Correlation between low handgrip strength and metabolic syndrome in older adults: a systematic review.

Muscle weakness has been associated to insulin resistance and metabolic syndrome in the general population. However, it is still unclear whether this association is maintained in older adults. This study investigated correlations between low handgrip strength (HGS) and metabolic syndrome, or some of its components, in older adults through a systematic review of the literature. Searches were conducted in the Virtual Health Library Regional Portal, Scopus, Cochrane, Embase, MEDLINE/ PubMed, SciELO, and Web of Science databases for relevant studiesinvestigating muscle weakness (measured by hand dynamometer) and metabolic syndrome or its components in older adult populations, published up to September 2023. From the 2050 references initially identified, 20 studies, comprising a total of 31,264 older adults of both genders, completely met the inclusion/exclusion criteria. Eighteen studies showed that lower HGS was associated with metabolic syndrome or some of its risk factors, such as abdominal obesity, hyperglycemia, insulin resistance, dyslipidemia, or high blood pressure. Two studies found that older men with high blood pressure had increased HGS. Most studies included in this systematic review revealed a significant correlation between reduced HGS and metabolic syndrome or some of its components, especially abdominal obesity and insulin resistance. We conclude that below-average HGS can be associated with metabolic syndrome in older adults.

Effect of polycystic ovary syndrome on the life quality of young women.

OBJECTIVE: The study evaluated the opinions of polycystic ovary syndrome on the life quality of women. METHODS: A total of 249 women with polycystic ovary syndrome participated in this descriptive study between October 2022 and July 2023 in Istanbul, Turkey. FINDINGS: Polycystic Ovary Syndrome and Quality of Life was significantly correlated with age (p=0.000) and frequent weight loss diets (p=0.000) (p<0.01). Among the Polycystic Ovary Syndrome and Quality of Life total score and polycystic ovary syndrome symptoms, those with hormone imbalance and insulin resistance had the highest mean scores, while those with menstrual irregularity and fatigue had the lowest. CONCLUSION: Advancing age changes the quality of life of women with polycystic ovary syndrome. To prevent the negative impact of polycystic ovary syndrome on women's quality of life, it is recommended that health professionals develop effective care plans utilizing available evidence.

The impact of androgen levels on serum metabolic profiles in patients with polycystic ovary syndrome.

OBJECTIVE: This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS). METHODS: We included 216 patients with PCOS and 216 healthy individuals selected as the control group. According to the measured serum androgen levels, patients with PCOS were divided into the hyperandrogenism group and non-hyperandrogenism group. Clinical metabolic indicators were assessed and compared between the two groups. Additionally, we assessed the correlation between androgen levels and clinical metabolic indicators. RESULTS: The body mass index, waist-to-hip ratio, mF-G score, and acne score, as well as T, LH, LSH/FSH, FPG, Cr, UA, TG, TC, and LDL-C levels were significantly higher in the PCOS group than in the control group. The incidence of hyperandrogenism and clinical hyperandrogenism in the PCOS group was significantly higher than that in the control group. Regarding clinical hyperandrogenism, hirsutism, acne, and acanthosis nigricans were significantly more common in the PCOS group than in the control group. Serum androgen levels were significantly correlated with the mF-G score, acne score, FSH, glucose concentration at 30 min, glucose concentration at 60 min, glucose concentration at 120 min, FINS, N120, HOMA-IR, HbA1c, AUCG, UA, TG, and hHDL-Clevels. CONCLUSION: Elevated serum androgen levels are commonly observed in patients with PCOS and are associated with multiple metabolic abnormalities. Therefore, it is recommended to regularly monitor glucose and lipid metabolism-related indicators in patients with PCOS who have elevated androgen levels.

Association Between Triglyceride-Glucose Index and Homeostasis Model Assessment for Insulin Resistance with Estimated Glucose Disposal Rate.

