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ABSTRACT: Reduced feed intake in early lactation prompts increased fat mobilization to meet dairy cow energy needs for milk production. The increased lipolysis in cows presents significant health risks with unclear mechanisms. The objectives of our study were to compare the longitudinal profiles of metabolites and lipids of serum from high- and low-lipolysis cows. Forty multiparous Holstein dairy cows were enrolled in the retrospective study. Serum samples were collected on d 7 before expected calving, as well as on d 5, 7, 14, and 21 postpartum. Dairy cows were grouped according to mean serum nonesterified fatty acids on d 5 and 7 after parturition as low (0.750 mmol/L; n = 8; HFM), indicating fat mobilization during early lactation. Lactational performance and serum metabolic parameters related to glucose and lipid metabolism, liver functions, oxidative status, and inflammatory responses were determined. Serum samples were subjected to liquid chromatography-MS-based metabolomics and lipidomics. Despite differences in postpartum BW change, there were no observed variations in milk yield and composition between the 2 groups. Serum β-hydroxybutyric acid, glucose, leptin, aspartate aminotransferase, IL-6, and tumor necrosis factor alpha were greater in cows with HFM than in cows with LFM. Serum adiponectin, revised quantitative insulin sensitivity check index, and albumin were lower in cows with HFM than in cows with LFM. Intensified fat mobilization in the HFM cows came along with reduced estimated insulin sensitivity, impaired liver functions, and increased oxidative stress and inflammatory responses. Differences in metabolic patterns were observed across the transition period when comparing serum blood matrixes (e.g., in different amino acids, acylcarnitines, and sphingolipids). The serum metabolome of the HFM cows was characterized by higher concentrations of glycine, acylcarnitines, carnosine, Cer(d20:0/18:0), Cer(d18:1/16:0), and Cer(t18:0/24:0) compared with LFM cows. The differential serum metabolites and lipids at different sampling times during the peripartum period were enriched in the sphingolipid metabolism. Differences in serum metabolic status parameters suggest that cows adopt varied metabolic adaptation strategies to cope with energy deficits postpartum. Our investigation found a comprehensive remodeling of the serum metabolic profiles in transition dairy cattle, highlighting the significance of alterations in sphingolipid species, as they play a crucial role in insulin resistance and metabolic disorders.

Background and aim: Type-2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) induced by hyperglycaemia and insufficient insulin secretion. We employed a diabetic fly model to examine the effect and molecular mechanism of Atractylodes macrocephala Koidz. and Cuscuta chinensis Lam. (AMK–CCL) extract as traditional Chinese medicine in treating IR and T2DM. Experimental procedure: The contents of the active ingredients (rhamnose, xylose, mannose, and hyperoside) in AMK–CCL extract were determined by high-performance liquid chromatography. Wild-type (Cg-GAL4/+) or diabetic (Cg > InRK1409A) Drosophila flies were divided into the control group or metformin group and AMK–CCL (0.0125, 0.025, 0.05, 0.1 g/ml) groups. Food intake, haemolymph glucose and trehalose, protein, weight, triglycerides (TAG), and glycogen were measured to assess glycolipid metabolism. Phosphatidylinositol-3-kinase (PI3K)/Akt signalling was detected using fluorescent reporters [tGPH, Drosophila forkhead box O (dFoxO)–green fluorescent protein (GFP), Glut1–GFP, 2-NBDG] in vivo. Glut1/3 mRNA levels and Akt phosphorylation levels were detected by quantitative polymerase chain reaction and western blotting, respectively, in vitro. Results: AMK–CCL extract contained 0.038 % rhamnose, 0.017 % xylose, 0.69 % mannose, and 0.039 % hyperoside. AMK–CCL at 0.0125 g/mL significantly suppressed the increase in circulating glucose, and the decrease in body weight, TAG, and glycogen contents of diabetic flies. AMK–CCL improved PI3K activity, Akt phosphorylation, Glut1/3 expression, and glucose uptake in diabetic flies, and also rescued diabetes-induced dFoxO nuclear localisation. Conclusions: These findings indicate that AMK–CCL extract ameliorates IR-induced diabetes via the PI3K/Akt signalling pathway, providing an experimental basis for clinical treatment.

Background: Liver plays a central role in systemic glucose and lipid metabolism. High-fat diet (HFD) and obesity are related to hepatic lipid accumulation and insulin resistance (InsR). Diacylglycerols (DAG) play a key role in the induction of InsR, however their involvement in hepatic InsR remains debated. This study aimed to clarify and confirm the role of glycero-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme in DAG synthesis, in the progression of hepatic InsR in the context of HFD-induced lipid accumulation and insulin resistance in the liver. Methods: Liver-targeted GPAT1 silencing was performed using shRNA-mediated hydrodynamic gene delivery. Lipid species including LCA-CoA, sphingolipids, DAG and acyl-carnitines were quantified using UHPLC/MS/MS while insulin signalling was assessed at protein level by Western Blot. Hepatic glucose metabolism, including glucose-6-pasphate content and gluconeogenesis rate was evaluated using GC/MS. Results: HFD-fed animals developed InsR, evidenced by increased HOMA-IR, enhanced gluconeogenesis and reduced glycogen content compared to controls. Hepatic GPAT1 silencing in HFD-fed animals resulted in a significant reduction of DAG and TAG levels, increased acyl-carnitines content and upregulated mitochondrial β-oxidation protein expression. These changes were accompanied by improved insulin signalling, enhanced glycogen storage, and reduced gluconeogenesis. Conclusions: Silencing GPAT1, and thereby reducing glycerolipid synthesis, promotes β-oxidation and ameliorates HFD-induced hepatic insulin resistance, confirming the enzyme's pivotal role in liver metabolic dysfunction associated with increased lipid supply.

Selaginella tamariscina extracts (STS), total flavonoids of Selaginella tamariscina (TFST) and the main active component amentoflavone (AMT) have hypoglycaemic-mitigating effects, but their efficacy and mechanism of action in db/db mice are unknown. This study aimed to evaluate the hypoglycaemic effects of Selaginella tamariscina and its extracts in db/db diabetic mice and explore their mechanisms through gut microbiota modulation and metabolomics. Sixty male db/db mice were divided into model (db/db), STS (1.1 g/kg), TFST (140 mg/kg), AMT (60 mg/kg), mulberry twig alkaloid tablets (MTA, 24 mg/kg), and metformin (Met, 160 mg/kg) groups. Another 10 db/m mice served as controls. Treatments lasted 4 weeks. Blood glucose, body weight, diabetes symptoms, lipid levels, pathological changes, oxidative stress markers and liver damage levels were assessed. The gut microbiota composition was analyzed via 16S rDNA sequencing, and urinary metabolomics was conducted to understand metabolic changes. Selaginella tamariscina and its extracts significantly improved hyperglycaemia, insulin sensitivity, lipid metabolism, oxidative stress and liver injury in db/db mice, among which TFST was the most effective, with an effect comparable to that of Met and superior to that of MTA. TFST regulates gut microbiota disorders and metabolic profiles in db/db diabetic mice and modulates Alloprevotella levels, affecting butyric acid content and, thus, exerting a hypoglycaemic effect. These findings suggest that TFST modulates Alloprevotella, influencing butyric acid levels, which improves glycaemic control, enhances insulin sensitivity, and prevents oxidative stress and tissue damage. In conclusion, TFST has potential as a natural therapeutic agent for the control of T2DM.

