Free fatty acids like palmitic acid (PA) are elevated in obesity and diabetes and dysregulate monocyte and macrophage functions, contributing to enhanced inflammation in these cardiometabolic diseases. Epigenetic mechanisms regulating enhancer functions play key roles in inflammatory gene expression, but their role in PA-induced monocyte/macrophage dysfunction is unknown. We found that PA treatment altered the epigenetic landscape of enhancers and super-enhancers (SEs) in human monocytes. Integration with RNA-seq data revealed that PA-induced enhancers/SEs correlated with PA-increased expression of inflammatory and immune response genes, while PA-inhibited enhancers correlated with downregulation of phagocytosis and efferocytosis genes. These genes were similarly regulated in macrophages from mouse models of diabetes and accelerated atherosclerosis, human atherosclerosis, and infectious agents. PA-regulated enhancers/SEs harbored SNPs associated with diabetes, obesity, and body mass index indicating disease relevance. We verified increased chromatin interactions between PA-regulated enhancers/SEs and inflammatory gene promoters and reduced interactions at efferocytosis genes. PA-induced gene expression was reduced by inhibitors of BRD4, and NF-κB. PA treatment inhibited phagocytosis and efferocytosis in human macrophages. Together, our findings demonstrate that PA-induced enhancer dynamics at key monocyte/macrophage enhancers/SEs regulate inflammatory and immune genes and responses. Targeting these PA-regulated epigenetic changes could provide novel therapeutic opportunities for cardiometabolic disorders.

A hallmark of subclinical metabolic decline is impaired metabolic flexibility, which refers to the ability to switch fuel utilization between glucose and fat according to energy demand and substrate availability. Herein, we propose optimizing metabolic health with digital twins that model an individual's metabolic flexibility profile to gamify the process of health optimization and predict long-term health outcomes. We explore key characteristics of this approach from technological and socioeconomical perspectives, with the objective of reducing the burden from metabolic disorders through driving behavior change and early detection of metabolic decline.

12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) was one of the newly found lipokines. The goal of this study was to investigate whether the 12,13-diHOME was associated with related metabolic markers of nonalcoholic fatty liver disease (NAFLD) in a Chinese population with type 2 diabetes (T2DM) and obesity.

This cross-sectional study enrolled 202 subjects with T2DM. Anthropometric parameters, 12,13-diHOME, serum lipids levels, fasting blood-glucose (FBG), serum glycosylated hemoglobin (HbA1c), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), liver and kidney function parameters were collected. NAFLD was diagnosed based on abdominal ultrasonography examination results. A computer-aided ultrasound quantitative method was applied to evaluate the liver fat content (LFC).

The number of the patients with fatty liver was 139 (68.81%) and those with non-fatty liver was 63 (31.19%). Subjects with NAFLD had a higher body mass index (BMI), diastolic blood pressure, serum alanine aminotransferase (ALT), triglyceride (TG), HOMA-IR, LFC, P<0.05 for all. But no significant difference was found in plasma 12,13-diHOME level (P=0.967), though its level trend was higher in non-NAFLD group. Plasma 12,13-diHOME was positively correlated with aspartate aminotransferase (AST), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), blood urea nitrogen (BUN), free fatty acid (FFA), C-peptide, FINS and HOMA-IR. It was negatively correlated with height, body weight, glomerular filtration rate (eGFR) and HbA1c.

Although 12,13-diHOME was correlated with AST, TC, HDL-C, BUN, FFA, C-peptide, FINS, HOMA-IR, eGFR and HbA1c, there was no significant difference in 12,13-diHOME level between the two groups. However, more research should be carried on about this newly-found lipokine.

Comprehensive analysis of serum lipidomics is important for the treatment and prevention of type 2 diabetes (T2DM). The purpose of this study was to provide a profile of lipid changes in the serum of T2DM patients and identify potential lipid biomarkers.

In this study, we collected clinical physiological parameters and determined the serum lipid profiles of 30 T2DM patients and 30 matched healthy volunteers using the UPLC-MS method. T test and multivariate statistical analyses were used to identify candidate lipid predictors using the GraphPad Prism 9.5 software and MetaboAnalyst 5.0 online platform.

Based on the above test, 1162 lipid metabolites were detected, of which 267 were significantly altered in the T2DM group (FDR < 0.05), which belonged to the five main lipid classes. Eleven lipids were identified as potential lipid biomarkers with the specific screening criteria (variable importance in the projection (VIP) >1.0; P < 0.05; log2(Fold Change) > 1) in the MetaboAnalyst 5.0 online platform. The Pearson rank correlation test showed that ten differential lipids were significantly correlated with T2DM-related physiological parameters (2h-loaded blood glucose and HbAc1 (glycated haemoglobin)). ROC curve analyses revealed that the combined 11 lipids or LPI classes can be as candidate features for the development of an integrated diagnostic biosignature for T2DM.

