore the circulating protein signatures associated with the administration of chiglitazar in T2D patients, we conducted a comparative longitudinal study using plasma proteome profiling. Of the 157 T2D patients included in the study, we administered chiglitazar to a specific group, while the controls were given either placebo or sitagliptin. The plasma proteomes were profiled at baseline and 12 and 24 weeks post-treatment using data-independent acquisition mass spectrometry (DIA-MS). Our study indicated that 13 proteins were associated with chiglitazar treatment in T2D patients, including 10 up-regulated proteins (SHBG, TF, APOA2, APOD, GSN, MBL2, CFD, PGLYRP2, A2M, and APOA1) and 3 down-regulated proteins (PRG4, FETUB, and C2) after treatment, which were implicated in the regulation of insulin sensitivity, lipid metabolism, and inflammation response. Our study provides insight into the response of chiglitazar treatment from a proteome perspective and demonstrates the multi-faceted effects of chiglitazar in T2D patients, which will help the clinical application of chiglitazar and further study of its action mechanism.

Natural Products and Diabetes: (-)-Epicatechin and Mechanisms Involved in the Regulation of Insulin Sensitivity.

Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.

Hormonal regulation in diabetes: Special emphasis on sex hormones and metabolic traits.

Diabetes constitutes a significant global public health challenge that is rapidly reaching epidemic proportions. Among the non-communicable diseases, the incidence of diabetes is rising at an alarming rate. The International Diabetes Federationhas documented a 9.09% prevalence of diabetes among individuals aged between 20 and 79 years. The interplay of gonadal hormones and gender differences is critical in regulating insulin sensitivity and glucose tolerance, and this dynamic is particularly crucial because of the escalating incidence of diabetes. Variations in insulin sensitivity are observed across genders, levels of adiposity, and age groups. Both estrogen and testosterone are seen to influence glucose metabolism and insulin sensitivity. This chapter surveys the present knowledge of sex differences, sex hormones, and chromosomes on insulin imbalance and diabetes development. It further highlights the influence of metabolic traits in diabetes and changes in sex hormones during diabetic pregnancy. Notably, even stressful lifestyles have been acknowledged to induce hormonal imbalances. Furthermore, it discusses the potential of hormonal therapy to help stabilize sex hormones in diabetic individuals and focuses on the most recent research investigating the correlation between sex hormones and diabetes.

Effect of Vitamin D and Calcium Supplementation on Insulin Resistance

As people spend more time indoors, Vitamin D deficiencies have increased drastically due to less sunlight exposure. New studies have linked Vitamin D deficiencies to calcium deficiencies since Vitamin D helps the human body absorb calcium properly. Calcium regulates insulin sensitivity, and calcium deficiencies reduce insulin sensitivity, indicating how Vitamin D deficiencies can lead to insulin resistance. I tested the individual and combined effects of calcium and Vitamin D supplementation on insulin resistance in Drosophila melanogaster, using physical activity to measure improvement in insulin resistance. There were 3 identical trials, and 5 vials in each trial. The control group was fed with only drosophila medium. The remaining vials had 3 grams of table sugar mixed with the medium. The second vial had no additions. The third vial had an addition of liquid calcium, and the fourth vial had Vitamin D instead. The last group had both supplements. After a week, the peristalsis contractions of each group’s larvae were counted in 30-second intervals. Additionally, adult flies from different groups were used for a climbing assay to measure the short-term impacts of these supplements on physical activity. Both measures yielded similar results: there was a visible increase in climbing performance and the number of peristalsis contractions in vials with supplementations compared to those without. The groups fed with individual supplements saw some increase, but the group with both supplements saw the most significant increase relative to sugar supplementation alone, supporting the hypothesis that calcium and Vitamin D supplementation improves insulin resistance.

Adipocyte-derived exosomal miR-22-3p modulated by circadian rhythm disruption regulates insulin sensitivity in skeletal muscle cells

Circadian rhythm disruption leads to dysregulation of lipid metabolism, which further drive the occurrence of insulin resistance (IR). Exosomes are natural carrier systems that advantageous for cell communication. In the present study, we aimed to explore whether and how the exosomal microRNAs (miRNAs) in circulation participate in modulating skeletal muscle IR induced by circadian rhythm disruption. In the present study, 24-h constant light (12-h light/12-h light, LL) was used to establish the mouse model of circadian rhythm disruption. Bmal1 interference was used to establish the cell model of circadian rhythm disruption. And in clinical experiments, we chose a relatively large group of rhythm disturbance-shift nurses. We showed that LL-induced circadian rhythm disruption led to increased body weight and visceral fat volume, as well as occurrence of IR invivo. Furthermore, exosomal miR-22-3p derived from adipocytes in the context of circadian rhythm disruption induced by Bmal1 interference could be uptaken by skeletal muscle cells to promote IR occurrence invitro. Moreover, miR-22-3p in circulation was positively correlated with the clinical IR-associated factors. Collectively, these data showed that exosomal miR-22-3p in circulation may act as potential biomarker and therapeutic target for skeletal muscle IR, contributing to the prevention of diabetes in the context of rhythm disturbance.