Background: Studies have linked per- and polyfluoroalkyl substances (PFAS) to chronic metabolic diseases. However, the relationship between PFAS exposure and insulin resistance (IR), a key pathophysiological basis of these metabolic diseases, in nondiabetic individuals have yet to be determined. Methods: This study analyzed data from 3909 participants (aged ≥20) from the NHANES 2003–2018 to investigate the associations between serum levels of seven PFAS and and IR indicators, including including HOMA-IR, HOMA-β, fasting insulin, QUICKI, and TyG index. Linear and logistic regression models were used, along with a restricted cubic spline to assess dose-response. Weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) models were used to assess the association between mixed PFAS exposure and IR. Results: Linear regression revealed that elevated exposure to PFOS [β (95 % CI): 0.04 (0.02, 0.06)], PFOA [0.04 (0.01, 0.06)], and Me_PFOSA_AcOH [0.04 (0.02, 0.06)] was associated with a higher TyG index in adults. Notably, Me_PFOSA_AcOH was negatively associated with IR when assessed by HOMA-IR >2.6 [OR (95 % CI): 0.88 (0.79, 0.98)], although this was not supported by linear regression findings. When IR was defined by a TyG index >8.6, exposure to the highest quartiles of PFOS, PFOA, and Me_PFOSA_AcOH was associated with an increased risk of IR by 63 %, 42 %, and 85 %, respectively [1.63 (1.21, 2.20); 1.42 (1.06, 1.92); 1.85 (1.37, 2.50)]. PFOS, PFOA, and Me_PFOSA_AcOH demonstrated a nonlinear dose-response relationship with IR risk. The WQS and qgcomp models revealed significant positive correlations with the TyG index. Conclusion: Mixed PFAS exposure in US nondiabetic adults was positively associated with IR, as indicated by the TyG index, particularly for PFOS, PFOA, and Me_PFOSA_AcOH. Further research is needed to establish causality, and reinforcing environmental risk mitigation strategies to reduce PFAS exposure is recommended.

Metabolic syndrome (MetS) is one of the most significant worldwide public health issues. Hypertension, visceral obesity, hyperglycemia, dyslipidemia, and insulin resistance are some of the contributing variables. The latest MetS preventative measures have focused on lifestyle factors and combination therapy, including exercise and herbal treatment. Cinnamon (Cinnamomum verum) is rich in phytochemicals, including phenolic and volatile compounds, responsible for its antitumor, anticancer, antidiabetic, and anti-hypertriglyceridemia potentials. Numerous clinical studies have demonstrated the value of cinnamon’s anti-inflammatory properties in treating diabetes. Cinnamon is crucial in maintaining normal levels of lipids in the blood. In the past ten years, several clinical studies have examined the effectiveness of cinnamon administration in managing inflammation-related diseases, metabolic abnormalities, and polycystic ovarian syndrome. Comprehensive information about the chemical composition, nutritional compounds, phytoconstituents, and protective role of cinnamon and cinnamaldehyde against metabolic syndrome has been presented in this review. An effort has also been made to explain the mechanisms of blood glucose management, visceral obesity management, and cinnamon safety and toxicity aspects.

The potential health-promoting effects of two edible seaweeds, Undaria pinnatifida sporophyll (UPS) and Gracilaria verrucosa (GV), were investigated by using in vitro and in vivo models. Water extracts of UPS and GV inhibited lipid accumulation in 3T3-L1 adipocytes by downregulating adipogenesis-related genes and stimulated lipolysis in mature adipocytes. In C57BL/6 mice, supplementation with UPS and GV powders ameliorated diet-induced obesity, insulin resistance, and systemic inflammation, resulting in lighter subcutaneous adipose tissue and decreased macrophage markers (F4/80, Cd11c, Cd206) and proinflammatory genes (Tnf-α, Il-1β, Il-6, Ccl2) in gonadal adipose tissue. Liver weight and hepatic triglyceride levels were also significantly lowered. Taken together, UPS and GV supplementation effectively prevented diet-induced obesity and chronic inflammation making them promising dietary ingredients for managing obesity and its associated disorders.

Background: Sarcopenic obesity (SO) and osteoarthritis (OA) are highly prevalent musculoskeletal conditions that significantly impair health-related quality of life. Aim: This study investigated the association between SO and OA, and explored the potential mediating role of insulin resistance in this relationship. We utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. Methods: This cross-sectional analysis employs NHANES data collected from 1999 to 2018, including participants aged 18 years and older. SO was assessed using dual-energy X-ray absorptiometry (DXA) measurements. Insulin resistance was estimated using the triglyceride-glucose (TyG) index. OA status was based on self-reported physician diagnosis. Statistical analyses included weighted logistic regression, restricted cubic spline (RCS) interaction analysis, mediation analysis using structural equation modeling (SEM), and receiver operating characteristic (ROC) curve analysis. Subgroup analyses were conducted based on age, sex, and diabetes status. Results: The sarcopenic obese group demonstrated the highest prevalence of OA (23.4 %), hypertension (47.8 %), and diabetes (12.0 %). Additionally, they exhibited elevated levels of triglycerides, cholesterol, glucose, blood urea nitrogen (BUN), creatinine, and uric acid. Logistic regression revealed significant positive associations between sarcopenic obesity, the TyG index, and OA risk. RCS analysis identified significant non-linear relationships and interactions of the TyG index with age, sex, and diabetes status on OA risk. Mediation analysis indicated that the TyG index mediated approximately 4.9 % of the effect of sarcopenic obesity on OA risk. ROC curve analysis demonstrated moderate diagnostic accuracy for the TyG index (AUC = 0.65), which improved when incorporated into the multivariate model (AUC = 0.78). Subgroup analyses confirmed significant associations between the TyG index and sarcopenic obesity with OA risk across different age, sex, and diabetes status categories. Conclusion: Our findings suggest a significant correlation between insulin resistance, as measured by the TyG index, and elevated OA risk in individuals with sarcopenic obesity. Targeting insulin resistance through future research may be a promising avenue to lower OA risk in this population.

Objectives: Insulin resistance determined by Homeostasis Model of Insulin Resistance (HOMA-IR) has been associated with functional decline in non-diabetic older subjects. However, insulin is not routinely assessed. The study evaluated the predictive value of non-insulin-dependent IR surrogates on functional decline in non-diabetic older men and women. Design and participants: Prospective cohort study over 5 years. The study included 615 older participants from the Toledo Study of Healthy Aging. Methods: Frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 5 years follow-up. 193 subjects experienced functional decline (2.5-point reduction in the FTS-5 score). Multivariate regression models analysed the effect of five described IR surrogates on functional decline considering potential confounders. Results: Among evaluated IR proxies, triglyceride glucose-body mass index (TyG-BMI) and HOMA-IR were significantly associated with an increased risk of functional decline (odd ratio (95% confidence interval) TyG-BMI: 1.16 (1.05, 1.28), p = 0.0035 and HOMA-IR: 1.59 (1.15, 2.21), p = 0.0056) among all participants. When stratified by gender, HOMA-IR was related to functional decline in men [2.02 (1.13, 3.59), p = 0.0173] and TyG-BMI in women [1.19 (1.05, 1.35), p = 0.0057]. Conclusions: Only TyG-BMI index mimics the predictive capacity of insulin-based IR marker. The predictive ability of IR indexes is gender-specific, being TyG-BMI the only index able to predict functional decline in women and HOMA-IR in men.