The results of this study revealed important changes in lipids in T2DM patients, expanded the knowledge of lipid levels and T2DM progression, and provided important metabolic information for the therapy and diagnosis of T2DM.

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) stems from disrupted lipid metabolism in the liver, often linked to obesity, type 2 diabetes, and dyslipidemia. In Mexico, where obesity affects 36.9% of adults, MASLD prevalence has risen, especially with metabolic syndrome affecting 56.31% by 2018. MASLD can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), affecting 5.27% globally, leading to severe complications like cirrhosis and hepatocellular carcinoma. Background: Visceral fat distribution varies by gender, impacting MASLD development due to hormonal influences. Insulin resistance plays a central role in MASLD pathogenesis, exacerbated by high-fat diets and specific fatty acids, leading to hepatic steatosis. Lipotoxicity from saturated fatty acids further damages hepatocytes, triggering inflammation and fibrosis progression in MASH. Diagnosing MASLD traditionally involves invasive liver biopsy, but non-invasive methods like ultrasound and transient elastography are preferred due to their safety and availability. These methods detect liver steatosis and fibrosis with reasonable accuracy, offering alternatives to biopsy despite varying sensitivity and specificity. Conclusions: MASLD as a metabolic disorder underscores its impact on public health, necessitating improved awareness and early management strategies to mitigate its progression to severe liver diseases.

This study aims to analyze baseline profiles and longitudinal changes in Atherogenic Index of Plasma (AIP) among individuals with prediabetes to identify distinct AIP trajectories and assess their significance in predicting diabetes onset.

This retrospective cohort study analyzed data from 8346 participants who underwent multiple general health checks. Utilizing latent class trajectory modeling and Cox proportional hazards analyses, it examined the association between the AIP index and health outcomes.

Over about 2 years, 2897 people progressed from prediabetes to diabetes. Individuals in the highest quartile of AIP had a higher diabetes risk compared to the lowest quartile (HR = 1.138, 95% CI1.013-1.278). Trajectory analysis revealed three groups: low-stable, moderate-stable, and high-stable, based on AIP index. The moderate-stable group showed a 1.117-fold risk of diabetes progression (95% CI1.026-1.217), while the high-stable group had an elevated risk (HR = 1.224, 95% CI1.059-1.415).

The study highlights a clear association between higher AIP index levels at baseline and an increased risk of diabetes progression. It underscores the significance of utilizing the AIP index as a predictive tool to identify those at risk, emphasizing the need for targeted preventive measures in managing diabetes progression.

Type 2 diabetes mellitus (T2DM) demonstrates a higher risk of fractures compared to the healthy population. Therefore, the aim of our study is to assess the risk of osteoporosis in T2DM patients.

A cross-sectional observational study was conducted in T2DM patients. The serum levels of bone resorption markers- carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1) and tartrate-resistant acid phosphatase 5b (TRACP-5b) were compared in the T2DM group (n = 43) and the control group (n = 43) and its association with duration of T2DM, HbA1c level, body mass index (BMI), oral hypoglycaemic agents (OHA), and level of functioning was evaluated.

CTX-1 and TRACP-5b were significantly lower in the T2DM group compared to the control group (p < 0.05). There was no significant correlation between the bone resorption markers and the duration of T2DM and HbA1c levels. However, a significant positive correlation was found between the level of functioning and TRACP-5b level, but no such correlation was observed in T2DM patients. The linear regression model revealed that none of the OHA affected the levels of CTX-1 and TRACP-5b.

The bone resorption markers are not influenced by the duration of T2DM and HbA1c level. However, they were significantly associated with BMI and the level of functionality. However, further research is needed to strengthen the evidence of the association between T2DM and osteoporosis.