This cross-sectional study was aimed to compare insulin resistance, Triglyceride- Glucose (TyG) index, fatty liver index (FLI) and hepatic steatosis index (HSI), glycaemic and lipids among groups/quartiles based upon estimated Glucose Disposal Rate (eGDR) from August 2022 to December 2022 among 249 male participants. The eGDR results in (mg/kg/min) were divided into four quartiles as: Group-I: {<6.88, n = 62}, Group-II: {<6.88-9.45, n = 63}, Group-III: {9.46-10.39, n = 62}, and Group-IV: {>10.39, n = 62}. Fasting plasma glucose (FPG), HbA1c, low density lipoprotein (LDL), homeostasis model assessment for insulin-resistance (HOMAIR), and TyG index demonstrated significant worsening increase from high to low eGDR groups. Receiver operating curve (ROC) analysis to calculate area under curve (AUC) for diagnostic efficiency candidate indices for eGDR demonstrated highest AUC for FLI as AUC: 0.736 (95% CI: 0.669-0.803), p < 0.001, followed by FPG: AUC: 0.682 (95% CI: 0.606-0.757), HOMAIR: AUC: 0.670 (95% CI: 0.602-0.739), HSI: AUC: 0.660 (95% CI: 0.589-0.731), TyG index: 0.658 (95% CI: 0.583-0.732), and HbA1c: 0.639 (95% CI: 0.583-0.732). Glycaemic measures, lipid indices, insulin resistance and TyG index deteriorated with declining eGDR. Diagnostic performance as evaluated by AUC for eGDR was highest for FLI, followed by FPG, HOMAIR, HSI, TyG index, HbA1c, and triglycerides. Key Words: Triglyceride, Insulin, Glucose, Diabetes.

Specific Knockout of Notch-1 in Macrophages Modulate the Progression of Hepatic Insulin Resistance in HFD Fed Mice via Regulating IRE1α-XBP1 Signals.

OBJECTIVE: To develop an intervention based on Notch-1 signalling pathway blockade by investigating the potential application of the neurogenic locus notch homologue protein 1(Notch-1) signalling pathway as a key regulator of chronic inflammation and adipogenesis in the treatment of hepatic insulin resistance (HIR). STUDY DESIGN: Experimental study. Place and Duration of the Study: Animal Laboratory of the Fourth Hospital of Hebei Medical University, Shijiazhuang, China, from April 2021 to June 2022. METHODOLOGY: HIR models were established in Notch-1WT and Notch-1MAC-KO mice by high fat diet (HFD) for 16 weeks. Haematoxylin and eosin (HE) staining and oil red O (ORO) staining were used to detect inflammatory infiltration and lipid accumulation in each group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of TNF-α and IL-6. Free fatty acid (FFA) and total cholesterol (TC) were measured with relevant kits. Moreover, real-time quantitative polymerase chain reaction (PCR) was performed to detect the relative expressions of F4/80, Mcp1, and CD11b in hepatic tissues. Mass spectrometry was used to analyse the levels of triglyceride (TG), diacylglycerol (DAG) and conformite europeenne (CE) in liver tissue. Western blotting was used to detect the expression of related proteins. RESULTS: Specific knockdown of Notch-1 in macrophages decreases the relative fluorescence intensity of CD68 and attenuates inflammatory infiltration and lipid degeneration. There was no difference in plasma levels of FFA and TG. Specific knockdown of Notch-1 in macrophages decreases the expression of F4/80, Mcp1, and CD11b, as well as the levels of TG, DAG, CE, IL-6, and TNF-α. CONCLUSION: Specific knockout of Notch-1 in macrophages may reduce HIR by inhibiting the IRE1α-XBP1 signalling pathway. KEY WORDS: Hepatic insulin resistance, Macrophages, Notch-1, IRE1α, XBP1.

MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.

BACKGROUND: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. RESULTS: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. CONCLUSION: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.

Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice.

OBJECTIVES: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice. METHODS: The CthΔskm mice and littermate Cth-floxed (Cthf/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle. RESULTS: Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cthf/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice. DISCUSSION: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

ß-Cell Insulin Resistance Plays a Causal Role in Fat-Induced ß-Cell Dysfunction In Vitro and In Vivo.