Global pandemic of obesity contributes to increasing the risk of diabetes and non-alcoholic fatty liver disease (NAFLD). To find an alternative approach to lower the risk caused by obesity. Aims: We investigated the antidiabetic and hepatoprotective activity of black rice bran extract (BRE) in obese, insulin-resistant rats induced by a high-fat diet (HFD). Main methods: After HFD feeding, the parameters related to glucose, lipid profiles, and liver injury were determined. Key findings: Rats on a HFD exhibited significantly elevated plasma glucose and lipid levels, as well as increased liver enzyme activities (aspartate transaminase and alanine transaminase), relative to the control group. Interestingly, those parameters in the BRE-treated group were significantly decreased. We investigated the liver histological study, and the BRE-treated group showed to ameliorate the liver injury accompanied by lower inflammatory and apoptotic markers. Significance: Our findings suggest that BRE has the potential to be used as a dietary supplement to lessen metabolic dysregulation and prevent liver impairment.

Background: Chronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. Methods: Male 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). Results: Four weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice. Conclusions: Chronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

Chickpea (Cicer arietinum L.) is a significant dietary source of flavonoids and the hypoglycemic activity were investigated in this study. Firstly, total twenty nine chickpea flavonoids were identified by UPLC-MS/MS with ononin, cyanidin-3-O-glucoside, astragalin, cynaroside, kaempferol-3-O-rutinoside, biochanin A, and daidzin being the most abundant among them. Our results demonstrated that chickpea flavonoids regulated glucose metabolism and lipid metabolism, and reduced oxidative stress in insulin resistance HepG2 cells. Furthermore, insulin resistance was ameliorated by chickpea flavonoids through the activation of insulin receptor substrate1 (IRS1), phosphoinositide 3-kinase (PI3K), and phosphorylated protein kinase B (Akt) in HepG2 cells. More importantly, key differential metabolites include L-tryptophan, L-tyrosine, l-glutamine and linoleic acid were reserved by chickpea flavonoids and correlated with glucolipid metabolism and oxidative stress in IR-HepG2 cells. In conclusion, these results indicated that chickpea flavonoids might act as potential natural products regulating insulin resistance in HepG2 cells.

Background and purpose: The composite score for insulin resistance (IR), known as the Metabolic Score of Insulin Resistance (METS-IR), serves as an assessment tool for IR and has been previously linked to symptomatic intracranial hemorrhage and poor functional outcomes in patients with acute ischemic stroke (AIS). Despite these associations, the impact of METS-IR on early neurological deterioration (END) in patients with minor AIS who underwent intravenous administration of recombinant tissue-type plasminogen activator (IV-rtPA) remains inadequately established. This investigation explored the link between METS-IR and END in patients with minor AIS receiving IV-rtPA treatment. Methods: In this study, a cohort comprising 425 consecutive patients with National Institutes of Health Stroke Scale Score (NIHSS)≤5 who underwent IV-rtPA treatment was included. The METS-IR was computed using the formula ln METS-IR=ln (2 × FBG + TG) × BMI/ln (HDL). END was defined as a NIHSS ≥2 within 24 h post IV-rtPA administration, while poor functional outcome was defined as a modified Rankin Scale (mRS) of 2–6. Multivariate logistical regression was performed to investigate the association between METS-IR and both poor functional outcomes and END. Results: Among the 425 enrolled patients, 64 (15.1 %) patients experienced END, while 80 (18.8 %) had poor functional outcomes three months post-discharge. Upon adjusting for confounding factors, a higher METS-IR emerged as an independent predictor for both END and poor functional outcomes. Similarly, noteworthy findings were observed when METS-IR was defined as a categorical group. The restricted cubic spline (RCS) analysis indicated a linear relationship between METS-IR and END (P = 0.593 for non-linearity, P = 0.034 for overall). The incorporation of METS-IR into the conventional model resulted in a significant enhancement of predictive accuracy for both END and poor functional outcomes. Conclusion: METS-IR emerges as an independent predictor for END and poor functional outcome at three months post-discharge in patients with minor AIS subjected to IV-rtPA. Considering its simplicity and clinical accessibility as an indicator of IR, METS-IR may hold guiding significance in clinical practice.

Patients with gain-of-function mutations of Dyrk1b have higher fasting blood glucose (FBG) levels. However, the role of Dyrk1b in glucose metabolism is not fully elucidated. Herein, we found that hepatic Dyrk1b overexpression in mice impaired systemic glucose tolerance and hepatic insulin signaling. Dyrk1b overexpression in vitro attenuated insulin signaling in a kinase activity-dependent manner, and its kinase activity was required for its effect on systemic glucose homeostasis and hepatic insulin signaling in vivo. Dyrk1b ablation improved systemic glucose tolerance and hepatic insulin signaling in mice. Quantitative proteomic analyses showed that Dyrk1b downregulated WW domain-binding protein 2 (Wbp2) protein abundance. Mechanistically, Dyrk1b enhanced Wbp2 ubiquitylation and proteasomal degradation. Restoration of hepatic Wbp2 partially rescued the impaired glucose homeostasis in Dyrk1b overexpression mice. In addition, Dyrk1b inhibition with AZ191 moderately improved systemic glucose homeostasis. Our study uncovers that hepatic Dyrk1b impairs systemic glucose homeostasis via its modulation of Wbp2 expression in a kinase activity-dependent manner.

This study aimed to examine the preventive effect of passion fruit extract (PFE) on HFD-induced hepatic steatosis. Forty-eight Male Sprague-Dawley (SD) rats were randomized into 6 groups;1) control, 2) HFD, 3) P250, 4) P500 (250 and 500 mg/kg BW of passion fruit, respectively), 5) P + SIM (250 mg/kg BW of passion fruit and 40 mg/kg BW of simvastatin), and 6) SIM (40 mg/kg BW of simvastatin). After 8 weeks, the passion fruit extract reduced the BW, lipids, oxidative stress, insulin resistance, increased fecal fat excretion, antioxidant enzymes, modulated related proteins and genes expressions (LDLR, ACC, FAS, Nrf2, NF-κB, IRS-1, Cd36, Hmgcr, Cyp7a1, and Bsep) in the liver. A histopathological study showed reduced fat droplets in the rat’s livers. The PFE possessed an anti-obesity property and was effective in improving hepatic steatosis, inflammation, oxidative stress, and insulin resistance in the HFD-fed rat. Therefore, this study clearly demonstrated that PFE effectively improves NAFLD.

Ophiopogonis radix has been used for both food and traditional Chinese medicine in China for millennia. Oligosaccharides of Ophiopogon japonicus (OOJ), the primary bioactive components of Ophiopogonis radix, have significant hypoglycemic and hypolipidemic effects. Insulin resistance (IR) and glucolipid metabolism were examined in vivo and in vitro in this work, utilizing IR-HepG2 cells and high-fat diet/streptozocin-induced type 2 diabetic mellitus (T2DM) rats as models. It was observed that OOJ efficiently improves various T2DM parameters, such as blood glucose, lipid profile, insulin sensitivity, glucose tolerance, glycogen content, glycogen consumption, liver index, and histopathology. These improvements may be attributed to the regulation and control of the insulin receptor substrate 1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/glycogen synthase kinase-3β (GSK-3β) signaling pathways. These findings suggest that OOJ has potential as a functional food ingredient and therapeutic agent for treating metabolic syndrome and T2DM.