Obesity-induced insulin resistance (IR) can precipitate metabolic disorders such as diabetes. Zeaxanthin, a crucial member of the carotenoid family, has been found to mitigate the damage caused by obesity. However, reports on the effects of zeaxanthin on obesity-induced IR are lacking. Our objective was to examine the metabolic regulatory impacts of zeaxanthin on mice subjected to a high-fat diet (HFD) that triggered IR and to explore their influence on gut microbiota regulation. This study constructed a mouse model of metabolic dysfunction caused by lipid-rich nutritional patterns to investigate physiological and biochemical indices, liver pathway expression, and the intestinal microbiota. The mechanisms by which zeaxanthin improved both IR and glucose metabolic disorders were elucidated. The results demonstrate that zeaxanthin effectively suppressed obesity. The fasting blood glucose, area under curve of oral glucose tolerance test and insulin tolerance test, and homeostatic model assessment-insulin resistance (HOMA-IR) indices in the HFDZEA group decreased by 14.9%, 25.2%, 28.9%, and 29.8%. Additionally, zeaxanthin improved the lipid metabolism and alleviated damage to the liver and pancreas while also activating the PI3K/Akt pathway, regulating hepatic gluconeogenesis and the glycogen metabolism. The number of OTUs in the HFDZEA group increased by 29.04%. Zeaxanthin improved the structure and profile of the gastrointestinal microbiome and enhanced its diversity, increasing probiotics abundance, decreasing pathogen abundance, and thereby ameliorating the dysbiosis of enteric microbial communities in rodents with obesity resulting from excessive fat consumption. The outcomes of our analysis provide a rational basis for advancing zeaxanthin-based nutritional products.

Pathologies in adipose (fat) tissue function are linked with human diseases such as diabetes, obesity, metabolic syndrome, and cancer. Dynamic, rapid release of metabolites has been observed in adipocyte cells and tissue, yet higher temporal resolution is needed to adequately study this process. In this work, a microfluidic device with precise and regular valve-automated droplet sampling, termed a microfluidic analog-to-digital converter (μADC), was used to sample secretions from ∼0.75 mm diameter adipose explants from mice, and on-chip salt water electrodes were used to merge sampled droplets with reagent droplets from two different fluorometric coupled enzyme assays. By integrating sampling and assays on-chip, either glycerol or non-esterified fatty acids (NEFA), or both, were quantified optically within merged 12 nanoliter droplets using a fluorescence microscope with as high as 20 second temporal resolution. Limits of detection were 6 μM for glycerol (70 fmol) and 0.9 μM for NEFA (10 fmol). Multiple ex vivo adipose tissue explants were analyzed with this system, all showing clear increases in lipolytic function after switching from feeding to fasting conditions. Enabled by high temporal resolution, lipolytic oscillations of both glycerol and NEFA were observed for the first time in the range of 0.2 to 1.6 min-1. Continuous wavelet transform (CWT) spectrograms and burst analyses (0.1 to 4.0 pmol bursts) revealed complex dynamics, with multiplexed assays (duplex for glycerol and NEFA) from the same explants showing mostly discordant bursts. These data support separate mechanisms of NEFA and glycerol release, although the connection to intracellular metabolic oscillations remains unknown. Overall, this device allowed automated and highly precise temporal sampling of tissue explants at high resolution and programmable downstream merging with multiple assay reagents, revealing unique biological information. Such device features should be applicable to various other tissue or spheroid types and to other assay formats.

Sphingolipids are linked to the pathogenesis of type 2 diabetes.

To test the hypothesis that plasma sphingolipid profiles predict incident prediabetes.

A case-control study nested in the Pathobiology of Prediabetes in a Biracial Cohort study, a 5-year follow-up study.

Academic health center.

Normoglycemic adults enrolled in the Pathobiology of Prediabetes in a Biracial Cohort study. Assessments included oral glucose tolerance test, insulin sensitivity, and insulin secretion. Participants with incident prediabetes were matched in age, sex, and ethnicity with nonprogressors.

We assayed 58 sphingolipid species (ceramides, monohexosyl ceramides, sphingomyelins, and sphingosine) using liquid chromatography/tandem mass spectrometry in baseline plasma levels from participants and determined association with prediabetes risk.

The primary outcome was progression from normoglycemia to prediabetes, defined as impaired fasting glucose or impaired glucose tolerance.

The mean age of participants (N = 140; 50% Black, 50% female) was 48.1 ± 8.69 years, body mass index 30.1 ± 5.78 kg/m2, fasting plasma glucose 92.7 ± 5.84 mg/dL, and 2-hour plasma glucose 121 ± 23.3 mg/dL. Of the 58 sphingolipid species assayed, higher ratios of sphingomyelin C26:0/C26:1 (OR, 2.73 [95% CI, 1.172-4.408], P = .015) and ceramide C18:0/C18:1 (OR, 1.236 [95% CI, 1.042-1.466], P = .015) in baseline plasma specimens were significantly associated with progression to prediabetes during the 5-year follow-up period, after adjustments for age, race, sex, body mass index, fasting plasma glucose, 2-hour plasma glucose, insulin sensitivity, and insulin secretion.

We conclude that the saturated-to-monounsaturated ratios of long-chain ceramide C18:0/C18:1 and very-long-chain sphingomyelin C26:0/C26:1 are potential biomarkers of prediabetes risk among individuals with parental history of type 2 diabetes.

