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Prediabetes is a serious metabolic disorder that is often overlooked and 70% of individuals with prediabetes would eventually develop type 2 diabetes. The diabetogenic effects of pesticides have been reported in toxicological studies but their association with prediabetes is rarely investigated. We aimed to evaluate the association between pesticide exposure and impaired glucose regulation (IGR), including prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and insulin resistance, in a general U.S. non-diabetic population. Three classes of urinary pesticides, including organophosphorus pesticides (OPs), pyrethroid, and herbicides were measured. Generalized linear regression, restricted cubic spline, and Bayesian kernel machine regression (BKMR) models were combined to evaluate their associations. 3,5,6-trichloropyridinol (TCPY) was positively associated with prediabetes and IGT (highest vs lowest TCPY quartile: prediabetes: OR: 1.97, 95% CI: 1.18, 3.31; IGT: OR: 2.03, 95% CI: 1.14, 3.66) in a linear dose-response manner (P for nonlinear<0.05). Another two metabolites of OPs, malathion dicarboxylic acid (MDCA) diacid and para-nitrophenol (PNP), were found to increase the odds ratio of insulin resistance (PNP: OR: 1.22, 95% CI: 1.05, 1.42; MDCA: OR: 1.36, 95% CI: 1.08, 1.70) with linear dose-response curves (P for nonlinear<0.05). Considering mutual exposure to multiple pesticides, TCPY, MDCA, and PNP made the most contributions in the mixture exposure and IGR. No obvious interactions among pesticides were found in the multiple exposure settings. The odds ratio of TCPY exposure and prediabetes was increased with advancing age but not related to body mass index (BMI). The results remained robust in sensitivity analysis with restricted participants without abnormal urinary creatinine and unsteady glucose or insulin levels. Our findings suggested the close relationship between OPs and impaired glucose regulation, especially in older adults, which provides insights into the prevention of diabetes at the earlier stage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Healthy dietary patterns rich in legumes can improve metabolic health, although their additional benefits in conjunction with calorie restriction have not been well-established. We investigated effects of a calorie-restricted, legume-enriched, multicomponent intervention diet compared with a calorie-restricted control diet in 127 Chinese prediabetes participants, living in Singapore. The study was a 16-week, single-blind, parallel-design, randomized controlled trial (n = 63 intervention group (IG), n = 64 control group (CG); mean ± SD age 62.2 ± 6.3 years, BMI 23.8 ± 2.6 kg/m 2 ). Primary outcomes were markers of glycemia and all measurements were taken at 2 or 4-weekly intervals. At the end of 16 weeks, both groups had significantly lower BMI (q (Time)  = 1.92 ×10 -42 , β  = -0.02) compared with baseline, with minimal difference between groups. The IG had significantly greater reductions in LDL cholesterol (q (Treatment×Time)  = 0.01, β  = -0.16), total cholesterol (q (Treatment×Time)  = 0.02, β  = -0.3) and HbA1c (q (Treatment×Time)  = 0.04, β  = -0.004) compared with CG, alongside increases in fiber degrading species in IG, mediated through metabolites such as bile acids and amino acids. A legume-enriched, multicomponent intervention diet can improve metabolic health in a prediabetes population, in addition to benefits obtained from calorie restriction alone, partially mediated through changes in gut microbial composition and function. Trial registration: Clinical Trials NCT04745702., Competing Interests: Competing interests: X.W., K.J.L., V.S.B.V., K.K., X.L., L.H.W., C.P.L.Y. and H.F. are employees of Wilmar International Limited. The remaining authors declare no competing interests. Inclusion & ethics: This study aligns by the guidelines of Nature Portfolio journals, with contributions of each author as disclosed in Author contributions., (© 2025. The Author(s).)

Prediabetes (PreDM) and obesity increase the risk of type 2 diabetes. Individuals with these conditions often consume diets higher in animal protein than in plant protein, which are associated with elevated levels of dietary advanced glycation end products (dAGEs). Increased dAGE intake has been linked to blood glucose abnormalities, oxidative stress, and dysbiosis of the microbiota, all of which exacerbate metabolic disorders. Black soybeans, as a plant-based protein source, contain substantially lower levels of dAGEs compared with pork. This study aimed to investigate the effects of substituting animal protein with black soybeans on advanced glycation end product (AGE) levels, oxidative stress, and the gut microbiota in individuals with both PreDM and obesity. This study was a randomized crossover intervention trial conducted over 16 weeks. We recruited men and women aged 20-64 years with both prediabetes and obesity. This study had four periods: 0-4 weeks for the run-in period, 4-8 weeks and 12-16 weeks for the pork or black soymilk intervention period, and 8-12 weeks for the wash-out period. During the intervention period, the participants consumed pork or black soymilk with similar protein content as their dietary protein source. The participants maintained 3 day dietary records, and we measured anthropometric items and collected blood and fecal samples for analysis. The results showed that partially substituting pork with black soymilk as a dietary protein source for 4 weeks significantly reduced dAGE intake. The black soymilk group also exhibited significantly lower blood AGE fluorescence intensity, oxidative stress, and levels of glycative stress markers. Furthermore, black soymilk consumption significantly increased the relative abundance of short-chain fatty acid-producing genera compared with pork consumption. In conclusion, partially substituting dietary pork with black soymilk may reduce serum AGE levels, reduce oxidative and glycation stress, and increase the abundance of short-chain fatty acid-producing microbiota in individuals with both PreDM and obesity. Registration number of Clinical Trial: NCT05290519 (ClinicalTrials.gov).

Aim: The aim was to study the effect of two low-calorie, high-protein (HP) diets, with most of the protein coming from animal or plant sources, on glycaemic and other cardiometabolic outcomes in subjects with overweight or obesity and glucose metabolism disorders., Materials and Methods: A total of 117 participants aged >18 years with body mass index over 27.5 kg/m 2 and prediabetes or type 2 diabetes mellitus (T2DM) were randomized to one of two HP low-calorie diets (35% of total calories from protein), in which 75% of the protein was from either plant-based sources (HPP) or animal sources (HPA). For both diets, 30% and 35% of the total calories were from fat and carbohydrates, respectively. The dietary intervention lasted 6 months., Results: Both diets improved body composition to a similar extent, including weight loss (-8.05 ± 5.12 kg for the HPA diet and -7.70 ± 5.47 kg for the HPP diet at 6 months) and fat mass, mainly visceral fat. Both diets had a similar beneficial effect on glucose metabolism, including fasting glucose, insulin, homeostasis model assessment of insulin resistance index and glycated haemoglobin. Other biochemical parameters, including lipid profiles, liver enzymes, adipokines and inflammatory biomarkers, similarly improved in both groups. Fasting incretins, mainly glucagon-like peptide 1, decreased significantly in both groups, and this effect correlated with weight loss., Conclusions: Low-calorie HP diets improved body composition, glucose metabolism and other cardiometabolic outcomes, regardless of protein source (either animal or plant sources), in outpatients with prediabetes or T2DM., Clinical Trial Registration: The clinical trial was registered in ClinicalTrials.gov (identifier: NCT05456347) https://clinicaltrials.gov/study/NCT05456347?term=NCT05456347&rank=1., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m 2 ) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70% HR peak ) or interval (n = 8, 90% HR peak and 50% HR peak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO 2 peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time-points of the OGTT, and levels of insulin signaling proteins (i.e., p-IRS-1, total-/p-Akt, pERK1/2, pJNK1/2, and pp38) and pro-BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60-0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO 2 peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (-0.4 ± 0.9 kg, p = 0.04) and whole-body glucose tAUC 120min (p = 0.02). Training lowered 0-min pro-BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT-stimulated tAkt (-51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Prediabetes is characterized as a transitional phase between normal blood glucose and diabetes, and the potential role of fucoidan in the progression of diabetes is still debated. The randomized, double-blind, placebo-controlled trial was designed to assess the effect of fucoidan supplementation on glycolipid metabolism, systemic inflammation and gut microbiota in individuals with prediabetes. A total of 70 Chinese participants with prediabetes were randomized to either fucoidan or placebo group, receiving daily doses of 1000 mg fucoidan or placebo capsules for 12 weeks. Glycolipid metabolism and systemic inflammation levels were assessed using standard laboratory techniques, while gut microbiota was analyzed by 16S rRNA sequencing. Following the 12-week intervention period, subjects consuming fucoidan exhibited a lower increase in GSP and a notable reduction in TNF-α, IL-6 and LPS compared to those receiving placebo (P < 0.05). Furthermore, fucoidan supplementation led to an increased abundance of Megamonas and Blautia while decreasing Klebsiella (P < 0.05). These findings suggested that the daily administration of 1000 mg fucoidan may partially modulate glucose metabolism and improve systemic inflammation, potentially linked to its modulation of gut microbiota in Chinese individuals with prediabetes. Thus, fucoidan could be considered as a potential dietary supplement for diabetes prevention., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Ethnic disparities in the prevalence and pathophysiology of type 2 diabetes are well documented, but prospective data on insulin dynamics vis-à-vis pre-diabetes/early dysglycemia risk in diverse populations are scant., Research Design and Methods: We analyzed insulin secretion, sensitivity, and clearance among participants in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. The POP-ABC study followed initially normoglycemic offspring of parents with type 2 diabetes for 5.5 years, the primary outcome being incident dysglycemia. Assessments included anthropometry, oral glucose tolerance test, insulin sensitivity (hyperinsulinemic euglycemic clamp, HEC), insulin secretion (intravenous glucose tolerance test, IVGT), and disposition index (DI). Insulin clearance was derived as the molar ratio of plasma C peptide to insulin and by calculating the metabolic clearance rate during HEC., Results: POP-ABC participants who completed IVGT and HEC at baseline (145 African American, 123 European American; 72% women; mean age 44.6±10.1 years) were included in the present analysis. The baseline fasting plasma glucose was 91.9±6.91 mg/dL (5.11±0.38 mmol/L) and 2-hour plasma glucose was 123±25.1 mg/dL (6.83±1.83 mmol/L). African American offspring of parents with type 2 diabetes had higher insulin secretion and DI, and lower insulin sensitivity and clearance, than their European American counterparts. During 5.5 years of follow-up, 91 of 268 participants developed incident dysglycemia and 177 maintained normoglycemia. In Cox proportional hazards models, insulin secretion (HR 0.997 (95% CI 0.996 to 0.999), p=0.005), insulin sensitivity (HR 0.948 (95% CI 0.913 to 0.984), p=0.005), DI (HR 0.945 (95% CI 0.909 to 0.983), p=0.005) and basal insulin clearance (HR 1.030 (95% CI 1.005 to 1.056), p=0.018) significantly predicted incident dysglycemia., Conclusions: Insulin sensitivity, secretion, and clearance differ significantly in normoglycemic African American versus European American offspring of parents with type 2 diabetes and are associated with the risk of incident dysglycemia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