Objective: Dietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8–12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors. Methods: The effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively. Results: MCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss. Conclusions: Dietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis.

The accumulation of advanced glycosylation end products (AGEs) from food in the body disrupts normal physiological insulin activity and causes insulin resistance. This study compared the effects of ten types of polyphenols on AGEs production in both chemical and food models. It also investigated the impact of polyphenols on AGEs-induced insulin resistance in HepG2 cell models. Results showed that luteolin had the strongest inhibitory effect on fluorescent AGEs in the three chemical models. Rutin exhibited the most potent capacity to inhibit AGEs in biscuit models. Moreover, rutin alleviated the glucose metabolism disorders induced by representative AGEs (methylglyoxal-modified bovine serum albumin, MGO-BSA) in HepG2 cells. Mechanistic studies revealed that rutin could inhibit the phosphorylation of insulin receptor substrate 1 (IRS1) and the activity of suppressor of cytokine signaling 3 (SOCS3), while activating the phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) to alleviate the MGO-BSA-induced insulin resistance in HepG2 cells.

This study was to examine the effects of fish oil on alcoholic brain damage in rats, focusing on the insulin signaling pathway. Thirty-six male Wistar rats were divided into control (Lieber-DeCarli control liquid diet), CF25 (control diet + 25 % fish oil substitution), CF57 (control diet + 57 % fish oil substitution), E (Lieber-DeCarli ethanol liquid diet), EF25 (ethanol diet + 25 % fish oil substitution), and EF57 (ethanol diet + 57 % fish oil substitution) groups. The behavioral test was also conducted. After 8 weeks, the E group exhibited brain damage, including nuclear-condensed pyramidal cells and positivity for ionized calcium-binding adaptor molecule 1 (Iba-1) antibody. The E group revealed the higher hippocampal insulin receptor substrate-1 (IRS-1) and hypothalamic glycogen synthase kinase 3β (GSK3β), while presented the lower hepatic IRS-1, hippocampal insulin-like growth factor-1 (IGF-1) receptor and glucose transporter 4 (GLUT4). After fish oil substitution, the brain nuclear condensation was attenuated and the hippocampal IRS-1 and hypothalamic GSK3β were significantly decreased.

Diabetes, a chronic condition characterized by an inability to maintain normal glucose levels significantly accounts for enhancing the cost of healthcare expenditure. Managing diabetes using a standard medication protocol more often leads to progressive failure in effectively treating the associated complications. The recent trends involve understanding of diabetes's genetic architecture and its consequences have provided the background for application of precision medicine for customizing protocols for preventing and managing the diabetes therapy. Further, utilizing the electronic health data and genetic information for assisting care and planning therapeutic protocol for monogenic form of diabetes is well-executed example of genomic medicine. The present write-up emphasized recent advances about the causes and effects of diabetes genetics. This also drive to the need for the further investigation for ensuring the appropriate knowledge to enable patients and healthcare providers to make informed decisions for obtaining the best possible outcome.

Background: We aimed to contrast plasma amino acid concentrations in pregnant women with Gestational Diabetes Mellitus (GDM) to those without, to analyze the link between plasma amino acid concentrations, GDM, insulin resistance, and insulin secretion at 24–28 weeks of gestation. Methods: The research employed a retrospective case-control study design at a single center. Basic demographic and laboratory data were procured from the hospital's case system. The study encompassed seventy women without gestational diabetes mellitus (GDM) and thirty-five women with GDM matched in a 1-to-2 ratio for age and pre-pregnancy BMI. Utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS), peripheral fasting plasma amino acid concentrations in these women, during mid-pregnancy, were duly measured. We carefully evaluated the significant differences in the quantitative data between the two groups and developed linear regression models to assess the independent risk factors affecting insulin resistance and insulin secretion. Results: Significant variations in insulin secretion and resistance levels distinguished GDM Group from the non-GDM group at three distinct time points, alongside relatively elevated serum Glycosylated Hemoglobin (HbA1c) levels. Triglycerides (TG) were also significantly increased in those with GDM during adipocytokine observations. Apart from glutamic acid and glutamine, the concentrations of the remaining 16 amino acids were notably increased in GDM patients, including all branched chain amino acids(BCAAs) and aromatic amino acids(AAAs). Ultimately, it was ascertained that fasting serum phenylalanine levels were independent risk factors affecting insulin resistance index and insulin secretion at various phases. Conclusions: Various fasting serum amino acid levels are markedly increased in patients with GDM, specifically phenylalanine, which may play role in insulin resistance and secretion.

Hyperglycemia, a hallmark of diabetes mellitus, significantly contributes to skeletal muscle atrophy, characterized by progressive muscle mass and strength loss. This review summarizes the mechanisms of hyperglycemia-induced muscle atrophy, examines clinical evidence, and discusses preventive and therapeutic strategies. A systematic search of electronic databases, including PubMed, Scopus, and Web of Science, was conducted to identify relevant papers on hyperglycemic skeletal muscle atrophy. Key mechanisms include insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Crucial molecular pathways involved are Phosphoinositide 3-kinase/Protein kinase B signaling, Forkhead box O transcription factors, the ubiquitin-proteasome system, and myostatin-mediated degradation. Hyperglycemia disrupts normal glucose and lipid metabolism, exacerbating muscle protein degradation and impairing synthesis. Clinical studies support the association between hyperglycemia and muscle atrophy, emphasizing the need for early diagnosis and intervention. Biomarkers, imaging techniques, and functional tests are vital for detecting and monitoring muscle atrophy in hyperglycemic patients. Management strategies focus on glycemic control, pharmacological interventions targeting specific molecular pathways, nutritional support, and tailored exercise regimens. Despite these advances, research gaps remain in understanding the long-term impact of hyperglycemia on muscle health and identifying novel therapeutic targets. The review aims to provide a comprehensive understanding of the mechanisms, clinical implications, and potential therapeutic strategies for addressing hyperglycemia-induced skeletal muscle atrophy.