Deciphering the mechanisms underlying the direct association between fructose consumption and the onset and progression of non-alcoholic fatty liver disease (NAFLD), as well as the high prevalence of metabolic syndrome (MetS), is of great importance for adopting potential nutritional strategies. Thus, an evaluation of the impact of sustained high fructose consumption on the liver physiology of Wistar rats was made. Moreover, the effectiveness of a dietary pomegranate-derived supplement (P) at counteracting fructose-induced liver injury was also assessed. For unveiling the underlying mechanisms, an untargeted proteomic analysis of the livers from nineteen Wistar rats fed on a basal commercial feed and supplemented with either drinking water (C) (n = 6), 30 % (w/v) fructose in drinking water (F) (n = 7) or 30 % (w/v) fructose solution plus 0.2 % (w/v) P (F+P) (n = 6) was assessed. Fructose intake severely increased the abundance of several energy-production related-proteins, such as fructose-bisphosphate aldolase or fatty acid synthase, among others, as well as diminished the amount of another ones, such as carnitine O-palmitoyl transferase or different subunits of acyl-coenzyme A oxidase. These changes could facilitate mitochondrial disturbances and oxidative stress. Regarding the hepatic proteome of F, P extract restored mitochondrial homeostasis and strengthened endogenous antioxidant mechanisms diminishing the amount of proteins involved in process that could increase the oxidative status, as well as increasing both the quantity of several proteins involved in proteasome functionality, as expressing changes in the amount of certain RNA-splicing related-proteins, regarding F proteome.

Ulcerative colitis (UC) and diabetic kidney disease (DKD) are chronic disorders with multifaceted pathogenesis, posing significant challenges in clinical management. While substantial efforts have been made to investigate the individual causes of these diseases, the interplay between UC and DKD is not well understood. This study aims to elucidate the genetic association between UC and DKD through Mendelian randomization (MR) analysis, offering new insights into common biological pathways and potential clinical implications.

We conducted a bidirectional two-sample MR study utilizing data from large-scale genome-wide association studies (GWAS) for both UC and DKD. Instrumental variables (IVs) were meticulously selected according to genome-wide significance and stringent statistical criteria, ensuring robust causal inference. Various MR methodologies, including inverse variance weighting (IVW), were employed to assess the causal relationships between UC and DKD. Sensitivity analyses were also performed to validate the robustness of our findings.

Our analysis revealed a significant causal relationship between genetic predisposition to UC and increased susceptibility to DKD. Specifically, individuals with a genetic susceptibility to UC exhibited a 17.3% higher risk of developing DKD. However, we found no evidence of a causal link between DKD and the risk of developing UC. Additionally, we identified shared genetic risk factors and molecular pathways linking UC and DKD, thereby highlighting potential therapeutic targets.

This study underscores the intricate genetic interplay between UC and DKD, suggesting that individuals with UC may be at an elevated risk for developing DKD. Understanding these shared genetic pathways could facilitate the development of early detection strategies and targeted interventions for individuals at risk of DKD. Ultimately, these insights could lead to improved clinical outcomes for patients suffering from both conditions.

Lipid metabolism is a critical component in preserving homeostasis and health, and lipids are significant chemicals involved in energy metabolism in living things. With the growing interest in lipid metabolism in recent years, an increasing number of studies have demonstrated the close relationship between abnormalities in lipid metabolism and the development of numerous human diseases, including cancer, cardiovascular, neurological, and endocrine system diseases. Thus, understanding how aberrant lipid metabolism contributes to the development of related diseases and how it works offers a theoretical foundation for treating and preventing related human diseases as well as new avenues for the targeted treatment of related diseases. Therefore, we discuss the processes of aberrant lipid metabolism in various human diseases in this review, including diseases of the cardiovascular system, neurodegenerative diseases, endocrine system diseases (such as obesity and type 2 diabetes mellitus), and other diseases including cancer.

There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = - 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative.

To identify predictors of incident type 2 diabetes using a mixed meal tolerance test (MMTT).

Adult Indigenous Americans without diabetes (n = 501) from a longitudinal cohort underwent at baseline a 4-h MMTT, measures of body composition, an oral glucose tolerance test, an intravenous glucose tolerance test for acute insulin response (AIR), and a hyperinsulinemic-euglycemic clamp for insulin action (M). Plasma glucose responses from the MMTT were quantified by the total and incremental area under the curve (AUC/iAUC).