SPINT1, a membrane-anchored serine protease inhibitor, regulates cascades of pericellular proteolysis while its tissue-specific functions remain incompletely characterized. In this study, we generate Spint1-lacZ knock-in mice and observe Spint1 expression in embryonic pancreatic epithelium. Pancreas-specific Spint1 disruption significantly diminishes islet size and mass, causing glucose intolerance and downregulation of MAFA and insulin. Mechanistically, the serine protease HEPSIN interacts with SPINT1 in β cells, and Hepsin silencing counteracts the downregulation of Mafa and Ins1 caused by Spint1 depletion. Furthermore, we demonstrate a potential interaction between HEPSIN and GLP1R in β cells. Spint1 silencing or Hepsin overexpression reduces GLP1R-related cyclic AMP levels and Mafa expression. Spint1-disrupted mice also exhibit a significant reduction in Exendin-4-induced insulin secretion. Moreover, SPINT1 expression increases in islets of prediabetic humans compared to non-prediabetic groups. The results unveil a role for SPINT1 in β cells, modulating glucose homeostasis and insulin production via HEPSIN/MAFA signaling., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To compare the efficacy of exercise, metformin and their combination on glucose metabolism in individuals with abnormal glycaemic control., Design: Systematic review and network meta-analysis., Data Sources: Embase, Web of Science, PubMed/MEDLINE and SPORTDiscus., Eligibility Criteria: Randomised controlled trials involving exercise, metformin or their combined treatments in individuals with prediabetes or type 2 diabetes mellitus (T2DM) were included. Outcomes included haemoglobin A1c (HbA1c), 2-hour glucose during oral glucose tolerance test, fasting glucose, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR)., Results: 407 articles with 410 randomised controlled trials (n=33 802) were included. In prediabetes, the exercise showed greater efficacy than metformin on HbA1c levels (mean difference -0.16%, 95% CI (-0.23 to -0.09) vs -0.10%, 95% CI (-0.21 to 0.02)), 2-hour glucose (-0.68 mmol/L, 95% CI (-0.97 to -0.39) vs 0.01 mmol/L, 95% CI (-0.38 to 0.41)) and HOMA-IR (-0.54, 95% CI (-0.71 to -0.36) vs -0.23, 95% CI (-0.55 to 0.10)), while the efficacy on fasting glucose was comparable (-0.26 mmol/L, 95% CI (-0.32 to -0.19) vs -0.33 mmol/L, 95% CI (-0.45 to -0.21)). In T2DM, metformin was more efficacious than exercise on HbA1c (-0.88%, 95% CI (-1.07 to -0.69) vs -0.48%, 95% CI (-0.58 to -0.38)), 2-hour glucose (-2.55 mmol/L, 95% CI (-3.24 to -1.86) vs -0.97 mmol/L, 95% CI (-1.52 to -0.42)) and fasting glucose (-1.52 mmol/L, 95% CI (-1.73 to -1.31) vs -0.85 mmol/L, 95% CI (-0.96 to -0.74)); exercise+metformin also showed greater efficacy in improving HbA1c (-1.23%, 95% CI (-2.41 to -0.05)) and fasting glucose (-2.02 mmol/L, 95% CI (-3.31 to -0.74)) than each treatment alone. However, the efficacies were modified by exercise modality and metformin dosage., Conclusion: Exercise, metformin and their combination are efficacious in improving glucose metabolism in both prediabetes and T2DM. The efficacy of exercise appears to be superior to metformin in prediabetes, but metformin appears to be superior to exercise in patients with T2DM., Prospero Registration Number: CRD42023400622., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The objective of this randomized controlled trial was to examine if exercise training can counteract energy restriction-induced impairment of mitochondrial capacity in skeletal muscle of 55-70-years people with prediabetes and metabolic syndrome. The potential impact of sex was explored. Fifty sedentary men and women with prediabetes and metabolic syndrome (age: 61 ± 6 (±SD) years, BMI: 29.6 ± 4.7 kg·m -2 , body fat content: 37.5% ± 8.2% and VO 2max : 22.3 ± 5.7 mL·min -1 ·kg -1 ) were randomized to either exercise training and dietary advice (EX-DI) or dietary advice only (DI). Dietary advice aimed to induce weight loss and improve glycemic control. Exercise consisted of 32 ± 2 mixed 30-60 min training sessions with recreational small-sided soccer distributed across 16 weeks. Maximal activity and protein abundance of key regulatory mitochondrial enzymes were determined in m. vastus lateralis pre- and post-intervention. Muscle glycogen content was also determined. Dietary advice only (DI), impaired (p < 0.001) citrate synthase (CS), and 3-hydroxyacyl-CoA dehydrogenase (HAD) maximal activity by 18% ± 43% and 23% ± 19%, respectively. When combined with exercise training, no dietary impairment of CS or HAD maximal activity was detectable. Superoxide dismutase 2 (SOD2) and CS protein expression also declined (p < 0.05) in DI and remained unchanged in EX-DI. In terms of sex differences, a decrease in maximal CS activity in both EX-DI and DI was observed exclusively in men (all p < 0.05). In conclusion, 16 weeks of exercise training counteracts energy restriction-induced impairment in skeletal mitochondrial function in 55- to 70-year-old women and men with prediabetes and metabolic syndrome., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims/hypothesis: Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes., Methods: As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively., Results: In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA 1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes., Conclusions/interpretation: Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions., Competing Interests: Acknowledgements: We extend our gratitude to the IMI-DIRECT study participants who willingly participated in phenotyping as well as to the clinical and technical staff across European study centres for their contributions to participant recruitment and clinical assessment. This publication’s development has been supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement 115317 (DIRECT), with resources derived from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contributions. Special thanks go to the study centre team, L. M. 't Hart, F. Rutters, J. Vangipurapu and T. H. Hansen, for providing internal review on this manuscript. Data availability: Access to the molecular and clinical raw data, as well as the processed data, is restricted. This is in accordance with the informed consent provided by study participants, the various national ethical approvals obtained for the study, and compliance with the European General Data Protection Regulation (GDPR). Individual-level clinical and molecular data cannot be transferred from the centralised IMI-DIRECT repository. Requests for access will receive guidance on accessing data through the DIRECT secure analysis platform after submitting an appropriate application. The IMI-DIRECT data access policy and additional information about the IMI-DIRECT research consortium’s initiatives and activities can be found at https://directdiabetes.org . Code used for MR in the study is included as ESM. Funding: Open Access funding enabled and organized by Projekt DEAL. We would like to thank Helmholtz Munich, German Diabetes Center (DZD) for their support in current research and China Research Council (CRC) funding for a PhD student hosted by Helmholtz Munich. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: SS, QD, MH, JA and HG conceptualised the analysis plan. RWK, PWF, MW, IF, GG, IP, HR, MD, MM, OP, JS, KT, FDM, SB, AV, AM, TM, TK, JA, EP and HG were involved in conception and design of the DIRECT study. SS, QD, MH, JA, GK, AA, CP, RB, JFT, AJ and AT were involved in the data acquisition, pre-processing and interpretation of data. SS organised inclusion of outlined sections and, along with QD, wrote the original draft of the manuscript. All authors contributed to drafting the article or critically revising it for significant intellectual content and have provided approval to the final version to be published. SS and HG are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s).)