Rational & Objective: Diabetes and uric acid kidney stones are strongly associated. Patients with calcium kidney stones also have higher risk of developing diabetes compared with nonkidney stone patients yet this has not been further investigated. We aimed to characterize insulin resistance in calcium kidney stone patients. Study Design: Observational. Setting & Population: This study was performed in the University of Chicago Clinical Research Center. Kidney stone patients (N = 42) were selected for having idiopathic hypercalciuria and calcium stones with no other medical conditions, and controls (N = 27) were healthy. Exposures: All participants presented to the Clinical Research Center in a fasting state and at least 2 timed fasting blood and urine collections were collected before a fixed breakfast. Six additional timed blood and urine collections were performed after breakfast. Outcomes: We compared fasting and fed indices of insulin resistance between the groups. Analytic Approach: We used t tests and multivariable linear regression models. A sensitivity analysis removing all patients who had ever been on a thiazide diuretic was also performed. Results: In separate multivariable linear models, kidney stone patients had higher fasting serum insulin levels (24 (3-46 pmol/L), P = 0.03) and higher homeostatic model of insulin resistance (HOMA-IR) (1.0 (0.2-1.8), P = 0.02). In separate multivariable linear models, kidney stone patients had higher fed serum glucose levels (10 (2-18 mg/dL), P = 0.01). Results were similar in a sensitivity analysis removing all patients who had ever been on a thiazide diuretic. There were no differences in urine composition based on HOMA-IR levels. Limitations: Single institution. Small sample size limited subanalyses by different calcium stone types. Conclusions: Calcium kidney stone patients without diabetes or other medical conditions demonstrated signs of insulin resistance compared with healthy matched controls. Plain-Language Summary: Diabetes is strongly associated with kidney stones, particularly uric acid kidney stones. However, patients who form calcium kidney stones may also have an increased risk of developing diabetes, but this has not been further explored. We collected markers of insulin resistance in otherwise healthy patients with calcium kidney stones and healthy control volunteers to evaluate for early signs of insulin resistance in patients with calcium kidney stones. Compared to healthy control participants, we found that patients with calcium kidney stones are more likely to have insulin resistance. Follow-up research is needed to determine the mechanisms contributing to insulin resistance in these patients. Earlier screening for insulin resistance may be beneficial for patients with calcium kidney stones.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood sugar levels (hyperglycemia). Poorly managed diabetes can lead to complications affecting multiple organ systems. Antioxidants play a crucial role in reducing oxidative stress caused by reactive oxygen species (ROS), primarily triggered by uncontrolled high blood sugar levels in diabetes. Antioxidants like vitamin C, E, selenium, and alpha-lipoic acid, when used as supplements, have shown promise in reducing oxidative stress markers and improving antioxidant status in laboratory and animal studies and diabetic patients. Antioxidant supplementation may help reduce the risk of diabetic complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Additionally, antioxidants also have anti-inflammatory properties, which could be beneficial in reducing inflammation associated with diabetes. Antioxidant supplementation has been shown to enhance endothelial function, insulin sensitivity, and glucose metabolism, thereby aiding in glycemic control and overall diabetic management. Combining antioxidants with certain medications may have therapeutic benefits, such as effectively neutralizing free radicals and enhancing the regulation of antioxidant defense systems. This review presents an update on diabetes, the sources of free radical generation, the body's natural defense mechanisms, the clinical evidence regarding using antioxidants in managing diabetic complications, and the potential new therapeutic approaches. Overall, antioxidant supplementation may offer some benefits in managing diabetic complications. However, further studies are needed to understand the mechanisms of action, determine the optimal supplementation, explore potential interactions with other medications, and conduct long-term studies to establish the possible use of antioxidants for optimal benefits in diabetes care.

Animal venoms are natural products that have served as a source of novel molecules that have inspired novel drugs for several diseases, including for metabolic diseases such as type-2 diabetes and obesity. From venoms, toxins such as exendin-4 (Heloderma suspectum) and crotamine (Crotalus durissus terrificus) have demonstrated their potential as treatments for obesity. Moreover, other toxins such as Phospholipases A2 and Disintegrins have shown their potential to modulate insulin secretion in vitro. This suggests an unexplored diversity of venom peptides with a potential anti-obesogenic in Mexican rattlesnake venoms. For that reason, this study explored the in vitro effect of Crotalus venom peptide-rich fractions on models for insulin resistance, adipocyte lipid accumulation, antioxidant activity, and inflammation process through nitric oxide production inhibition. Our results demonstrated that the peptide-rich fractions of C. aquilus, C. ravus, and C. scutulatus scutulatus were capable of reverting insulin resistance, enhancing glucose consumption to normal control; C. culminatus, C. molossus oaxacus, and C. polystictus diminished the lipid accumulation on adipocytes by 20%; C. aquilus, C. ravus, and C. s. salvini had the most significant cellular antioxidant activity, having nearly 80% of ROS inhibition. C. aquilus, C. pyrrhus, and C. s. salvini inhibited nitric oxide production by about 85%. We demonstrated the potential of these peptides from Crotalus venoms to develop novel drugs to treat type-2 diabetes and obesity. Moreover, we described for the first time that Crotalus venom peptide fractions have antioxidant and inflammatory properties in vitro models.

The complementary intervention to modulate diabetes mellitus (DM) metabolism has recently brought the global attention, since DM has become among the global burden diseases. Where, several related pathways elevate the production of superoxide in consequences. For example, the flux of glycation-derived end products (AGEs) could lead to the deactivation of insulin signaling pathways. In that context, many vitamins and phytochemicals in natural sources have high antioxidant impacts that reduce oxidative stress and cell damages. These chemicals could be applied as bioactive antidiabetic agents. Their mode of actions could be from regulating the intracellular reactive oxygen species (ROS) which cause several pro-inflammatory pathways related to the oxidative stress (OS) and DM. Besides, they have a great potential to control the epigenetic mutations and hyperglycemia and help in back the blood glucose to the normal level. Therefore, the current review addresses the important role of natural functional antioxidants in DM management and its association with its OS complications.

Background: Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition of increasing prevalence, is closely related to various metabolic disorders. Hemoglobin, a protein that transports oxygen in red blood cells, is the focus of this study, which seeks to investigate its potential association with NAFLD. Methods: We selected 6,516 eligible adult participants from the United States using the 2017–2020 National Health and Nutrition Examination Survey database for cross-sectional analyses. We analyzed the association of hemoglobin with NAFLD using weighted logistic regression models. Results: The study performed a weighted logistic regression modeling analysis, which verified that hemoglobin levels were positively associated with NAFLD, especially in the higher hemoglobin quartile groups. Subgroup analyses revealed no significant interactions, demonstrating the robustness of the model. The analysis of mediation effects showed that Gamma-Glutamyl Transferase, Alanine Aminotransferase, and triglycerides were important mediating variables in the relationship between hemoglobin and NAFLD. Conclusion: Increased hemoglobin levels were found to be significantly and independently associated with an increased NAFLD risk. This insight is crucial for the risk assessment and early detection of NAFLD, underscoring the need for heightened vigilance in individuals with higher hemoglobin levels.

Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.

Vitamin D's role extends beyond classical calcium and phosphate homeostasis to encompass a pivotal influence on immune modulation and metabolic health. The mechanisms by which vitamin D exerts these effects involve its conversion to hormonally active calcitriol, which binds intracellular vitamin D receptors, initiating various downstream cascades. In this review, we tease out the evidence showing the relationship between vitamin D deficiency and prediabetes within the context of subclinical inflammation, with a special focus on the novel monocyte-to-HDL ratio (MHR), a novel inflammatory marker reflecting subclinical inflammation. This was based on a thorough literature review using reputable databases covering the period from 1980 to 2024. In light of this, we discuss calcitriol's anti-inflammatory effects and consequently link vitamin D deficiency to both overt and subclinical inflammation. Additionally, the utility of several biomarkers, notably MHR, in investigating this association is also discussed. We further reviewed the role of vitamin D deficiency in precipitating prediabetes and type 2 diabetes mellitus (T2DM) via insulin resistance, decreased insulin synthesis and secretion, and subclinical inflammation. Taken together, this mini review highlights that vitamin D deficiency is significantly associated with subclinical inflammation, playing a critical role in the development of prediabetes and the progression to T2DM. Addressing vitamin D deficiency through appropriate interventions may serve as a preventative measure against the development of prediabetes and T2DM.