In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in ß-cells where they play a role in ß-cell function. Therefore, inhibition of the insulin/insulin-like growth factor 1 pathway may be involved in fat-induced ß-cell dysfunction. To address the role of ß-cell insulin resistance in FFA-induced ß-cell dysfunction we co-infused bisperoxovanadate (BPV) with oleate or olive oil for 48 hours in rats. BPV, a tyrosine phosphatase inhibitor, acts as an insulin mimetic and is devoid of any antioxidant effect that could prevent ß-cell dysfunction, unlike most insulin sensitizers. Following fat infusion, rats either underwent hyperglycemic clamps for assessment of ß-cell function in vivo or islets were isolated for ex vivo assessment of glucose-stimulated insulin secretion (GSIS). We also incubated islets with oleate or palmitate and BPV for in vitro assessment of GSIS and Akt (protein kinase B) phosphorylation. Next, mice with ß-cell specific deletion of PTEN (phosphatase and tensin homolog; negative regulator of insulin signaling) and littermate controls were infused with oleate for 48 hours, followed by hyperglycemic clamps or ex vivo evaluation of GSIS. In rat experiments, BPV protected against fat-induced impairment of ß-cell function in vivo, ex vivo, and in vitro. In mice, ß-cell specific deletion of PTEN protected against oleate-induced ß-cell dysfunction in vivo and ex vivo. These data support the hypothesis that ß-cell insulin resistance plays a causal role in FFA-induced ß-cell dysfunction.

Assessment of Serum Atherogenic Indices and Insulin Resistance in Retinal Vein Occlusion.

Objectives: This study aimed to investigate serum atherogenic indices as novel cardiovascular risk factors associated with retinal vein occlusion (RVO). Materials and Methods: This retrospective case-control study included 57 patients with newly diagnosed RVO whose plasma lipid profile (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglycerides [TG]) and insulin resistance were examined. Serum atherogenic indices (LDL-C/HDL-C, TC/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios) and presence of insulin resistance were compared between the patients and 63 healthy subjects. Cut-off values were determined by receiver operating characteristic curve analysis. Results: The mean age of the RVO patients was 63.7±9.4 years. Plasma levels of LDL-C, HDL-C, TC, and TG showed no significant difference between the patient and control groups (p>0.05). However, LDL-C/HDL-C, non-HDL-C/HDL-C, and TC/HDL-C ratios were higher in the RVO group compared to healthy subjects (p=0.015, p=0.036, and p=0.015, respectively). Fasting insulin concentrations, plasma insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were higher in the RVO patients compared to controls (p=0.003, p=0.001, and p=0.001, respectively). Conclusion: LDL-C/HDL-C, TC/HDL-C, and non-HDL-C/HDL-C ratios were found to be increased in RVO. Compared to the traditional plasma lipid profile, serum atherogenic indices were found to be superior predictors of RVO development. Measurement of HOMA-IR index should be taken into consideration in the evaluation of insulin resistance. High serum atherogenic indexes in RVO patients reveal the need to take precautions against the risk of cardiovascular disease and stroke.

Serum adiponectin and peroxisome proliferator-activated receptors-γ levels in obese patients with and without prediabetes.

OBJECTIVE: Obesity is an increasingly prevalent global health problem, which is generally caused by the increase in body fat mass above normal and observed in all societies. If the blood glucose level is higher than normal but not high enough to diagnose diabetes, this condition is defined as prediabetes. Adiponectin increases fatty acid oxidation and insulin sensitivity and is closely associated with obesity. One of the nuclear receptor superfamily member peroxisome proliferator-activated receptors is shown to have an important role in various metabolic reactions. This study aimed to investigate the serum levels of adiponectin and peroxisome proliferator-activated receptors-gamma parameters, which are closely related to adipose tissue, energy metabolism, and insulin sensitivity, in obese patients with and without prediabetes. METHODS: For this purpose, 52 obese patients with prediabetes, 48 obese patients with non-prediabetes, and 76 healthy individuals were included in this study. Serum adiponectin and peroxisome proliferator-activated receptors-γ levels were analyzed by ELISA. RESULTS: Serum adiponectin levels were significantly higher in obese patients with prediabetes (18.15±15.99) compared with the control group (15.17±15.67; p=0.42). No significant difference was observed in both adiponectin and peroxisome proliferator-activated receptors-γ levels in the obese patients with the non-prediabetes group compared with the control group. However, no significant difference was observed in the obese patients with prediabetes group and obese patients with non-prediabetes group. CONCLUSION: Our results suggest that adiponectin may serve as an indicator of prediabetes. This implies that examining adiponectin levels in individuals diagnosed with prediabetes may enhance our understanding of the metabolic processes closely linked to prediabetes and related conditions.

Janus kinase-signal transducer and activator of transcription signaling pathway in the ocular cells of rat fetuses exposed to maternal saturated fat ingestion.