Background: Type 2 diabetes (T2DM) and obesity are characterized by altered insulin metabolism and action. Reduced hepatic insulin clearance is increasingly recognized as a key contributor to hyperinsulinemia and insulin resistance. CEACAM1 promotes hepatic insulin clearance, and its loss in hepatocytes is associated with reduced insulin clearance in mice and men. This study examines whether CEACAM1 circulating levels reflect compromised insulin metabolism and resistance in the PREVADIAB2 cohort., Methods: A total of 1019 individuals from the PREVADIAB2 cohort were evaluated for diabetes by 75 g-OGTT and classified according to WHO 2019 criteria. CEACAM1 circulating levels were measured by ELISA, and insulin metabolism parameters were calculated. Hierarchical clustering of insulin metabolic indices and CEACAM1 levels was performed. Statistical significance was assessed using Kruskal-Wallis and Wilcoxon-Mann-Whitney tests., Results: BMI, insulin resistance (HOMA-IR), and hepatic steatosis progressively increased with disease severity. Insulin secretion rose and its clearance declined in parallel to circulating CEACAM1 levels in prediabetes and T2DM, indicating compensatory hyperinsulinemia. Hierarchical metabolic clustering identified four clusters with distinct patterns and further showed that insulin clearance positively correlated with circulating CEACAM1, especially in individuals with normoglycemia, lower obesity and hepatic steatosis. This suggests that circulating CEACAM1 can reflect the status of hepatic insulin clearance., Conclusions: This study demonstrates a progressive increase in insulin resistance and hyperinsulinemia in parallel to elevated BMI and hepatic steatosis prevalence, accompanied by declining circulating CEACAM1 levels. Cluster analysis further linked reduced insulin clearance to lower circulating CEACAM1 levels, suggesting its potential usefulness as a biomarker for metabolic disease progression., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: The objective of this study was to identify sex differences in ntrahepatocellular (HCL) and intramyocardial lipids (MYCL) and cardiac function in participants with different grades of glucometabolic impairment and different BMI strata., Methods: Data from 503 individuals from 17 clinical experimental studies were analyzed. HCL and MYCL were assessed with 3T and 7T scanners by magnetic resonance spectroscopy. Cardiac function was measured with a 3T scanner using electrocardiogram-gated TrueFISP sequences. Participants were classified as having normoglycemia, prediabetes, or type 2 diabetes. Three-way ANCOVA with post hoc simple effects analyses was used for statistical assessment., Results: Consistent increases of HCL with BMI and deterioration of glucose metabolism, especially in female individuals, were detected. MYCL increased with BMI and glucose impairment in female individuals, but not in male individuals. Sex differences were found in cardiac function loss, with significant effects found among male individuals with worsening glucose metabolism. Myocardial mass and volume of the ventricle were higher in male individuals in all groups. This sex difference narrowed with increasing BMI and with progressing dysglycemia., Conclusions: Sex differences in HCL and MYCL may be associated with a higher cardiovascular disease risk observed in female individuals progressing to diabetes. Further studies are needed to elucidate possible sex differences with advancing glucometabolic impairment and obesity and their potential impact on cardiovascular outcomes., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: The activity of perivascular adipose tissue (PVAT), a specific deposit of adipose tissue surrounding blood vessels, could contribute to sex differences in vascular tone control, particularly in dyslipidemic disorders; however, the mutual associations remain unclear. This study aimed to evaluate the relationships among sex, PVAT and vascular function in Wistar and hereditary hypertriglyceridemic (HTG) rats. Vasoactive responses of the isolated thoracic aorta with preserved or removed PVAT were compared in adult male and female Wistar and HTG rats, and the roles of nitric oxide (NO), hydrogen sulfide (H 2 S), cyclooxygenase (COX) and inflammatory signaling in vascular function were monitored in females., Results: HTG rats were hypertensive, but females less than males. Increased 2-h glycemia was observed in HTG rats regardless of sex; however, HTG females exhibited better glucose utilization than males did. Females, independent of strain, had better preserved endothelial function than males did. PVAT inhibited endothelium-dependent relaxation in all the rats except HTG females. In HTG males, pathologically increased aortic contractility was noted; however, in HTG females, the contractile responses were lower, thus approaching physiological levels despite the pro-contractile action of COX products. In HTG females, NO contributed to endothelial function to a lesser extent than it did in controls, but the presence of PVAT eliminated this difference, which corresponded with increased NO synthase activity. Although increased protein expression of several proinflammatory factors (TNFα, IL-6, iNOS, and NfκB) was confirmed in the aortic and PVAT tissue of HTG females, the protein expression of factors regulating the adhesion and infiltration of monocytes (ICAM-1 and MCP-1) was decreased in PVAT. Moreover, in HTG females, unlike in controls, H 2 S produced by PVAT did not inhibit endothelial relaxation, and regardless of PVAT, endogenous H 2 S had beneficial anticontractile effects, which were associated with increased protein expression of H 2 S-producing enzymes in both aortic and PVAT tissues., Conclusions: Despite increased inflammation and the pathological impact of cyclooxygenase signaling in female HTG rats, protective vasoactive mechanisms associated with milder hypertension and improved endothelial function and contractility linked to PVAT activity were triggered. Sulfide and nitroso signaling represent important compensatory vasoactive mechanisms against hypertriglyceridemia-associated metabolic disorders and may be promising therapeutic targets in prediabetic females., Competing Interests: Declarations. Competing interests: The authors declare that they have no competing interests. Ethics approval and consent to participate: The animals were bred in accordance with the institutional guidelines of the State Veterinary and Food Administration of the Slovak Republic and the Committee on the Ethics of Procedures in Animal, Clinical and other Biomedical Experiments (record number: 9704/2022) of the Centre of Experimental Medicine as well as in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes, Directive 2010/63/EU of the European Parliament. The Wistar rats used in this study were obtained from the Department of Toxicology and Laboratory Animal Breeding at Voda, Slovak Academy of Sciences, Slovakia. The HTG rats were obtained from the Institute of Clinical and Experimental Medicine (Czech Republic). The rats were housed under a 12 h light–12 h dark cycle at a constant humidity and temperature (45–65% and 20–22 °C, respectively) with free access to standard laboratory rat chow and drinking water ad libitum. Consent for publication: Not applicable., (© 2024. The Author(s).)

Gossypetin (GTIN) is a naturally occurring flavonoid recognised for its pharmacological properties. This study examined the effects of GTIN on cardiovascular function in a diet-induced pre-diabetic rat model, which has not been previously studied. Pre-diabetes was induced using a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Thereafter, the pre-diabetic animals were sub-divided into five groups ( n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both in the presence and absence of dietary intervention for 12 weeks. The results demonstrated that the pre-diabetic (PD) control group exhibited significantly higher plasma triglyceride, total cholesterol, low-density lipoprotein and very low-density lipoprotein levels, along with decreased high-density lipoprotein (HDL) levels in comparison to the non-pre-diabetic (NPD) group. This was accompanied by significantly higher mean arterial pressure (MAP), body mass index (BMI), waist circumference (WC) and plasma endothelial nitric oxide (eNOS) levels in PD control. Additionally, there were increased heart malondialdehyde levels, reduced heart superoxide dismutase and glutathione peroxidase activity as well as increased plasma interleukin-6, tumour necrosis factor alpha and c-reactive protein levels present in the PD control group. Notably, both GTIN-treated groups showed significantly reduced plasma lipid levels and increased HDL, as well as decreases in MAP, BMI, WC and eNOS levels in comparison to PD control. Additionally, GTIN significantly decreased heart lipid peroxidation, enhanced antioxidant activity and decreased plasma inflammation markers. These findings may suggest that GTIN administration in both the presence and absence of dietary intervention may offer therapeutic potential in ameliorating cardiovascular disturbances associated with the PD state. However, future studies are needed to determine the physiological mechanisms by which GTIN improves cardiovascular function in the PD state.