The global prevalence of Metabolic Syndrome (MetS) is continuously rising and exposure to environmental toxicants such as arsenic could be contributing to this rapid surge. In this study, we have assessed the effects of prenatal arsenic exposure on insulin resistance and MetS parameters in a mouse model, and an underlying mechanism was identified. We found that prenatal arsenic exposure promotes insulin resistance and adipocyte dysfunction which leads to the early onset of MetS in male offspring. Primary adipocytes isolated from 20-week-old arsenic-exposed offspring showed hypertrophy, elevated basal lipolysis, and impaired insulin response along with enhanced expression of Tumor necrosis factor-alpha (TNF-α). TNF-α levels were consistently high at gestational day 15.5 (GD15.5) as well as primary adipocytes of 6-week-old arsenic-exposed male offspring. Along with TNF-α, downstream p-JNK1/2 levels were also increased, which led to inhibitory phosphorylation of IRS1and reduced GLUT4 translocation upon insulin stimulation in adipocytes. Insulin response and downstream signaling were restored upon TNF-α inhibition, confirming its central role. The persistent overexpression of TNF-α in adipocytes of arsenic-exposed mice resulted from diminished EZH2 occupancy and reduced H3K27me3 (gene silencing histone marks) at the TNF-α promoter. This further led to chromatin relaxation, recruitment of c-Jun and CBP/p300, formation of an enhanceosome complex, and TNF-α expression. Our findings show how prenatal arsenic exposure can epigenetically modulate TNF-α expression to promote adipocyte dysfunction and insulin resistance which contributes to the early onset of MetS in offspring.

Objective: The current study aimed to investigate the potential therapeutic impact of allantoin on diabetes produced by a high-fat diet (HFD) and streptozotocin (STZ) in rats. Subjects and methods: Male Sprague-Dawley rats were fed a high-fat diet to induce insulin resistance, followed by streptozotocin injection to induce diabetes. The effect of oral treatment of allantoin (200, 400 and 800 mg/kg/day) for 8 weeks was evaluated by calculating the alteration in metabolic parameters, biochemical indicators, the oral glucose tolerance tests (OGTT) and hyperinsulinemic-euglycemic clamp tests were performed. Histopathological studies were performed in the liver, kidney and pancreas. Next, the expressions of the MAPK and insulin signaling pathway were measured by Western blot analysis to elucidate the potential mechanism underlying these antidiabetic activities. Results: The administration of allantoin resulted in a significant decrease in fasting blood glucose (FBG) levels, glycogen levels, and glycosylated hemoglobin levels in diabetic rats. Additionally, allantoin therapy led to a dose-dependent increase in body weight growth and serum insulin levels. In addition, the administration of allantoin resulted in a considerable reduction in lipid profile levels and amelioration of histological alterations in rats with diabetes. The administration of allantoin to diabetic rats resulted in a notable decrease in Malondialdehyde (MDA) levels, accompanied by an increase in the activity of antioxidant enzymes in the serum, liver, and kidney. The findings of oral glucose tolerance and hyperinsulinemic-euglycemic clamp tests demonstrated a significant rise in insulin resistance following the administration of allantoin. The upregulation of IRS-2/PI3K/p-Akt/GLUT expression by allantoin suggests a mechanistic relationship between the PI3K/Akt signaling pathway and the antihyperglycemic activity of allantoin. Furthermore, it resulted in a reduction in the levels of TGF-β1/p38MAPK/Caspase-3 expression in the aforementioned rat tissues affected by diabetes. Conclusions: This study implies that allantoin treats type 2 diabetes by activating PI3K. Additionally, it reduces liver, kidney, and pancreatic apoptosis and inflammation-induced insulin resistance.re

Objective: The main objective of this study was to find if thiamine disulfide (TD) lowers blood glucose level and improves insulin resistance (IR) in liver and muscle in rats with chronic type 1 diabetes (T1DM) using euglycemic-hyperinsulinemic clamp technique. Methods: A total of fifty male Wistar rats were assigned to five groups consisted of: non-diabetic control (NDC), diabetic control (DC), diabetic treated with thiamine disulfide (D-TD), diabetic treated with insulin (D-insulin), and diabetic treated with both TD and insulin (D-insulin+TD). Diabetes was induced by a 60 mg/kg dose of streptozotocin. Blood glucose levels, pyruvate tolerance test (PTT), intraperitoneal glucose tolerance test (IPGTT), levels of glycosylated hemoglobin (HbA1c), glucose infusion rate (GIR), liver and serum lipid profiles, liver glycogen stores, liver enzymes ([ALT], [AST]), and serum calcium and magnesium levels. were evaluated. Additionally, gene expression levels of phosphoenolpyruvate carboxykinase (Pepck), forkhead box O1 (Foxo1), and glucose transporter type 4 (Glut4) were assessed in liver and skeletal muscle tissues. Results: Blood glucose level was reduced by TD treatment. In addition, TyG index, HOMA-IR, serum and liver lipid profiles, HbA1c levels, and expressions of Foxo1 and Pepck genes were decreased significantly (P

Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP. Objective: To determine the role of miPEP in insulin resistance. Methods: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance. Results: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway. Conclusion: These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.

Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes.

Background: The triglyceride-glucose (TyG) index has been recommended as a practical surrogate of insulin resistance (IR). However, the association between the TyG index and hyperuricemia among adults with hypertension remains to be elucidated. Methods: We included and analyzed 3134 HTN patients and 4233 non-HTN participants from the cross-sectional 2013–2018 U.S. National Health and Nutrition Examination Surveys (NHANES). Multivariable logistic regression and restricted cubic splines (RCS) were used to explore the association between the TyG index and hyperuricemia. Stratifed analyses were performed to assess the association in populations with different subgroups of hypertension. Results: The prevalence of hyperuricemia was higher in HTN patients (28.00 %) than in non-HTN participants (12.47 %). The multivariable logistic regression showed that the TyG index was significantly associated with hyperuricemia. After multivariable adjustment, higher TyG index levels were found to be associated with a higher prevalence of hyperuricemia in HTN patients (OR: 2.39, 95 % CI: 1.37–4.17, Ptrend 0.05). In the subgroup analysis suggested that the positive association seemed to be strong among male, alcohol use, and diabetes group (P for interaction

Background: This investigation delineates the influence of resistance training on the expression of synaptic plasticity-related proteins in the hippocampi of insulin-resistant mice and explores the underlying molecular mechanisms. Methods: Six-week-old male C57BL/6 J mice were stratified into a control group and a high-fat diet group to induce insulin resistance over a 12-week period. Subsequently, the mice were further divided into sedentary and resistance training cohorts, with the latter engaging in a 12-week ladder-climbing regimen. Post-intervention, blood, and hippocampal specimens were harvested for analytical evaluation. Results: In the insulin-resistant mice, elevated blood lactate levels were observed alongside diminished expression of synaptic plasticity-related proteins, monocarboxylate transporters (MCTs), and reduced phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). In contrast, the expression of eukaryotic translation initiation factor 4 E-binding protein 2 was significantly augmented. Resistance training mitigated insulin resistance, decreased blood lactate levels, and enhanced the expression and phosphorylation of mTOR, regulatory-associated protein of mTOR, MCTs, and synaptic plasticity-related proteins. Conclusions: Resistance training mitigates insulin resistance and improves hippocampal synaptic plasticity by normalizing blood lactate levels and enhancing mTOR, MCTs, and synaptic plasticity-related proteins. It may also activate mTORC1 via the PI3K/Akt pathway, promote lactate utilization, and enhance synaptic plasticity proteins, potentially alleviating peripheral insulin resistance. Further research is needed to confirm these mechanisms.