At follow-up (median time 9.6 [inter-quartile range: 5.6-13.5] years), 169 participants were diagnosed with diabetes. Unadjusted Cox proportional hazards models, glucose AUC180-min (HR: 1.98, 95% CI: 1.67, 2.34, p < 0.0001), AUC240-min (HR: 1.93, 95% CI: 1.62, 2.31, p < 0.0001), and iAUC180-min (HR: 1.43, 95% CI: 1.20, 1.71, p < 0.0001) were associated with an increased risk of diabetes. After adjustment for covariates (age, sex, body fat percentage, M, AIR, Indigenous American heritage) in three subsequent models, AUC180-min (HR: 1.44, 95% CI: 1.10, 1.88, p = 0.007) and AUC240-min (HR: 1.41, 95% CI: 1.09, 1.84, p < 0.01) remained associated with increased risk of diabetes.

Glucose responses to a mixed meal predicted the development of type 2 diabetes. This indicates that a mixed nutritional challenge provides important information on disease risk.

ClinicalTrials.gov identifier : NCT00340132, NCT00339482.

The consumption of added sugar has increased rapidly in recent years. Limited knowledge exists regarding the association between added sugar intake and muscle strength, although the latter is a predictor of physical disability in older adults. This study aimed to investigate the association between added sugar intake and longitudinal changes in handgrip strength among middle-aged and elderly Chinese adults.

This prospective cohort study included 5298 adults aged 40 years and older (62.6% men) from the TCLSIH (Tianjin Chronic Low-grade Systemic Inflammation and Health) cohort study. Added sugar intake was obtained through a frequency questionnaire containing 100 items of food. Handgrip strength is measured annually using a handheld digital dynamometer. Multivariate linear regression models were used to examine the association between added sugars intake and the annual changes in handgrip strength and weight-adjusted handgrip strength.

In the fully adjusted model, the annual change in handgrip strength for one unit increase in total added sugar, solid added sugar, and liquid added sugar intake was -0.0353 kg, (95% confidence intervals (CI) -0.000148, -0.0000164; P = 0.01), -0.0348 kg (95% CI: -0.000227, -0.0000269; P = 0.01) and -0.0189 kg (95% CI -0.000187, 0.0000338; P = 0.17), respectively. Added sugar from bread and biscuits sources were remarkably associated with a decline in handgrip strength (β = -0.0498; 95%CI -0.00281, -0.000787) and (β = -0.0459; 95%CI 0.00158, 0.00733) (P < 0.01).

Our data suggest that the higher the intake of solid added sugars, but not liquid sugars, were associated with the declined handgrip strength in the Chinese middle-aged and elderly population. In addition, the consumption of added sugars from bread and biscuits sources was also associated with a decline in grip strength.

Statins were regarded as a main medication for managing hypercholesterolemia. Administration of statin therapy could reduce the incidence of cardiovascular disease in individuals diagnosed with type 2 diabetes mellitus (DM), which was recognized by multipal clinical guidelines. But previous studies had conflicting results on whether the long-term use of statins could benefit the renal function in diabetic patients.

To evaluate the association between statin treatment and Chronic Kidney Disease in DM patients.

This is a retrospective disproportionality analysis and cohort study based on real-world data. All DM cases reported in US Food and Drug Administration adverse event reporting system (FAERS) between the first quarter of 2004 and the fourth quarter of 2022 were included. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). We further compared the CKD odds ratio (OR) between the statins group and the other primary suspected drug group among the included diabetes mellitus cases.

We finally included 593647 DM cases from FAERS, 5113 (5.31%) CKD cases in the statins group and 8810 (1.77%) CKD cases in the control group. Data analysis showed that the statins group showed a significant CKD signal (ROR: 3.11, 95% CI: 3.00-3.22; IC: 1.18, 95% CI: 1.07-1.29). In case group with two or more statins treatment history, the CKD signal was even stronger (ROR: 19.56, 95% CI: 18.10-21.13; IC: 3.70, 95% CI:3.44-3.93) compared with cases with one statin treatment history.

The impact of statin therapy on the progression of renal disease in individuals diagnosed with type 2 diabetes mellitus (DM) remains inconclusive. After data mining on the current FAERS dataset, we discovered significant signals between statin treatment and CKD in diabetic patients. Furthermore, the incidence rate of CKD was higher among DM patients who used statins compared to those who did not.