Obesity induced disruption on diurnal rhythm of insulin sensitivity via gut microbiome-bile acid metabolism

The disruption of the diurnal rhythm has been recognized as a significant contributing factor to metabolic dysregulation. The important role of gut microbiota and bile acid metabolism has attracted extensive attention. However, the function of the gut microbiota-bile acid axis in regulating the diurnal rhythms of metabolic homeostasis remains largely unknown. Herein, we aimed to investigate the interplay between rhythmicity of host metabolism and gut microbiota-bile acid axis, as well as to assess the impact of obesity on them. We found that high fat diet feeding and Leptin gene deficiency (ob/ob) significantly disturbed the rhythmic patterns of insulin sensitivity and serum total cholesterol levels. The bile acid profiling unveiled a conspicuous diurnal rhythm oscillation of ursodeoxycholic acid (UDCA) in lean mice, concomitant with fluctuations in insulin sensitivity, whereas it was absent in obese mice. The aforementioned diurnal rhythm oscillations were largely desynchronized by gut microbiota depletion, suggesting the indispensable role of gut microbiota in diurnal regulation of insulin sensitivity and bile acid metabolism. Consistently, 16S rRNA sequencing revealed that UDCA-associated bacteria exhibited diurnal rhythm oscillations that paralleled the fluctuation in insulin sensitivity. Collectively, the current study provides compelling evidence regarding the association between diurnal rhythm of insulin sensitivity and gut microbiota-bile acid axis. Moreover, we have elucidated the deleterious effects of obesity on gut microbiome-bile acid metabolism in both the genetic obesity model and the diet-induced obesity model.

Regulation of Macronutrients in Insulin Resistance and Glucose Homeostasis during Type 2 Diabetes Mellitus.

Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. Here, we reviewed the effects of different components of macronutrients on insulin sensitivity and their underlying mechanisms, including fructose, dietary fiber, saturated and unsaturated fatty acids, and amino acids. Understanding the diet-gene interaction will help us to better uncover the molecular mechanisms of T2DM and promote the application of precision nutrition in practice by integrating multi-omics analysis.

MiR-143-3p/FNDC5 axis: a novel regulator of insulin sensitivity.

Insulin resistance is a key hallmark in type 2 diabetes. In recent decades, there have been numerous studies of the causes of insulin resistance. microRNAs (miRNAs) participate in the regulation of multiple aspects of energy metabolism and miR-143-3p has been shown to induce insulin resistance. We aimed to predict the downstream targets of miR-143-3p and found a miR-143-3p binding site on the 3'-untranslated region of FNDC5 (Fibronectin type III domain containing 5) mRNA. We first confirmed that FNDC5 mRNA is a target of miR-143-3p using a double luciferase experiment, then constructed a prokaryotic expression system for the mature form of FNDC5, irisin, and expressed and purified irisin protein. We transfected a miR-143-3p mimic into HepG2-NTCP (Na+-taurocholate cotransporting polypeptide) cells using an NTCP targeting vector, then 24 h later, the glucose concentration of the culture medium, western blot analysis was analyzed. We next co-incubated the cells transfected with the miR-143-3p mimic with irisin for 12 h following by the assay of glucose uptake and AKT phosphorylation. The glucose concentration of the culture medium was higher than that associated with control miRNA-transfected cells (p < 0.01). Western blot analysis showed that the miR-143-3p mimic significantly reduced the expression of FNDC5 (p < 0.05) and the phosphorylation of AKT (Protein kinase B) (p < 0.05), implying impaired insulin signaling. which increased the glucose uptake (p < 0.0001) and AKT phosphorylation in the cells (p < 0.05). We conclude that FNDC5 is a direct target of miR-143-3p and that miR-143-3p induces insulin resistance by reducing its expression.

The correlation between two potentially antagonistic human adipocytokines, WISP-1 and CTRP1, and their association with insulin resistance.