Objective: This research sought to explore the association between the triglyceride-glucose (TyG) index and the risk of sarcopenia in patients with chronic inflammatory airway disease (CIAD). Methods: Data were obtained from the National Health and Nutrition Examination Survey 2011–2018. Grouping was performed using TyG index tertiles and multiple logistic regression was employed to assess the correlation between TyG levels and the risk of sarcopenia. The Receiver Operating Characteristic (ROC) curve analysis was conducted to determine the prognostic value of the TyG index for sarcopenia. Linear regression analysis was utilized to elucidate the direct relationship between TyG index and sarcopenia. Additionally, the curve between the TyG and sarcopenia indices was examined using a generalized additive model. Results: The study included 981 individuals diagnosed with CIAD. After adjusting for potential confounders, a significant positive correlation was observed between TyG and sarcopenia (OR = 1.70, 95 % CI: 1.20–2.39, P = 0.002). Trend analysis using the chi-square test revealed an increase in sarcopenia prevalence concomitant with higher TyG levels (P

Insulin resistance (IR) is the main cause of type 2 diabetes mellitus (T2DM). The specific targets and underlying mechanisms responsible for the ameliorative effects of the stilbenoid compounds found in fenugreek seeds for ameliorating IR require further study. Here, we were predicted by using the network pharmacology prediction, molecular docking and molecular dynamics simulation approach the targets in common and the potential mechanismsof three stilbenoid compounds (rhaponticin, desoxyrhaponticin, and rhapontigenin) in relation to T2DM and IR. The results showed that the compounds may improve IR through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Molecular docking studies revealed that they exhibit high binding affinity with the structural domains of peroxisome proliferator-activated receptor gamma (PPARG), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), PI3K, and AKT. These results suggest that PPARG and GAPDH may be the potential targets for these three compounds in the treatment of T2DM.Subsequently, experiments using the zebrafish T2DM model showed that the stilbenoid compounds had varying degrees of efficacy in improving IR through the PI3K/AKT/mTOR signaling pathway, and rhaponticin had the most promising effects. The findings implicate a potential mechanism of action for the three stilbenoid compounds in enhancing insulin resistance (IR) through modulation of the PI3K/AKT/mTOR pathway.

Metabolic syndrome (MetS) is a widespread and multifactorial disorder, and the study of its pathogenesis and treatment remains challenging. Autophagy, an intracellular degradation system that maintains cellular renewal and homeostasis, is essential for maintaining antimicrobial defense, preserving epithelial barrier integrity, promoting mucosal immune response, maintaining intestinal homeostasis, and regulating gut microbiota and microbial metabolites. Dysfunctional autophagy is implicated in the pathological mechanisms of MetS, involving insulin resistance (IR), chronic inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, with IR being a predominant feature. The study of autophagy represents a valuable field of research with significant clinical implications for identifying autophagy-related signals, pathways, mechanisms, and treatment options for MetS. Given the multifactorial etiology and various potential risk factors, it is imperative to explore the interplay between autophagy and gut microbiota in MetS more thoroughly. This will facilitate the elucidation of new mechanisms underlying the crosstalk among autophagy, gut microbiota, and MetS, thereby providing new insights into the diagnosis and treatment of MetS.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 μm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Adipose tissue is a crucial metabolic organ in the human body. It stores and exerts distinct physiological functions in different body regions. Fat not only serves as a cushion and insulator but also stores energy and conveys endocrine signals within the body. There is a growing recognition that adipose tissue is an organ that is misunderstood and underestimated in contribution to human health and disease progression by regulating its size and functionality. In mammals, the adipose tissue reservoir consists of three functionally distinct types of fat: white adipose tissue (WAT), brown adipose tissue (BAT), and beige or inducible brown adipose tissue (iWAT), which exhibits thermogenic capabilities intermediate between the other two. Fat in different depots exhibits considerable differences in origin, characteristics, and functions. They vary not only in adipocyte lineage, properties, thermogenesis, and endocrine functions but also in their immunological functions. In a recent study published in Nature Metabolism, Zhang et al. investigated the role of JunB in the thermogenic capacity of adipocytes and its significance in obesity and metabolic disorders. The study revealed that JunB expression in BAT coexists with both low and high thermogenic adipocytes, indicating a fundamental feature of heterogeneity and plasticity within BAT. In summary, this article demonstrates that research targeting JunB holds promise for improving diet-induced obesity and insulin resistance, offering new avenues for treating metabolic disorders.

Background: 1.8% of youth identify as transgender; a growing proportion are transgender male (female sex, male gender identity). Many receive gonadotropin releasing hormone agonist (GnRHa) therapy to suppress endogenous puberty and/or will start testosterone to induce secondary sex characteristics that align with gender identity. Objective(s): To determine the effects of 12 months of testosterone on cardiometabolic health among transgender youth, including insulin sensitivity, body composition, and bone mineral density and whether changes in outcomes differ based on prior GnRHa treatment. Methods: Participants (n = 19, baseline age 15.0 ± 1.0 years) were examined prior to and 12 months after testosterone therapy in a longitudinal observational study. Fasted morning blood draw, a 2-hour 75-gram oral glucose tolerance test, body composition and bone mineral density (dual-energy X-ray absorptiometry) were assessed at baseline and 12 months. Insulin sensitivity was estimated by HOMA-IR and Matsuda index. Changes were compared with mixed linear regression models evaluating time (baseline, 12 months), group (GnRHa treatment yes/no), and their interaction. Results: In the entire cohort, fasted insulin decreased (median [25,75 %ile]: −3 [-5, 0] mIU/L, p = 0.044) and 2-hour glucose increased (mean ± standard deviation): +18.5 ± 28.9 mg/dL, p = 0.013 from baseline after 12 months of testosterone therapy. There were no significant changes in HOMA-IR (p = 0.062) or Matsuda index (p = 0.096), nor by GnRHa status. Absolute (+6.2 [4.7, 7.5] kg, p = 0.016) and percent fat-free mass increased (+7.3 [5.4, 9.1] %, p = 0.003) and percent fat mass declined (−7.4 [-9.3, 5.3]%, p = 0.005) for the entire cohort. There were time*group interactions for absolute (p = 0.0007) and percent fat-free mass (p = 0.033). There were time*group interactions for bone mineral content (p = 0.006). Conclusions: Twelve months of testosterone in transgender adolescents resulted in changes in body composition and bone mineral density, with baseline differences between the +/-GnRHa group and convergence after 12 months. There were no changes in insulin sensitivity over time or between groups.