OBJECTIVE: The aim of this study was to analyze possible alterations (morphological and inflammatory) in the ocular cells of fetuses from mothers with insulin resistance exposed to saturated fatty acids through the period of pregnancy. METHODS: Wistar female rats were induced to develop insulin resistance before pregnancy. Fetuses' skulls were collected on the 20th day of intrauterine life. The rats were separated on the first day of management into two groups according to the diet applied: control group (C): diet containing soybean oil as a source of fat; and saturated fatty acid group (S): diet containing butter as a source of fat. RESULTS: Histological and immunohistochemical analyses have been conducted. The immunohistochemical analyses of interleukin 6, suppressor of cytokine signaling, 3 and signal transducer and activator of transcription 3 did not demonstrate alterations in the expression of proteins in the fetuses of mothers fed with a saturated fatty diet. Moreover, no histopathological changes were noticed between groups. CONCLUSION: The saturated fatty diet does not induce tissue changes or activate the Janus kinase/signal transducer and activator of transcription signaling pathway during eye development in the fetuses of mothers with insulin resistance.

Serum Klotho and insulin resistance: Insights from a cross-sectional analysis.

The prevalence of diabetes has surged globally, posing significant health and economic burdens. Insulin resistance underlies the initiation and development of type 2 diabetes. Klotho is a crucial endogenous antiaging factor, associated with atherosclerotic cardiovascular diseases, cancer, neurological disorders, and renal diseases. It additionally has a function in controlling glucose metabolism and holds promise as a new therapeutic target for diabetes. However, its relationship with insulin resistance remains unclear. This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2007 to 2016 data to investigate the relationship between serum Klotho concentrations and insulin resistance. In this observational study, information from the NHANES spanning 2007 to 2016 was employed. The sample consisted of 6371 participants. Weighted linear regression model and chi-square tests were utilized to assess differences in continuous and categorical variables, respectively, among groups categorized by Klotho quartiles. The relationship between Klotho and HOMA-IR (homeostatic model assessment of insulin resistance) was studied using multiple linear regression. Smooth curve fitting was used to analyze nonlinear relationships and the inflection point was determined through a 2-stage linear regression method. After adjusting for multiple confounding factors, serum Klotho levels were found to be positively correlated with insulin resistance [0.90 (0.68, 1.13)]. This correlation is nonlinear and exhibits a saturation effect, with the inflection point identified at 1.24 pg/µL. When Klotho levels are below 1.24 pg/µL, for every unit increase in Klotho, HOMA-IR increases by 1.30 units. Conversely, when Klotho levels exceed 1.24 pg/µL, there is no correlation between HOMA-IR and Klotho. Subgroup analysis reveals that the relationship between HOMA-IR and Klotho varies depending on diabetes and body mass index (BMI). This positive correlation was most prominent in the obese nondiabetic population. There is a positive correlation between serum Klotho and insulin resistance.

Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Mitochondria-associated membranes contribution to exercise-mediated alleviation of hepatic insulin resistance: Contrasting high-intensity interval training with moderate-intensity continuous training in a high-fat diet mouse model.

OBJECTIVE: Mitochondria-associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high-fat diet (HFD) mice. METHODS: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin-eosin (H&E) and oil red O staining. The phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K-AKT-GSK3ß) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage-dependent anion-selective channel 1 [VDAC1] and inositol 1,4,5-triphosphate receptor [IP3R]). RESULTS: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3ß signaling pathway, accompanied by a marked reduction in hepatic IP3R-VDAC1 colocalization levels. Both 8-week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3ß signaling and colocalization levels of IP3R-VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R-VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p-AKT) and phosphorylation of glycogen synthase kinase 3 beta (p-GSK3ß), while displaying a negative correlation with serum triglyceride/high-density lipoprotein cholesterol levels. CONCLUSION: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise-induced alleviation of hepatic IR.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Resveratrol relieves HFD-induced insulin resistance in skeletal muscle tissue through antioxidant capacity enhancement and the Nrf2-Keap1 signaling pathway.