A detailed study of palmitate metabolism in pancreatic islets subject to different experimental conditions, like varying concentrations of glucose, as well as fed or starved conditions, has allowed us to explore the interaction between the two main plasma nutrients and its consequences on hormone secretion. Palmitate potentiates glucose-induced insulin secretion in a concentration-dependent manner, in a physiological range of both palmitate (0-2 mM) and glucose (6-20 mM) concentrations; at glucose concentrations lower than 6 mM, no metabolic interaction with palmitate was apparent. Starvation (48 h) increased islet palmitate oxidation two-fold, and the effect was resistant to its inhibition by glucose (6-20 mM). Consequently, labelled palmitate and glucose incorporation into complex lipids were strongly suppressed, as well as glucose-induced insulin secretion and its potentiation by palmitate. 2-bromostearate, a palmitate oxidation inhibitor, fully recovered the synthesis of complex lipids and insulin secretion. We concluded that palmitate potentiation of the insulin response to glucose is not attributable to its catabolic mitochondrial oxidation but to its anabolism to complex lipids: islet lipid biosynthesis is dependent on the uptake of plasma fatty acids and the supply of α-glycerol phosphate from glycolysis. Islet secretion of glucagon and somatostatin showed a similar dependence on palmitate anabolism as insulin. The possible mechanisms implicated in the metabolic coupling between glucose and palmitate were commented on. Moreover, possible mechanisms responsible for islet gluco- or lipotoxicity after a long-term stimulation of insulin secretion were also discussed. Our own data on the simultaneous stimulation of insulin, glucagon, and somatostatin by glucose, as well as their modification by 2-bromostearate in perifused rat islets, give support to the conclusion that increased FFA anabolism, rather than its mitochondrial oxidation, results in a potentiation of their stimulated release. Starvation, besides suppressing glucose stimulation of insulin secretion, also blocks the inhibitory effect of glucose on glucagon secretion: this suggests that glucagon inhibition might be an indirect or direct effect of insulin, but not of glucose. In summary, there seems to exist three mechanisms of glucagon secretion stimulation: 1. glucagon stimulation through the same secretion coupling mechanism as insulin, but in a different range of glucose concentrations (0 to 5 mM). 2. Direct or indirect inhibition by secreted insulin in response to glucose (5-20 mM). 3. Stimulation by increased FFA anabolism in glucose intolerance or diabetes in the context of hyperlipidemia, hyperglycemia, and hypo-insulinemia. These conclusions were discussed and compared with previous published data in the literature. Specially, we discussed the mechanism for inhibition of glucagon release by glucose, which was apparently contradictory with the secretion coupling mechanism of its stimulation.

Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae. These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases.

Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice.

We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved β-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits.

Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.

Long-chain fatty acyl-CoAs (LCACoAs) are intermediates in lipid metabolism that exert a wide range of cellular functions. However, our knowledge about the subcellular distribution and regulatory impacts of LCACoAs is limited by a lack of methods for detecting LCACoAs in living cells and tissues. Here, we report our development of LACSerHR, a genetically encoded fluorescent biosensor that enables precise measurement of subtle fluctuations in the levels of endogenous LCACoAs in vivo. LACSerHR significantly improve the fluorescent brightness and analyte affinity, in vitro and in vivo testing showcased LACSerHR's large dynamic range. We demonstrate LACSerHR's capacity for real-time evaluation of LCACoA levels in specific subcellular compartments, for example in response to disruption of ACSL enzyme function in HEK293T cells. Moreover, we show the application of LACSerHR for sensitive measurement of elevated LCACoA levels in the livers of mouse models for two common metabolic diseases (NAFLD and type 2 diabetes). Thus, our LACSerHR sensor is a powerful, broadly applicable tool for studying LCACoAs metabolism and disease.

To identify the influence of healthy lifestyles on the incidence of the first NCD (FNCD), multiple chronic conditions (MCCs), and the progression from FNCD to MCCs.

cohort study.

Zhejiang, China PARTICIPANTS: 10566 subjects (55.5 ± 13.5 years, 43.1% male) free of NCDs at baseline from the Zhejiang Metabolic Syndrome prospective cohort.

Healthy lifestyle score (HLS) was developed by 6 common healthy lifestyle factors as smoking, alcohol drinking, physical activity, body mass index (BMI) and waist-to-hip ratio (WHR). Healthy lifestyle data and metabolic biomarkers collected via a face-to-face questionnaire-based interview, clinical health examination and routine biochemical determination. Biochemical variables were determined using biochemical auto-analyzer. Participants were stratified into four group based on the levels of HLS as ≤2, 3, 4 and ≥5. Multiple Cox proportional hazards model was applied to examine the relationship between HLS and the risk of FNCD, MCCs and the progression from FNCD to MCCs. The population-attributable fractions (PAF) were used to assess the attributable role of HLS. Mediating effect was examined by mediation package in R.

After a median of 9.92 years of follow-up, 1572 participants (14.9%) developed FNCD, and 149 (1.4%) developed MCCs. In the fully adjusted model, the higher HLS group (≥5) was associated with lower risk of FNCD (HR = 0.68 and 95% CI: 0.56-0.82), MCCs (HR = 0.31 and 95%CI: 0.14-0.69); and the progression from FNCD to MCCs (HR = 0.39 and 95%CI: 0.18-0.85). Metabolic components (TC, TG, HDL-C, LDC-C, FPG, and UA) played the mediating roles with the proportion ranging from 5.02% to 22.2% for FNCD and 5.94% to 20.1% for MCCs. PAFs (95%CI) for poor adherence to the overall healthy lifestyle (HLS ≤ 3) were 17.5% (11.2%, 23.7%) for FNCD, 42.9% (23.4%, 61.0%) for MCCs, and 37.0% (15.5%, 56.3%) for the progression from FNCD to MCCs.