Objective: Few studies have evaluated the changes in blood glucose status in individuals with prediabetes, and this study aimed to analyze the association between metabolic score for insulin resistance (MetS-IR) and the progression or regression of prediabetes., Methods: This retrospective cohort study used research data from medical examination institutions under the Rich Healthcare Group in 32 regions across 11 cities in China. Progression of prediabetes to diabetes and regression to normal fasting glucose (NFG) were defined based on glycemic changes during follow-up. The association between MetS-IR and the progression or regression of prediabetes was analyzed using multivariate Cox regression, restricted cubic splines, and piecewise regression models., Results: Data from 15,421 prediabetic subjects were analyzed. Over an average follow-up of 2.96 years, 6,481 individuals (42.03%) returned to NFG, and 2,424 (15.72%) progressed to diabetes. After controlling for confounding factors, an increase in MetS-IR was observed to increase the risk of diabetes onset in the prediabetic population, whereas a decrease in MetS-IR had a protective effect for returning to NFG. Additionally, a nonlinear relationship between MetS-IR and prediabetes regression was observed, with 37.22 identified as the inflection point; prediabetes regression rates were significantly higher before this point and markedly decreased after it., Conclusion: For individuals with prediabetes, an increase in MetS-IR may lead to an increased risk of diabetes; conversely, a decrease in MetS-IR enhances the protective effect for returning to NFG and keeping MetS-IR below 37.22 is significant for the regression of prediabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sheng, Kuang, Yang and Zou.)

Background: Type 2 diabetes (T2D) is preceded by prediabetes, and these conditions place a great burden on patients and society. These conditions are significantly associated with poor glycemic control, which is improved by resistance exercise. It has been suggested that resistance exercise should be performed with a high degree of effort to improve glucose metabolism, but this is associated with negative psychological responses that might lead to lower long-term adherence., Objective: This study aimed to investigate the effect of the degree of effort during a resistance exercise session on glycemic control and psychological responses in individuals living with prediabetes or T2D., Methods: This study will be a crossover, 3-arm, randomized controlled trial. A total of 15 participants living with prediabetes or T2D will be thoroughly familiarized with 7 resistance exercises; afterward, they will perform 3 randomized experimental sessions, each lasting approximately 48 hours each, separated by at least 4 washout days. In 2 of these sessions, supervised resistance exercise will be performed, but the sessions will differ in the degree of effort in each set (high vs low) and will be equalized in terms of total weight lifted and session duration. For this, proximity to failure will be manipulated by changing the number of sets per exercise, the number of repetitions per set, and the resting interval between sets and exercises. Participants will also complete a sedentary (control) session, where they will not perform any exercise. In response to each session, psychological responses will be assessed (exertion, affect, enjoyment, self-efficacy, and discomfort). Glycemic control will be assessed by a continuous glucose monitoring device every 5 minutes, throughout the approximately 48 hours of each experimental session. Food and drink will be individually prescribed by a registered dietitian nutritionist and provided to participants, in order to control for the confounding effect of energy intake and diet composition. Physical activity levels will be assessed by accelerometry. Randomization will be done using the opaque, sequentially numbered envelopes technique. Participants and researchers will be blinded for continuous glucose monitoring and accelerometry data, and data will be analyzed by a blinded statistician., Results: This study has been funded, and data collection is expected to take place between June 2024 and May 2025. Final manuscript submission should happen by August 2025., Conclusions: The results of this project might encourage individuals living with prediabetes and T2D to engage in resistance exercise while better informing exercise specialists on how to best incorporate resistance exercise in their client's or patient's routine., Trial Registration: ClinicalTrials.gov NCT06208189; https://clinicaltrials.gov/study/NCT06208189., International Registered Report Identifier (irrid): PRR1-10.2196/63598., (©Marissa Ramirez, Maja Gebauer, Christine Mermier, Jonathan Peter Little, Luotao Lin, Gabriel Palley, Yu Yu Hsiao, Roberto Ivan Mota Alvidrez, Zach A Mang, Fabiano Trigueiro Amorim, Valmor Tricoli, Flavio De Castro Magalhaes. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 05.11.2024.)

Objective: This study aimed to evaluate the association between salivary adipokine levels, including leptin, chemerin, resistin and interleukin-6, with body mass index (BMI), waist and wrist circumference and appetite in patients with type 2 diabetes., Methods: In this cross-sectional study, 104 participants were divided into three groups: 35 diabetic patients, 35 pre-diabetic individuals and 34 healthy controls. Unstimulated saliva samples were collected using the spitting method, and salivary levels of leptin, chemerin, resistin and interleukin-6 were measured via ELISA. Appetite was assessed using a standard questionnaire, and BMI, waist and wrist circumferences were measured with a tape measure. Statistical analysis was performed using SPSS 26, with a significance threshold set at 0.01., Results: Significant differences were found in the salivary levels of leptin, chemerin, and resistin among the three groups (p < 0.01), but no significant difference was observed in the salivary levels of interleukin-6 (p > 0.01). Analysis also revealed significant differences in appetite traits among the groups, with the highest appetite trait observed in pre-diabetic subjects (p = 0.0002). The salivary level of chemerin was significantly associated with appetite traits regardless of diabetic status (p = 0.009). Appetite was also significantly related to BMI (p = 0.002) and waist circumference (p = 0.001) in all subjects. However, no significant relationship was observed between appetite and fasting plasma glucose or HbA1c levels (p > 0.01)., Conclusion: The results of this study indicate that salivary levels of certain adipokines, such as leptin, chemerin and resistin, may be significantly higher in diabetic patients, although this is not true for all adipokines. While pre-diabetic patients exhibited a higher level of appetite, no positive correlation was found between salivary adipokine levels (except chemerin) and appetite or anthropometric characteristics, irrespective of diabetic status., (© 2024 The Author(s). Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

GPR10 and neuropeptide FF receptor 2 (NPFFR2) play important role in the regulation of food intake and energy homeostasis. Understanding the interaction between these receptors and their specific ligands, such as prolactin-releasing peptide, is essential for developing stable peptide analogs with potential for treating obesity. By breeding and characterizing double knockout (dKO) mice fed standard or high-fat diet (HFD), we provide insights into the metabolic regulation associated with the GPR10 and NPFFR2 deficiency. Both WT and dKO mice were subjected to behavioral tests and an oral glucose tolerance test. Moreover, dual-energy X-ray absorptiometry (DEXA) followed by indirect calorimetry were performed to characterize dKO mice. dKO mice of both sexes, when exposed to an HFD, showed reduced glucose tolerance, hyperinsulinemia, and insulin resistance compared with controls. Moreover, they displayed increased liver weight with worsened hepatic steatosis. Mice displayed significantly increased body weight, which was more pronounced in dKO males and caused by higher caloric intake on a standard diet, while dKO females displayed obesity characterized by increased white adipose tissue and enhanced hepatic lipid accumulation on an HFD. Moreover, dKO females exhibited anxiety-like behavior in the open field test. dKO mice on a standard diet had a lower respiratory quotient, with no significant changes in energy expenditure. These results provide insights into alterations associated with disrupted GPR10 and NPFFR2 signaling, contributing to the development of potential anti-obesity treatment., (© 2024 The Author(s).)

Objective: Previous research points to a role of the brain in the regulation of glucose and pathogenesis of type 2 diabetes (T2D) via modulation of counter-regulatory hormone secretion and activity in the autonomic nervous system (ANS). The aim of this study was to investigate glucose-dependent responses of catecholamines and ANS activity in individuals with T2D, prediabetes (PD), and normoglycemia (NG)., Design: Cross-sectional., Methods: Individuals with T2D (n = 19, 7 men, HbA1c 49 mmol/mol), PD (n = 18, 8 men), and NG (n = 17, 3 men) underwent 1 stepwise hyperinsulinemic-euglycemic-hypoglycemic and 1 hyperglycemic clamp with repeated measurements of catecholamines, symptoms, heart rate variability (HRV), and hemodynamics., Results: The hypoglycemic response of adrenaline was augmented in T2D and PD vs NG (both P < .05), and there was a strong association with insulin resistance (P < .05 for M-value). In relation to achieved glucose levels in both clamps, noradrenaline exhibited a steeper rise during hypoglycemia in T2D vs NG and PD (both P < .05). There were trends toward more marked autonomic hypoglycemic symptoms in T2D vs PD and NG. By contrast, insulin resistance was associated with attenuated responses of heart rate and HRV indices PLF and PHF at the target glucose plateau of 2.7 mmol/L (P < .05), independent of BMI and HbA1c., Conclusion: Alterations in glucose-dependent responses of counter-regulatory hormones and the ANS appear before, and probably contribute to, the onset of T2D. Together with other reported alterations in neuroendocrine pathways, the findings suggest that a maladaptation of the brain's responses to glucose fluctuations is important in T2D progression., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare in relation to the current work., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Galectin-3 is an endogenous lectin which binds mainly to β-galactosides on the cell surface and extracellular matrix (ECM) glycoproteins. In the thymus, this lectin is constitutively expressed, being involved in thymocyte adhesion, migration, and death. Galectin-3 has been related to type 1 diabetes, an autoimmune disease characterized by pancreatic β-cell destruction mediated by autoreactive T lymphocytes. Non-obese diabetic (NOD) mice represent a suitable model to study type 1 diabetes, as they develop the disease like humans. We previously described important thymic alterations in these animals such as the development of giant perivascular spaces (PVS), characterized by the retention of T and B cells, intermingled with an ECM network, and associated with a defect in the expression of the fibronectin receptor VLA-5 and reduced sphingosine-1-phosphate receptor expression on developing thymocytes. In order to investigate galectin-3 expression in thymic microenvironmental cells and verify its interaction with cells and ECM molecules in PVS, we performed immunofluorescence following colocalization analysis in the thymic parenchyma of pre-diabetic NOD mice by confocal microscopy. In addition, thymocyte migration assays were performed to evaluate the effect of galectin-3 on NOD thymocyte migration. Herein, we showed a significant enhancement of colocalization with cortical and medullary thymic epithelial cells in NOD mice, as compared to controls. In the giant PVS of these animals, we observed a heterogeneous distribution of galectin-3, predominantly found in clusters of B lymphocytes and dendritic cells. Functionally, NOD thymocyte migratory response towards galectin-3 was impaired and a similar decrease was seen in transendothelial thymocyte migration. Taken together, our data provide the histological and functional background for a potential defective thymocyte migration involving galectin-3, thus placing this molecule as a further player in the intrathymic disturbances observed in pre-diabetic NOD mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ramos, Ventura, Lemos, Chammas, Savino, Carvalho-Pinto, Mendes-da-Cruz and Villa-Verde.)