Diabetes mellitus is a global pandemic that is also fast rising in Africa, including Nigeria. Chronic consumption of white rice (WR) increases the risk of developing insulin resistance (IR) and type 2 diabetes (T2D). Similarly, Drosophila melanogaster is a suitable model organism for studying metabolic disorders. We hypothesized that maternal WR consumption could alter offspring's metabolic health and predispose to IR. Drosophila melanogaster (fruit fly) eggs were laid and developed on either Control, 50 % WR and 50 % brown rice (BR); and female adults maintained on these dietary regimens for 7 days. F1 and F2 offspring of these flies were fed either a normal diet or high sugar diet (HSD). The effects of maternal WR consumption on indices related to IR and T2D such as weight, locomotor activity, glucose, trehalose, glycogen and triglyceride (TG) were assessed in the parent and offspring generations. Similarly, the mRNA expression levels of ILP2, IRS, PEPCK and ACC were investigated. We found that WR consumption induced IR in the parent as evidenced by weight gain, significant increases in glucose, trehalose and TG levels, and reduced glycogen levels. Similarly, maternal WR consumption appeared to program for elevated glucose, trehalose and TG levels in F1 offspring with significant increases in trehalose and TG levels in the F2 offspring. These metabolic perturbations were accompanied by overexpression of ILP2, IRS, PEPCK and ACC. Offspring reared on HSD exhibited worsened conditions. In contrast, the levels of these metabolic signatures in the BR groups were comparable with the control. Taken together, our study demonstrates the potential of WR but not BR to program for transgenerational inheritance of IR-T2D-like phenotypes. This suggests that offspring of chronic WR consumers may be at risk of developing IR, affecting the development and health of future generations.

Gestational diabetes mellitus (GDM) has been linked with adverse pregnancy outcomes. Vitamin D receptor (VDR) gene variants have been associated with diabetes mellitus susceptibility and related complications. This study assessed the association between VDR gene polymorphism (rs2228570) and GDM risk among pregnant Arab women. A total of 368 pregnant Saudi women who were screened for GDM at 24−28 weeks of gestation and genotyped for the VDR gene variant (rs2228570) were included in this cross-sectional study. Circulatory insulin levels, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and vitamin D (25(OH)D) were measured. There were 108 women with GDM and 260 women without GDM. The genotype frequency of women with GDM was CC 60.2 %, CT 33.3 %, TT 6.9 %, and CT + TT 39.8 %; for non-GDM women, were CC 61.1 %, CT 31.5 %, TT 6.9 %, and CT + TT 38.4 %. No association was found between the VDR gene variant (rs2228570-FokI) and GDM susceptibility after adjustment for covariates. Serum 25(OH)D had a significant inverse association with FBG (r = −0.49, p = 0.01) and HbA1c (r = −0.45, p = 0.03) among carriers of the TT-genotype. Furthermore, a significant inverse correlation was observed between serum 25(OH)D and HOMA-β (r = −0.20, p = 0.035) in individuals with the T-allele. Among pregnant Saudi women, glycemic indices appear to be influenced by vitamin D, suggesting a possible role it may play in mitigating the metabolic changes associated with GDM, particularly among individuals with specific genetic backgrounds. In our study population, rs2228570-FokI did not appear to be a significant contributor to GDM risk.

Even in the absence of hyperglycemia or hyperlipidemia, it has been demonstrated that insulin resistance is an independent risk factor for atherosclerosis. Finding markers of insulin resistance that are associated with markers of atherosclerosis could help identify patients early in their disease course and allow for earlier initiation of preventative treatments. We reviewed available evidence regarding associations between known markers of insulin resistance and known markers of atherosclerosis. Serum triglycerides (TG), triglyceride-glucose index (TyG), and homeostasis model assessment (HOMA) were the insulin resistance markers reviewed. The coronary artery calcium score (CAC), carotid intimal medium thickness (cIMT), and pulse wave velocity (PWV) were reviewed as markers of atherosclerosis. TyG showed the most consistent association with CAC across broad demographic groups, though HOMA showed potential in obese individuals and those without diabetes. The data regarding cIMT and the reviewed insulin resistance markers did not yield any consistent associations, though very elevated TyG did appear to be associated with cIMT among normal weight individuals. Serum triglycerides showed a strong and consistent association with PWV across numerous studies and populations, though TyG index also demonstrated a strong association with PWV in a large systematic review. Of the insulin resistance markers reviewed, the TyG index appears to be most consistently associated with markers of atherosclerosis. TyG can be easily calculated with routine labwork and has the potential to inform decisions regarding early initiation of therapies in patients who would otherwise not be treated. Targeting insulin sensitivity prior to the development of T2DM has the potential to reduce development and progression of atherosclerosis, and patients without T2DM but who have elevated TyG index should be the topic of further research.

Gestational diabetes mellitus (GDM) is a pregnancy-specific disease characterized by impaired glucose tolerance during pregnancy. Although diagnosis and clinical management have improved significantly, there are still areas where therapeutic approaches need further improvement. Recent evidence suggests that CCL2, a chemokine involved in immunoregulatory and inflammatory processes, is closely related to GDM. However, the potential value for clinical therapeutic applications and the mechanism of CCL2 in adipose tissue macrophages (ATMs) of GDM remain to be elucidated. Here, we found that CCL2 was enriched in macrophages of the visceral adipose tissue from GDM women and HFD-induced GDM mice. The combination of in vitro and in vivo experiments showed that Ccl2 silencing inhibited the inflammatory response of macrophage by blocking calcium transport between ER and mitochondria and reducing excessive ROS generation. Additionally, the ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue was created. Under the delivery of ATS-9R peptide, Ccl2 siRNA is expressed in ATMs, which reduces inflammation in adipose tissue and, as a result, mitigates insulin resistance. All of these findings point to the possibility that the ATS-9R/siCcl2 complex, which targets adipose tissue, is able to reduce insulin resistance in GDM and the inflammatory response in macrophages. The ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue seems to be a viable treatment for GDM pregnancies.

Objective: Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout. Methods: Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. Results: Assessed on 45% fat diet to promote adipose expansion, global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression. Conclusions: Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.

The complex and multidimensional landscape of type 2 diabetes mellitus (T2D) is a major global concern. Despite several years of extensive research, the precise underlying causes of T2D remain elusive, but evidence suggests that it is influenced by a myriad of interconnected risk factors such as epigenetics, genetics, gut microbiome, environmental factors, organelle stress, and dietary habits. The number of factors influencing the pathogenesis is increasing day by day which worsens the scenario; meanwhile, the interconnections shoot up the frame. By gaining deeper insights into the contributing factors, we may pave the way for the development of personalized medicine, which could unlock more precise and impactful treatment pathways for individuals with T2D. This review summarizes the state of knowledge about T2D pathogenesis, focusing on the interplay between various risk factors and their implications for future therapeutic strategies. Understanding these factors could lead to tailored treatments targeting specific risk factors and inform prevention efforts on a population level, ultimately improving outcomes for individuals with T2D and reducing its burden globally.

Wheat alkylresorcinols (ARs) are phenolic lipids present in the bran part of whole grain wheat, which have been proven to improve obesity and atherosclerosis. However, the effects of ARs on hepatic steatosis and their possible mechanisms remain unclear. In the present study, ARs intervention significantly attenuated high-fat diet-induced hepatic steatosis, insulin resistance, and dyslipidemia. Meanwhile, RNA-seq and western-blot analysis in liver tissues among different treatment groups detected significant changes in pathways related to glycolipid metabolism, especially AMPK signaling pathway and transmission. Moreover, ARs treatment dose-dependently improved glucolipid metabolism through AMPK activation and GLUT4 translocation in PA-treated AML12 mouse hepatocytes model. However, the protective effect of ARs was reversed after pretreatment with AMPK inhibitor. Taken together, ARs can be used as a dietary functional ingredient to ameliorate glycolipid metabolic disorders.