High HLS decreases the risk of FNCD, MCCs, and the progression from FNCD to MCCs. These effects are partially mediated by metabolic components. Maintaining healthy lifestyles might reduce the disease burden of common chronic diseases.

Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed.

Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole-room calorimetry and is expressed as a respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. The clinical, metabolic, and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (β-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (β-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (β-coefficient 0.447, p = 0.02) directly correlated with the severity of weight gain. No statistically significant relationship between peak RQ, trough RQ, and weight change was demonstrated. Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity after LT with the potential to develop new diagnostics and therapeutics.

The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.

Although studies suggest that maternal high glucose (HG) increases offspring susceptibility to type 2 diabetes mellitus (T2DM), the underlying mechanisms are largely unclear. We studied whether glucose levels in oviducts are elevated when pregestational diabetic females get pregnant and whether the oviductal HG (OVHG) would act directly on embryos to increase offspring's T2DM susceptibility.

We established an in vivo model of OVHG by injecting female mice with streptozotocin (STZ) during the preimplantation period and an in vitro model of embryo culture with HG (ECHG) by culturing preimplantation embryos with HG, before examining glucose tolerance and insulin resistance (IR) in F1 and F2 offspring.

Injection of female mice with STZ induced a lasting significant glucose elevation in blood and oviduct fluid during the preimplantation period. The glucose tolerance test showed that both the STZ-induced OVHG and the ECHG caused glucose intolerance in F1 male and F1-sired F2 male offspring but had no effect on female offspring. Insulin tolerance test and the analysis for IR-related gene expression and glycogen contents in liver and muscle revealed significant IR in these male offspring.

This study provided evidence that HG can act directly on preimplantation embryos to increase offspring's T2DM susceptibility suggesting that the preimplantation period is a critical stage for transmission of mother's diabetes to offspring. FUND: This study was supported by grants from the China National Natural Science Foundation (Nos. 31772599, 32072738, 31702114, and 31902160), and the Natural Science Foundation of Shandong Province (Nos. ZR2022MC036, ZR2017BC025 and ZR2020QC102).

Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f).

LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied.

We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM-Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway.

These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity.

Gut microbiota refers to the population of trillions of microorganisms present in the human intestine. The gut microbiota in the gastrointestinal system is important for an individual's good health and well-being. The possibility of an intrauterine colonization of the placenta further suggests that the fetal environment before birth may also affect early microbiome development. Various factors influence the gut microbiota. Dysbiosis of microbiota may be associated with various diseases. Insulin regulates blood glucose levels, and disruption of the insulin signaling pathway results in insulin resistance. Insulin resistance or hyperinsulinemia is a pathological state in which the insulin-responsive cells have a diminished response to the hormone compared to normal physiological responses, resulting in reduced glucose uptake by the tissue cells. Insulin resistance is an important cause of type 2 diabetes mellitus. While there are various factors responsible for the etiology of insulin resistance, dysbiosis of gut microbiota may be an important contributing cause for metabolic disturbances. We discuss the mechanisms in skeletal muscles, adipose tissue, liver, and intestine by which insulin resistance can occur due to gut microbiota's metabolites. A better understanding of gut microbiota may help in the effective treatment of type 2 diabetes mellitus and metabolic syndrome.