Background: The cardiometabolic index (CMI) is a novel metric for assessing cardiometabolic health and type 2 diabetes mellitus (DM), yet its relationship with insulin resistance (IR) and prediabetes (preDM) is not well-studied. There is also a gap in understanding the nonlinear associations between CMI and these conditions. Our study aimed to elucidate these associations., Methods: We included 13,142 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2020. CMI was calculated by multiplying the triglyceride-to-high density lipoprotein cholesterol (TG/HDL-C) by waist-to-height ratio (WHtR). Using weighted multivariable linear and logistic regression explored the relationships of CMI with glucose metabolism markers, IR, preDM, and DM. Nonlinear associations were assessed using generalized additive models (GAM), smooth curve fittings, and two-piecewise logistic regression., Results: Multivariate regression revealed positive correlations between CMI and glucose metabolic biomarkers, including FBG (β = 0.08, 95% CI: 0.06-0.10), HbA1c (β = 0.26, 95% CI: 0.22-0.31), FSI (β = 4.88, 95% CI: 4.23-5.54), and HOMA-IR (β = 1.85, 95% CI: 1.56-2.14). There were also significant correlations between CMI and increased risk of IR (OR = 3.51, 95% CI: 2.94-4.20), preDM (OR = 1.49, 95% CI: 1.29-1.71), and DM (OR = 2.22, 95% CI: 2.00-2.47). Inverse nonlinear L-shaped associations were found between CMI and IR, preDM, and DM, with saturation inflection points at 1.1, 1.45, and 1.6, respectively. Below these thresholds, increments in CMI significantly correlated with heightened risks of IR, preDM, and DM., Conclusions: CMI exhibited inverse L-shaped nonlinear relationships with IR, preDM, and DM, suggesting that reducing CMI to a certain level might significantly prevent these conditions., (© 2024. The Author(s).)

Background: The endocannabinoid system over-activation is associated with type-2 diabetes mellitus onset, involving physiological, metabolic, and genetic alterations in pancreatic islets. The use of Δ9-Tetrahydrocannabinol (THC) as treatment is still controversial since its effects and mechanisms on insulin secretion are unclear. The aim of this study was to evaluate the effects of THC treatment in pancreatic islets from prediabetic mice. Methods: Prediabetes was induced in mice by hypercaloric diet, and then treated with THC for 3 weeks. Blood glucose and body weight were determined, after behavior tests. Histological changes were evaluated in whole pancreas; in isolated islets we analyzed the effect of THC exposure in glucose-stimulated insulin secretion (GSIS), gene expression, intracellular cyclic adenosine monophosphate (cAMP), and cytosolic calcium changes. Results: THC treatment in prediabetic mice enhanced anxiety and antidepressive behavior without changes in food ingestion, decreased oral-glucose tolerance test, plasma insulin and weight, with small alterations on pancreatic histology. In isolated islets from healthy mice THC increased GSIS, cAMP, and CB1 receptor (CB1r) expression, meanwhile calcium release was diminished. Small changes were observed in islets from prediabetic mice. Conclusions: THC treatment improves some clinical parameters in prediabetic mice, however, in isolated islets, modifies GSIS, intracellular calcium and gene expression, suggesting specific effects related to diabetes evolution.

Aim: This study aims to investigate the optimal dose of metformin for controlling the transition to diabetes in patients diagnosed with prediabetes., Methods: We systematically searched randomized controlled trials (RCTs) in CNKI, Wanfang, VIP, SinoMed, Scopus, PubMed, Embase, Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to February 2024. Meta-analysis was conducted using RevMan 5.4 software., Results: We included 25 randomized controlled trials comprising 2437 patients. The results of the meta-analysis revealed that compared to dose groups of 500 mg/d, 850 mg/d, 1000 mg/d, 1500 mg/d, 1700 mg/d, and 2000 mg/d, a dosage of 750 mg/d of metformin significantly reduced the incidence of diabetes in patients (risk ratio [RR] = 0.21, 95 % confidence interval [CI]: 0.11, 0.41; p < 0.00001), lowered Postprandial Blood Glucose (PBG) (mean difference[MD] = -2.60, 95 % CI: -4.34, -0.86; p = 0.003), and promoted the normalization of blood glucose levels (RR = 2.13, 95 % CI: 1.68, 2.71; p < 0.00001). Regarding safety evaluation, no significant differences were identified among the various dose groups. In contrast, the cohort receiving a daily dosage of 750 mg demonstrated the most pronounced decrease in the incidence of adverse reactions., Conclusion: Based on the efficacy and safety evaluation results, our findings suggest that a daily dosage of 750 mg of metformin may represent the optimal dose for controlling the progression from pre-diabetes to diabetes., Registration: PROSPERO registration ID: CRD42024538322., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Few studies have examined the link between systemic oxidative stress and mortality risk in diabetes and prediabetes patients. The Oxidative Balance Score (OBS) is a novel measure of systemic oxidative stress, with higher scores indicating greater antioxidant exposure. This study investigates the relationship between OBS and all-cause and cardiovascular mortality in these patients., Methods: This study analyzed 10,591 diabetes and prediabetes patients from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). The endpoints were all-cause and cardiovascular mortality, determined from the National Death Index (NDI). OBS was calculated using 20 dietary and lifestyle factors. Kaplan-Meier survival analysis, multivariable Cox regression models, restricted cubic splines (RCS), and subgroup analyses were used to assess the relationship between OBS and mortality risks., Results: Over an average follow-up of 99.8 months, 2900 (26.4 %) participants died, including 765 (8.9 %) from cardiovascular diseases. Kaplan-Meier analysis showed the lowest all-cause and cardiovascular mortality in the highest OBS quartile (Q4) and the highest mortality in the lowest quartile (Q1) (p < 0.001). In the fully adjusted model, multivariable Cox regression revealed that each unit increase in OBS was linked to a 1.8 % decrease in all-cause mortality risk (HR 0.982, 95 % CI 0.976-0.987, p < 0.0001) and a 4 % decrease in cardiovascular mortality risk (HR 0.960, 95 % CI 0.949-0.970, p < 0.0001). Compared to Q1, those in Q4 had significantly lower all-cause mortality (HR 0.719, 95 % CI 0.643-0.804, p < 0.0001, p for trend <0.0001) and cardiovascular mortality (HR 0.567, 95 % CI 0.455-0.705, p < 0.0001, p for trend <0.0001). These findings were consistent across subgroups. RCS curves showed a negative correlation between OBS and both mortality types., Conclusion: Higher OBS is linked to reduced all-cause and cardiovascular mortality in diabetes and prediabetes patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic disease complications pose a significant health risk due to their early development, making their diagnosis and radical therapy a considerable challenge. Here, we present a protocol for producing a rat model of non-obese prediabetes characterized by hyperinsulinemia, normoglycemia, and normal body weight. We describe steps for inducing the model in Sprague-Dawley (SD) male and ovariectomized female rats by free feeding on a mild hypercaloric diet. This protocol offers a potential model of metabolically unhealthy lean individuals. For complete details on the use and execution of this protocol, please refer to Elkhatib et al. 1 and Dwaib et al. 2 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Natural flavonoids exert many potential health benefits, including anti-hyperglycaemic effects. However, the effects of gossypetin (GTIN) on glucose homeostasis in pre-diabetes have not yet been investigated. This study examined the effects of GTIN on key markers of glucose homeostasis in a diet-induced pre-diabetic rat model. Pre-diabetes was induced by allowing the animals to feed on a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Following pre-diabetes induction, the pre-diabetic animals were sub-divided into five groups ( n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both with and without dietary intervention, over a 12-week period. The results demonstrated that animals in the untreated pre-diabetic (PD) control group exhibited significantly higher fasting and postprandial blood glucose levels, as well as elevated plasma insulin concentrations and increased homeostatic model assessment for insulin resistance (HOMA2-IR) index, relative to the non-pre-diabetic (NPD) group. Similarly, increased caloric intake, body weight and plasma ghrelin levels were observed in the PD control group. Notably, these parameters were significantly reduced in the PD animals receiving GTIN treatment. Additionally, glycogen levels in the liver and skeletal muscle, which were disturbed in the PD control group, showed significant improvement in both GTIN-treated groups. These findings may suggest that GTIN administration, with or without dietary modifications, may offer therapeutic benefits in ameliorating glucose homeostasis disturbances associated with the PD state.