Wnt-1 signaling pathway protein 1 (WISP-1) and complement-C1q TNF-related protein 1 (CTRP1) are adipokines with possible opposite effects in regulating insulin sensitivity. The study investigated the correlation between circulating WISP-1 and CTRP1 in non-diabetic patients. Correlations between adipokines concentrations and biochemical and anthropometric parameters were also studied. The cross-sectional study enrolled 107 adult patients without diabetes. Patients with obesity accounted for 52.3% of the study group. Clinical, anthropometric, and laboratory data, including serum levels of WISP-1 and CTRP1, were obtained. The moderate positive correlation between serum WISP-1 and CTRP1 concentrations was observed (p<0.000001, r=0.49). The correlation was more substantial in non-obese patients than in the obese group (r=0.66 and r=0.36, respectively; p<0.01). Circulating CTRP1 correlated positively with fasting insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), total cholesterol, HDL cholesterol, and LDL cholesterol (p<0.05). WISP-1 level correlated with total cholesterol and HDL cholesterol concentrations (p<0.05). There was no significant difference in WISP-1 and CTRP1 concentrations between the groups with and without insulin resistance. The concentrations of WISP-1 and CTRP1 were significantly higher in females than in males (p<0.05). WISP-1 and CTRP1 may represent interrelated factors that antagonistically affect insulin resistance.

METTL3 exacerbates insulin resistance in hepatocytes by regulating m6A modification of cytochrome P450 2B6

BackgroundInsulin resistance (IR) in hepatocytes endangers human health, and frequently results in the development of non-alcoholic fatty liver disease (NAFLD). Research on m6A methylation of RNA molecules has gained popularity in recent years; however, the molecular mechanisms regulating the processes of m6A modification and IR are not known. The cytochrome P450 (CYP450) enzyme system, which is mainly found in the liver, is associated with the pathogenesis of NAFLD. However, few studies have been conducted on CYP450 related m6A methylation. Here, we investigated the role of the methyltransferase METTL3 in exacerbating IR in hepatocytes, mainly focusing on the regulation of m6A modifications in CYP2B6.Methods and resultsAnalysis using dot blot and epitranscriptomic chips revealed that the m6A modification pattern of the transcriptome in high-fat diet (HFD)-induced fatty liver and free fatty acid (FFA)-induced fatty hepatocytes showed significant changes. CYP450 family members, especially Cyp2b10, whose homolog in humans is CYP2B6, led to a noticeable increase in m6A levels in HFD-induced mice livers. Application of the METTL3 methyltransferase inhibitor, STM2457, increased the level of insulin sensitivity in hepatocytes. We then analyzed the role of METTL3 in regulating m6A modification of CYP2B6 in hepatocytes. METTL3 regulated the m6A modification of CYP2B6, and a positive correlation was found between the levels of CYP2B6 translation and m6A modifications. Furthermore, interference with METTL3 expression and exposure to STM2457 inhibited METTL3 activity, which in turn interfered with the phosphorylated insulin receptor substrate (pIRS)-glucose transporter 2 (GLUT2) insulin signaling pathway; overexpression of CYP2B6 hindered IRS phosphorylation and translocation of GLUT2 to membranes, which ultimately exacerbated IR.ConclusionThese findings offer unique insights into the role that METTL3-mediated m6A modifications of CYP2B6 play in regulating insulin sensitivity in hepatocytes and provide key information for the development of strategies to induce m6A modifications for the clinical treatment of NAFLD.

Preptin: A New Bone Metabolic Parameter?

Preptin is a 34-aminoacid peptide derived from the E-peptide of pro-insulin-like growth factor 2 (pro-IGF2) that is co-secreted with insulin and upregulates glucose-mediated insulin secretion. High serum preptin levels were described in conditions associated with insulin resistance, such as polycystic ovary syndrome and type 2 diabetes mellitus (T2M). Insulin and also IGF2 are known to be anabolic bone hormones. The "sweet bone" in T2M usually associates increased density, but altered microarchitecture. Therefore, preptin was proposed to be one of the energy regulatory hormones that positively impacts bone health. Experimental data demonstrate a beneficial impact of preptin upon the osteoblasts. Preptin also appears to regulate osteocalcin secretion, which in turn regulates insulin sensitivity. Preptin is greatly influenced by the glucose tolerance status and the level of physical exercise, both influencing the bone mass. Clinical studies describe low serum preptin concentrations in osteoporosis in both men and women, therefore opening the way towards considering preptin a potential bone anabolic therapy. The current review addresses the relationship between preptin and bone mass and metabolism in the experimental and clinical setting, also considering the effects of preptin on carbohydrate metabolism and the pancreatic-bone loop.