Type 2 diabetes mellitus (T2DM) has become a worldwide public health problem. Epimedin C is considered one of the most important flavonoids in Epimedium, a famous edible herb in China and Southeast Asia that is traditionally used in herbal medicine to treat diabetes. In the present study, the therapeutic potential of epimedin C against T2DM was ascertained using a mouse model, and the mechanism underlying the hypoglycemic activity of epimedin C was explored using a label-free proteomic technique for the first time. Levels of fasting blood glucose (FBG), homeostasis model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance, as well as contents of malondialdehyde (MDA) and low-density lipoprotein cholesterol (LDL-C) in the 30 mg·kg-1 epimedin C group (EC30 group), were significantly lower than those in the model control group (MC group) (p < 0.05), while the contents of hepatic glycogen, insulin, and high-density lipoprotein cholesterol (HDL-C), as well as activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the EC30 group were notably higher than those in the MC group (p < 0.05). The structures of liver cells and tissues were greatly destroyed in the MC group, whereas the structures of cells and tissues were basically complete in the EC30 group, which were similar to those in the normal control group (NC group). A total of 92 differentially expressed proteins (DEPs) were enriched in the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In the EC30 vs. MC groups, the expression level of cytosolic phosphoenolpyruvate carboxykinase (Pck1) was down-regulated, while the expression levels of group XIIB secretory phospholipase A2-like protein (Pla2g12b), apolipoprotein B-100 (Apob), and cytochrome P450 4A14 (Cyp4a14) were up-regulated. According to the KEGG pathway assay, Pck1 participated in the gluconeogenesis and insulin signaling pathways, and Pla2g12b, Apob, and Cyp4a14 were the key proteins in the fat digestion and fatty acid degradation pathways. Pck1, Pla2g12b, Apob, and Cyp4a14 seemed to play important roles in the prevention and treatment of T2DM. In summary, epimedin C inhibited Pck1 expression to maintain FBG at a relatively stable level, promoted Pla2g12b, Apob, and Cyp4a14 expressions to alleviate liver lipotoxicity, and protected liver tissues and cells from oxidant stress possibly by its phenolic hydroxyl groups.

Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non-syndromic, obesity-associated non-alcoholic fatty liver disease (NS-NAFLD).

In a cross-sectional comparison of people with NS-NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan® controlled attenuation parameter (CAP) and insulin resistance by HOMA-IR, Adipo-IR, and NMR-based LP-IR.

Insulin resistance was greater in PL versus NS-NAFLD by HOMA-IR (p = 0.005), Adipo-IR (p = 0.01) and LP-IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA-IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS-NAFLD for any given HOMA-IR. In contrast, Adipo-IR and LP-IR correlated with CAP only in the NS-NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of β-hydroxybutyrate, a marker of β-oxidation, and large triglyceride-rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both).

Liver fat content was comparable in subjects with PL-associated NAFLD and NS-NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS-NAFLD.

Cardiovascular disease risk is known to be influenced by both the severity of a risk factor and the duration of exposure (eg, LDL [low-density lipoprotein] cholesterol, tobacco smoke). However, this concept has been largely neglected within the obesity literature. While obesity severity has been closely linked with cardiometabolic diseases, the risk of developing these conditions among those with obesity may be augmented by greater obesity duration over the life span. Few longitudinal or contemporary studies have investigated the influence of both factors in combination-cumulative obesity exposure-instead generally focusing on obesity severity, often at a single time point, given ease of use and lack of established methods to encapsulate duration. Our review focuses on what is known about the influence of the duration of exposure to excess adiposity within the obesity-associated cardiometabolic disease risk equation by means of summarizing the hypothesized mechanisms for and evidence surrounding the relationships of obesity duration with diverse cardiovascular and metabolic disease. Through the synthesis of the currently available data, we aim to highlight the importance of a better understanding of the influence of obesity duration in cardiovascular and metabolic disease pathogenesis. We underscore the clinical importance of aggressive early attention to obesity identification and intervention to prevent the development of chronic diseases that arise from exposure to excess body weight.

This study aimed to determine the association of blood lipid and insulin levels with the development of prediabetes. In this prospective cohort study, we collected and analyzed data related to demographic characteristics, lipid profiles, and insulin parameters at baseline (2008-2012) and at follow-up (2019-2020). A total of 1205 participants were included. The study found that maintained or elevated Homeostatic Model Assessment for Insulin Resistance (HOMO-IR) score and elevated triglyceride (TG) levels from baseline to follow-up were associated with an increased risk of prediabetes. However, the interaction between blood lipids and insulin had no significant effect on the risk of prediabetes. Our findings indicate that elevated TG or HOMA-IR levels are associated with an increased risk of prediabetes. These findings emphasize the need to formulate initiatives that can help reduce dyslipidemia to prevent the onset of prediabetes and diabetes.

The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type 2 diabetes (T2D). β-cells are electrically coupled via connexin-36 (Cx36) gap junction channels, which coordinates the pulsatile dynamics of [Ca2+ ] and insulin release across the islet. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under in vitro conditions. Here we test whether gap junction coupling and coordinated [Ca2+ ] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with pro-inflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca2+ ] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with pro-inflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca2+ ] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by pro-inflammatory cytokines. Critically, S293 peptide rescued gap junction coupling and [Ca2+ ] dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes. KEY POINTS: Connexin-36 (Cx36) gap junction permeability and associated coordination of [Ca2+ ] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D. Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca2+ ] dynamics. A novel peptide mimetic of the Cx36 c-terminal regulatory region protects against declines in Cx36 gap junction permeability. Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca2+ ] dynamics and glucose-stimulated insulin secretion in human T2D and mouse models of T2D.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients.

40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa).

Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed.

In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity.

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.