Context: Glucagon plays a role in the development of type 2 diabetes, yet its role in prediabetes (preDM) remains uncertain., Objective: To evaluate glucagon levels in the fasting state and its response to glucose inhibition in preDM through meta-analysis., Methods: A systematic search across Pubmed, Embase, Web of Science, and Cochrane Library identified studies assessing glucagon levels during 75 g oral glucose tolerance test (OGTT) in both preDM and normal glucose tolerance (NGT) cohorts. Data on glucagon, glucose, and insulin were pooled using a random-effect model., Results: Although glucagon levels decreased in both preDM and NGT groups upon glucose challenge, glucagon levels at 0 hours, 0.5 hours, 1 hour, and 1.5 hours in preDM were significantly higher compared to NGT, despite higher glucose levels at all time points and higher insulin levels at 0 hours, 1 hour, 1.5 hours, and 2 hours during OGTT. Subgroup analysis revealed that in studies using the radioimmunoassay method, glucagon levels in preDM were higher at 0.5 hours and 1 hour than NGT, while in studies using the ELISA method, glucagon levels were similar to those of the NGT group despite higher glucose in preDM compared to NGT. Fasting glucagon level was inadequately suppressed in both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Responsiveness to glucose inhibition was preserved in IFG, while glucagon level in IGT group at 0.5 hours after glucose intake was not suppressed and was higher than NGT., Conclusion: Glucagon was not adequately suppressed during OGTT in preDM. Glucagon dysregulation is a contributing mechanism underlying both IFG and IGT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: Disorders of glucose metabolism in children with obesity are less common than in adults. There is also evidence that they may be transient. The aims of this study were to determine the prevalences of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (DM2) and its reversibility in pediatric patients with obesity and to define the factors determining the reversibility of prediabetes or progression to diabetes., Methods: Retrospective analysis included of young patients with obesity. Patients presented and were treated between 2000-2022 at a single center., Results: The study included 573 (316 girls; 55.15%) Caucasian patients with median body mass index (BMI) Z-score of 3.95 (range 2.0-9.9) and median age 13.9 (2.9-17.1) years old. OGTT results were normal in 90.8% (n=520) and signs of prediabetes occurred in 9.2% (n=53); IFG 17%, IGT 88.7%, DM 0%. Among those who underwent OGTT twice (n=53), impaired glucose regulation was present in 9.3% (n=5) (IFG 40%, IGT 80%, DM 0%) at baseline and in 14.8% subject (n=8) (IFG 25%, IGT 50%, DM 25%) at follow-up after lifestyle modification only. After 12-36 months of follow up, in those with a history of IGT, 60% reverted to normal glucose tolerance, while IFG and IGT persisted in 20% and 20%, respectively, and none progressed to DM. The risk factors for progression of glucose metabolism disorders were increase of BMI Z-score, higher insulin levels and elevated homeostatic model assessment-insulin resistance., Conclusion: IFG and IGT are common in pediatric patients with obesity, while the progression to DM2 is rare. Disorders of glucose metabolism have reversible character., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Aims/hypothesis: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites., Methods: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA 1c ) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors., Results: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures., Conclusions/interpretation: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Determining the relationship between cardiovascular risks, carbohydrate metabolism disorders, and renal dysfunction can help in creating new tools for their management and for better interaction of specialists in a multidisciplinary team. The purpose of this study was to determine the functional state of the kidneys and carbohydrate metabolism in patients with acute coronary syndrome without a history of such disorders., Methods: 200 patients of the cardiology department of the City Clinical Hospital No. 7 in Almaty were examined using laboratory diagnostics and subsequent statistical data processing., Results: Acute coronary syndrome develops in 63% of cases against the background of previous disorders of carbohydrate metabolism - prediabetes (45.5%) and type 2 diabetes mellitus (17.5%). In this group of patients, in the presence of disorders of carbohydrate metabolism, in all cases, it is accompanied by acute renal damage. It was noted that diabetes mellitus in newly diagnosed patients actually had a certain duration and occurred much earlier than cardiovascular complications - this was evidenced by an increased level of glycated hemoglobin., Conclusions: Such results indicate the need for early diagnosis of cardio-reno-metabolic syndrome in patients with cardiovascular complications, as well as timely administration of drugs that simultaneously have antidiabetic, cardio- and nephroprotective effects.

Chromium as the trivalent ion is believed to pharmaceutically active, increasing insulin sensitivity in high doses in genetic rodent models of diabetes. However, contradictory results have been obtained chemical rodent models of diabetes. The current review analyses the effects of dietary Cr supplementation of rodent models of prediabetes, where the condition is administered using a high-fat or high-sugar diet. Rat model studies display a range of quality, with studies utilizing basal diets of known Cr content suggesting Cr beneficially affects insulin sensitivity. Mouse model studies display too much heterogeneity in results for any firm conclusions to be drawn. Comparison of these results with those of clinical trials suggest that the effective dose of Cr may be proportionally lower for rodents than humans, if one exists for humans., Competing Interests: Declaration of Competing Interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Type-2 diabetes influences the course and severity of hand infections., Methods: We prospectively examined glucose metabolism in 90 patients with hand infection, distinguishing between normal, prediabetic and diabetic states. HbA1c-levels were evaluated prior to surgery. Patients with normal levels took an oral glucose tolerance test and those diagnosed with prediabetes were retested after the infection subsided. Hospital stay, number of surgical interventions and inflammatory markers were examined per group., Results: Sixty-two patients (68.8%) had abnormal glucose metabolism: 17 (18.9%) with history of diabetes and 11 (12.2%) newly diagnosed. Prediabetes was observed in 34 patients (37.8%). At follow-up, prediabetes and diabetes were diagnosed in 7 cases each, and physiological glucose metabolism was observed in 3 patients. For the 11 patients unable to undergo a second oral glucose tolerance test, detailed phone calls confirmed absence of diabetes. C-reactive protein levels were significantly elevated in diabetic patients compared to those with normal glucose metabolism (p = 0.001) or prediabetes (p = 0.034). Patients with history of diabetes were significantly older than those with normal glucose tolerance (p = 0.001) or prediabetes (p = 0.017). There were no significant intergroup differences in thrombocyte count, length of hospital stay, interval from injury to admission or the number surgical interventions., Conclusion: Glucose metabolism should be assessed in patients with hand infections and reassessed after the infection has subsided in prediabetic cases., (Copyright © 2024 SFCM. Published by Elsevier Masson SAS. All rights reserved.)