BACKGROUND: Resveratrol has received much attention due to its beneficial effects including antioxidant activity. The purpose of this study was to investigate the therapeutic effects of resveratrol treatment on oxidative stress and insulin resistance in the skeletal muscle of high-fat diet (HFD)-fed animals. METHODS AND RESULTS: A total of 30 six-week-old C57BL/6J mice were randomly allocated to three groups (10 animals in each group): The control group in which mice were fed a normal chow diet (NCD); the HFD group in which mice were fed an HFD for 26 weeks; and the HFD-resveratrol group in which HFD was replaced by a resveratrol supplemented-HFD (400 mg/kg diet) after 10 weeks of HFD feeding. At the end of this period, gastrocnemius muscle samples were examined to determine insulin resistance and the oxidative status in the presence of HFD and resveratrol. Resveratrol supplementation in HFD-fed mice reduced body and adipose tissue weight, improved insulin sensitivity, and decreased oxidative stress as indicated by lower malonaldehyde (MDA) levels and higher total antioxidant capacity. The supplement also increased the expression and activity of antioxidative enzymes in gastrocnemius muscle and modulated Nrf2 and Keap1 expression levels. CONCLUSIONS: These results suggest that resveratrol is effective in improving the antioxidant defense system of the skeletal muscle in HFD-fed mice, indicating its therapeutic potential to combat diseases associated with insulin resistance and oxidative stress.

Effects of Saikosaponin-A on Insulin Resistance in Obesity: Computational and Animal Experimental Study.

Obesity is known to be associated with increased inflammation and dysregulated autophagy, both of which contribute to insulin resistance. Saikosaponin-A (SSA) has been reported to exhibit anti-inflammatory and lipid-lowering properties. In this research, we employed a combination of computational modeling and animal experiments to explore the effects of SSA. Male C57BL/6 mice were categorized into four groups: normal diet, high-fat diet (HFD), HFD + atorvastatin 10 mg/kg, and HFD + SSA 10 mg/kg. We conducted oral glucose and fat tolerance tests to assess metabolic parameters and histological changes. Furthermore, we evaluated the population of Kupffer cells (KCs) and examined gene expressions related to inflammation and autophagy. Computational analysis revealed that SSA displayed high binding affinity to tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, fibroblast growth factor 21 (FGF21), and autophagy-related 7 (ATG7). Animal study demonstrated that SSA administration improved fasting and postprandial glucose levels, homeostatic model assessment of insulin resistance (HOMA-IR) index, as well as triglyceride, free fatty acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C)-cholesterol, and high-density lipoprotein cholesterol (HDL-C)-cholesterol levels in HFD-fed mice. Moreover, SSA significantly reduced liver weight and fat accumulation, while inhibiting the infiltration and M1 activation of KCs. At the mRNA level, SSA downregulated TNF-α and NF-κB expression, while upregulating FGF21 and ATG7 expression. In conclusion, our study suggests that SSA may serve as a therapeutic agent for addressing the metabolic complications associated with obesity. This potential therapeutic effect is attributed to the suppression of inflammatory cytokines and the upregulation of FGF21 and ATG7.

Discordant gene expression in subcutaneous adipose and skeletal muscle tissues in response to exercise training.

Exercise has different effects on different tissues in the body, the sum of which may determine the response to exercise and the health benefits. In the present study, we aimed to investigate whether physical training regulates transcriptional network communites common to both skeletal muscle (SM) and subcutaneous adipose tissue (SAT). Eight such shared transcriptional communities were found in both tissues. Eighteen young overweight adults voluntarily participated in 7 weeks of combined strength and endurance training (five training sessions per week). Biopsies were taken from SM and SAT before and after training. Five of the network communities were regulated by training in SM but showed no change in SAT. One community involved in insulin- AMPK signaling and glucose utilization was upregulated in SM but downregulated in SAT. This diverging exercise regulation was confirmed in two independent studies and was also associated with BMI and diabetes in an independent cohort. Thus, the current finding is consistent with the differential responses of different tissues and suggests that body composition may influence the observed individual whole-body metabolic response to exercise training and help explain the observed attenuated whole-body insulin sensitivity after exercise training, even if it has significant effects on the exercising muscle.

Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet.

Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic ß-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.

Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center.

BACKGROUND: Rare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications. OBJECTIVE: We aimed to evaluate the patients' age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care. PATIENTS AND METHODS: We analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares). RESULTS: A cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes (n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31-60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8-42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3-19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4-27.8] with a diagnostic delay of 10.5 years [IQR: 1.8-27.0]. CONCLUSION: The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.