Aim: To examine physical activity levels in association with metabolic health and estimate the stability of metabolically healthy obese (MHO) phenotypes over a 2-year period., Methods: In total, 2848 men and women from families at risk of the development of diabetes were recruited. Participants were classified as obese or non-obese and metabolic health was defined using five existing definitions. Physical activity was estimated with the International Physical Activity Questionnaire and pedometers., Results: Prevalence of the MHO phenotype varied among definitions (0% to 20.2%). Overall, the MHO were more active than the metabolically unhealthy obese (MUO). Daily sitting hours (odds ratio [OR] = 1.055, 95% confidence interval [CI]: 1.009-1.104) and daily steps (per 500; OR = 0.934, 95% CI: 0.896-0.973) were remarkable predictors of metabolic health in individuals with obesity; and likewise, in individuals without obesity. After 2 years, 44.1% of baseline MHO adults transitioned to MUO, while 84.0% of the MUO at baseline remained at the same phenotype. Although physical activity was not a major determinant in phenotype transitioning, daily steps were associated with the maintenance of metabolic health over time in the non-obese group., Conclusion: A universally accepted definition for MHO is needed. Being physically active can contribute to a metabolically healthy profile even in the presence of obesity; still, MHO is a transient condition and physical activity alone may not be an adequate factor for its maintenance., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To determine risk factors for 1-year postpartum weight retention (PPWR) and glucose intolerance (prediabetes + diabetes) in women with a previous history of gestational diabetes (GDM) and prediabetes in early postpartum., Methods: In this exploratory analysis of the MELINDA randomized controlled trial, we report data of 167 women with prediabetes at the 6-16 weeks (early) postpartum oral glucose tolerance test after a recent history of GDM., Results: Of all participants, 45% (75) had PPWR >0 kg at 1-year postpartum. Compared to women without PPWR, women with PPWR had higher gestational weight gain [10.5 ± 6.4 vs. 6.5 ± 4.5 kg, p < 0.001], higher BMI (p < 0.01) and a worse metabolic profile (higher waist circumference, worse lipid profile and more insulin resistance) (all p < 0.05) both in early and late postpartum. Of all women with PPWR, 40.0% developed metabolic syndrome, compared to 18.9% of women without late PPWR (p = 0.003). The only independent predictor for late PPWR was weight retention in early postpartum (p < 0.001). Of all participants, 55.1% (92) had glucose intolerance (84 prediabetes, 8 diabetes) 1-year postpartum. Independent predictors for late postpartum glucose intolerance were lower gestational age at start insulin therapy in pregnancy and delivery by caesarean section (resp. p = 0.044 and 0.014)., Conclusions: In women with a previous history of GDM and prediabetes in early postpartum, PPWR in early postpartum was a strong independent predictor for late PPWR, while earlier start of insulin therapy during pregnancy and delivery by caesarean section were independent predictors of glucose intolerance in late postpartum., (© 2024 Diabetes UK.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder strongly linked to type 2 diabetes mellitus (T2DM). Understanding the predictive value of lipid parameters in identifying abnormal glucose metabolism in NAFLD patients is crucial for early intervention., Methods: This study analyzed data from the National Health and Nutrition Examination Survey(NHANES) database (2017-2020) involving 1066 NAFLD patients. Participants were categorized into three groups: T2DM (n=414), prediabetes mellitus (pre-DM) (n=507), and normoglycemia (NG) (n=145). Traditional lipid parameters [triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)] and nontraditional lipid parameters [atherogenic index of plasma (AIP), residual cholesterol (RC), and non-high-density lipoprotein cholesterol (non-HDL-C)] were evaluated for their association with T2DM and pre-DM., Results: Elevated TG levels were significantly associated with an increased risk of T2DM and pre-DM, whereas high HDL-C demonstrated a protective effect. Among nontraditional lipid parameters, increased AIP and RC were most strongly associated with T2DM risk, while high non-HDL-C was best associated with the development of pre-DM. Stratified analyses revealed that these associations were stronger in younger, non-obese, smoking, and female NAFLD patients., Conclusion: Nontraditional lipid parameters, particularly AIP and RC, show superior predictive value over traditional lipid parameters in identifying abnormal glucose metabolism in NAFLD patients. Incorporating these novel biomarkers into clinical practice could enhance early detection and prevention strategies for T2DM and pre-DM in this high-risk population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Fu, Su, Liu, Wu, Li, Wu and Zhang.)

Context: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood., Objective: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D., Methods: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D., Results: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes., Conclusion: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Free Fatty Acids (FFAs) are vital for energy homeostasis and the pathogenesis of a variety of diseases, including diabetes. For the first time, we presumed and investigated the types and levels of FFAs and their links to Insulin Resistance (IR) and Oxidative Stress (OS) in T2DM. A case-control study was conducted on 60 individuals with diabetes, 60 prediabetics with IFG, and 60 control groups. A Gas Chromatography Flame Ionization Detector (GC-FID) was used to estimate FFAs, which were then classified based on length and saturation. Indeed, antioxidant parameters such as TAC, MDA levels, PON-1, SOD-3, and CAT activity were assessed. Higher levels of LCFFA, SFFA, USFFA, and total FFA were found in people with diabetes and prediabetes. These levels were also linked to higher levels of HOMA-IR, BMI, FBS, HbA1C, and MDA, but lower levels of antioxidants. Furthermore, adjusting the above FFAs with age, sex, and antihypertensive medication increased T2DM development. SCFFA and ω3/6 fatty acids had a negative relationship with HOMA-IR, FBS, and insulin and a positive relationship with TAC. Adjusted SCFFA reduces T2DM risk. According to our models, total FFA is utilized to diagnose diabetes (AUC = 83.98, cut-off > 919 μM) and SCFFA for prediabetes (AUC = 82.32, cut-off < 39.56 μM). Total FFA (≥ 776 μM), LCFFA (≥ 613 μM), SFFA (≥ 471 μM), and USFFA (≥ 398 μM) all increase the risk of T2DM by increasing OS, BMI, and HOMA-IR. On the other hand, SCFFAs (≥ 38.7 μM) reduce the risk of T2DM by reducing BMI, HOMA-IR, and OS. SCFFAs and total FFAs can be used for the diagnosis of prediabetes and diabetes, respectively., Competing Interests: The authors state no conflict of interest., (Copyright: © 2024 Shiri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Metabolic score for insulin resistance (METS-IR) is a surrogate index to estimate insulin sensitivity. The aim of this study was to examine the association between METS-IR and regression to normoglycemia in Chinese adults with prediabetes., Methods: A total of 15,415 Chinese adults with prediabetes defined by their fasting blood glucose were included in this retrospective study. The association between METS-IR and regression to normoglycemia from prediabetes was evaluated using the Cox proportional hazards regression model. A Cox proportional hazards regression with cubic spline function was performed to explore the nonlinear association between METS-IR and regression to normoglycemia. Kaplan-Meier curves was used to describe the probability of regression to normoglycemia from prediabetes., Results: In multivariate Cox proportional hazards regression analyses, the increase in METS-IR was independently associated with a reduced probability of regression to normoglycemia from prediabetes (all p < 0.01 in models 1-3). A nonlinear association between METS-IR and the probability of regression to normoglycemia was observed, with an inflection point of 49.3. The hazard ratio on the left side of the inflection point was 0.965 (95% CI 0.953-0.976). Subgroup analyses demonstrated the robustness of our findings., Conclusion: This study demonstrated a negative and nonlinear association between METS-IR and regression to normoglycemia in Chinese adults with prediabetes. When METS-IR is below 49.3, reducing METS-IR could significantly increase the probability of regression to normoglycemia from prediabetes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk for heart failure, yet preventive cardiac care is suboptimal in this population. Pyridoxamine (PM), a vitamin B 6 analog, has been shown to exert protective effects in metabolic and cardiovascular diseases. In this study, we aimed to investigate whether PM limits adverse cardiac remodeling and dysfunction in rats who develop T2DM. Male rats received a standard chow diet or Western diet (WD) for 18 weeks to induce prediabetes. One WD group received additional PM (1 g/L) via drinking water. Glucose tolerance was assessed with a 1 h oral glucose tolerance test. Cardiac function was evaluated using echocardiography and hemodynamic measurements. Histology on left ventricular (LV) tissue was performed. Treatment with PM prevented the increase in fasting plasma glucose levels compared to WD-fed rats ( p < 0.05). LV cardiac dilation tended to be prevented using PM supplementation. In LV tissue, PM limited an increase in interstitial collagen deposition ( p < 0.05) seen in WD-fed rats. PM tended to decrease 3-nitrotyrosine and significantly lowered 4-hydroxynonenal content compared to WD-fed rats. We conclude that PM alleviates interstitial fibrosis and oxidative stress in the hearts of WD-induced prediabetic rats.

Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. Self-organizing map and differentially expressed gene analyses followed by pathway enrichment analysis identified genes and pathways altered across disease stage and injury site. Pathways related to immune response, inflammation, and glucose and lipid metabolism were consistently dysregulated with HFD-induced PN, irrespective of injury site. However, regulation of oxidative stress was unique to the SCN while dysregulated Hippo and Notch signaling were only observed in the DRG. The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets., Competing Interests: Declaration of competing interest Lucy M. Hinder is currently employed by Rhythm Pharmaceuticals, but all contributions made by Lucy M. Hinder occurred while she was employed by the University of Michigan. The other authors declare that they have no competing interests. All authors have read the journal's policy on conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Previous studies have shown that skin autofluorescence (SAF), measured with an advanced glycation end product (AGE) reader, estimates the accumulation of AGEs in tissues. SAF is predictive of incident type 2 diabetes, cardiovascular disease (CVD), and CV mortality in the general population. Studies in diabetic mice have shown that activation of the receptor for AGEs in hematopoietic progenitor cells increases blood neutrophils and monocytes, impairing atherosclerosis regression. We asked whether SAF is associated with blood neutrophil and monocyte counts in the general population, and whether this was moderated by prediabetes, diabetes, and sex., Methods: We examined the associations between SAF and blood neutrophil/monocyte counts in participants of the Lifelines cohort (n = 58,923: n = 24,382 men, and n = 34,541 women), a prospective population-based cohort from the North of the Netherlands, employing multivariable regression analyses., Results: SAF positively associated with blood neutrophil and monocyte counts in the whole cohort. The positive association between SAF and monocyte, but not neutrophil, counts was moderated by prediabetes and diabetes. Positive associations between SAF and blood neutrophil and monocyte counts were moderated by male sex. Moreover, three-way interaction analyses revealed that the positive associations between SAF and neutrophil and monocyte counts were moderated by prediabetes, but not diabetes, in male sex., Conclusions: SAF is positively associated with blood neutrophil and monocyte counts in the general population, especially in men with prediabetes. This may contribute to the increased CV risk in men with prediabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Prediabetes is a risk state that defines a high chance of developing diabetes and cardiovascular disease. Oxidative stress mediated by hyperglycemia-induced production of reactive species could play a crucial role in this context. In the present study, we investigated whether the anion exchange capability mediated by AE1 (SLC4A1), which is sensitive to oxidative stress, was altered in human red blood cells (RBCs) obtained from prediabetic volunteers. In addition, we assessed the precise composition of bioactive compounds and the potential benefits of finger lime juice extract (Citrus australasica, Faustrime cultivar) in counteracting oxidative stress-related functional alterations. Human RBCs from normal and prediabetic volunteers were incubated with 50 µg/mL juice extract for 2 h at 25°C. Juice extract restored alterations of the anion exchange capability mediated by AE1 and prevented the structural rearrangements of AE1 and α/β-spectrin in prediabetic RBCs. AE1 functional and structural alterations were not associated with an increase in lipid peroxidation or protein oxidation at the level of the plasma membrane. An increased production of intracellular ROS, which provoked the oxidation of hemoglobin to methemoglobin, both reverted by juice extract, was instead observed. Importantly, juice extract also induced a reduction in glycated hemoglobin levels in prediabetic RBCs. Finally, juice extract blunted the overactivation of the endogenous antioxidant enzymes catalase and superoxide dismutase and prevented glutathione depletion in prediabetic RBCs. These findings contribute to clarifying cellular and molecular mechanisms related to oxidative stress and glycation events that may influence RBC and systemic homeostasis in prediabetes, identify AE1 as a sensitive biomarker of RBC structural and function alterations in prediabetes and propose finger lime juice extract as a natural antioxidant for the treatment and/or prevention of the complications associated with the prediabetic condition., (© 2024 The Author(s). Cell Biochemistry and Function published by John Wiley & Sons Ltd.)

Aims/hypothesis: Prediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells' functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes., Methods: Islets from male and female transgenic Ins1 CreERT2 -GCaMP3 mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca 2+ ] i ) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca 2+ ] i dynamics in line with single beta cell [Ca 2+ ] i analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca 2+ ] i dynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca 2+ ] i dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10., Results: Mice fed a WD for 1 month displayed increased beta cell [Ca 2+ ] i dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca 2+ ] i dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes., Conclusions/interpretation: We identified increased coordination of [Ca 2+ ] i dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca 2+ ] i dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca 2+ ] i dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca 2+ ] i dynamics may thus serve as an early marker for beta cell failure in prediabetes., (© 2024. The Author(s).)

Observational studies have shown correlations between intramyocellular lipid (IMCL) content and muscle strength and contractile function in people with metabolically abnormal obesity. However, a clear physiologic mechanism for this association is lacking, and causation is debated. We combined immunofluorescent confocal imaging with force measurements on permeabilized muscle fibers from metabolically normal and metabolically abnormal mice and people with metabolically normal (defined as normal fasting plasma glucose and glucose tolerance) and metabolically abnormal (defined as prediabetes and type 2 diabetes) overweight/obesity to evaluate relationships among myocellular lipid droplet characteristics (droplet size and density) and biophysical (active contractile and passive viscoelastic) properties. The fiber type specificity of lipid droplet parameters varied by metabolic status and by species. It was different between mice and people across the board and different between people of different metabolic status. However, despite considerable quantities of IMCL in the metabolically abnormal groups, there were no significant differences in peak active tension or passive viscoelasticity between the metabolically abnormal and control groups in mice or people. Additionally, there were no significant relationships among IMCL parameters and biophysical variables. Thus, we conclude that IMCL accumulation per se does not impact muscle fiber biophysical properties or physically impede contraction., (© 2024 by the American Diabetes Association.)

Prediabetes is a crucial stage for prevention and treatment of diabetes, and vitamin D (VD) has been found to be linked to the development of prediabetes and diabetes. Thus, we aimed to identify the effect of VD supplementation on glucose metabolism in prediabetic participants and mice. A 1:1 paired design of randomized, placebo-controlled trial with 1600 IU/day VD 3 or placebo was administered to individuals with prediabetes, two-way repeated-measures ANCOVA was used to analyze glycolipid and inflammatory factors. A high-fat diet induced prediabetic KKay mice were utilized to evaluate the effects of VD 3 with 16 weeks supplementation. Generalized estimation equation, one way ANOVA were used to analyze continuous monitoring indexes and terminal indexes, respectively. Exercise capacity, skeletal muscle pathological features and relevant proteins were examined. The clinical results showed that VD 3 could improve insulin secretion and decrease inflammation. Results of KKay mice exhibited that VD 3 not only ameliorate glycolipid metabolism and inflammatory indicators, but also regulated pathological changes of skeletal muscle and exercise capacity. Mechanistically, our results demonstrated that VD 3 could inhibit the TLR4/NFκB and activate PI3K/AKT signaling pathway. Collectively, the study indicated that VD 3 exerts its beneficial effects by inhibiting TLR4/NFκB to decrease inflammatory response, and activating PI3K/AKT signaling pathway to regulate glucose homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Prediabetes, characterized by a series of metabolic abnormalities, increases the risk of diabetes and cardiovascular diseases. Tangzhiping (TZP), a clinically validated traditional Chinese medicine formula, is used to treat impaired glucose tolerance. However, the underlying mechanism of TZP in intervening prediabetes is not fully elucidated., Purpose: The current study aimed to evaluate the protective effect of TZP against prediabetes mice and explore its potential mechanism., Methods: After establishing a prediabetic animal model through 12 weeks of high-fat diet (HFD) feeding, mice were subjected to TZP for 8 weeks. Various parameters related to body weight, glucose and lipid metabolism, and insulin sensitivity were measured. Histopathological examinations observed adipose cell size and liver lipid deposition. The Sable Promethion system assessed energy metabolism activity. Transcriptomic analysis of Epididymal white adipose tissue (EWAT) identified enriched pathways and genes. The key genes in the enriched pathways were identified through RT-PCR., Results: Our data revealed that the administration of TZP reduced body weight and fat mass in a prediabetes mouse model. TZP normalized the glucose and insulin levels, improved insulin resistance, and decreased plasma TC and FFA. The alleviation of adipose tissue hypertrophy and lipid deposition by TZP was demonstrated through pathological examination. Indirect calorimetry measurements indicated a potential increase in VO 2 and EE levels with TZP. The results of EWAT transcription showed that TZP reversed pathways and genes related to inflammation and catabolic metabolism. RT-PCR demonstrated that the mRNA expression of inflammation and lipolysis, including Tlr2, Ccr5, Ccl9, Itgb2, Lipe, Pnpla2, Cdo1, Ces1d, Echs1, and Acad11, were changed by TZP treatment., Conclusion: TZP effectively alleviates obesity, impaired glucose and lipid metabolism, and insulin resistance. The effect of TZP might be associated with the regulation of gene expression in dysfunctional adipose tissue., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Wang et al.)

The increasing prevalence of type 2 diabetes mellitus (T2DM) is a significant worldwide health concern caused by sedentary lifestyles and unhealthy diets. Beyond glycemic control, T2DM impacts multiple organ systems, leading to various complications. While traditionally associated with cardiovascular and microvascular complications, emerging evidence indicates significant effects on pulmonary health. Pulmonary vascular dysfunction and fibrosis, characterized by alterations in vascular tone and excessive extracellular matrix deposition, are increasingly recognized in individuals with T2DM. The onset of T2DM is often preceded by prediabetes, an intermediate hyperglycemic state that is associated with increased diabetes and cardiovascular disease risk. This review explores the relationship between T2DM, pulmonary vascular dysfunction and pulmonary fibrosis, with a focus on potential links with prediabetes. Pulmonary vascular function, including the roles of nitric oxide (NO), prostacyclin (PGI2), endothelin-1 (ET-1), thromboxane A2 (TxA2) and thrombospondin-1 (THBS1), is discussed in the context of T2DM and prediabetes. Mechanisms linking T2DM to pulmonary fibrosis, such as oxidative stress, dysregulated fibrotic signaling, and chronic inflammation, are explained. The impact of prediabetes on pulmonary health, including endothelial dysfunction, oxidative stress, and dysregulated vasoactive mediators, is highlighted. Early detection and intervention during the prediabetic stage may reduce respiratory complications associated with T2DM, emphasizing the importance of management strategies targeting blood glucose regulation and vascular health. More research that looks into the mechanisms underlying pulmonary complications in T2DM and prediabetes is needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mzimela, Dimba, Sosibo and Khathi.)