Insulin Sensitivity In Individuals Research Articles

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

7449 A Genome-wide CRISPR Screen Identifies Drivers of Impaired Glucose Uptake in Human Insulin Resistance

Abstract Disclosure: N. Haider: None. Y. Lee: None. P. Yi: None. C.R. Kahn: None. Insulin resistance is a major risk factor in the development of type 2 diabetes (T2D), and metabolic syndrome. Although 25% of people within the general non-diabetic population are insulin resistant, the primary underlying cause of insulin resistance remains elusive. In this study, we have used induced pluripotent stem cells (iPSC) derived from non-diabetic humans at both ends of the insulin sensitivity spectrum, i.e., the top 20% of insulin resistance vs. the top 20% of insulin sensitive, as well as individuals with T2D to model human insulin resistance. We find that iPSCs differentiated into myoblasts (iMyos) from T2D and non-diabetic individuals in the highest quintile of insulin resistance (I-Res) show impaired insulin signaling and defective insulin-stimulated glucose uptake, as compared to iMyos from the insulin sensitive individuals (I-Sen), indicating that these cells in vitro mirror the alterations seen in vivo in a cell autonomous manner. To uncover the primary upstream drivers that contribute to the impaired glucose uptake associated with insulin resistance, we conducted a genome-wide loss-of-function screen using a CRISPR-based approach to identify genes that positively or negatively regulated glucose uptake in I-Res and T2D iMyos. Knockdown of ∼525 genes show effect to rescue the impaired glucose uptake in both I-Res and T2D iMyos, i.e., were negative regulators of glucose uptake. We hypothesized that important negative regulators of glucose uptake might be over-expressed at the protein level in I-Res and T2D iMyos and crossing the iMyos proteomics data with the CRISPR screen revealed 8 top candidates that are increased at the protein level and whose knockdown rescued glucose uptake in I-Res and T2D iMyos. These included candidates associated with cytoskeleton changes, protein kinases, transmembrane transport, mitochondrial and nuclear proteins. In summary, iPSC derived myoblasts from patients with insulin resistance and T2D mirror defects in glucose uptake observed in vivo. Combining CRISPR screening and global proteomics, we have identified important upstream regulators of insulin resistance in humans. Presentation: 6/2/2024

A 3-Week Ketogenic Diet Increases Skeletal Muscle Insulin Sensitivity in Individuals With Obesity: A Randomized Controlled Crossover Trial.

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of developing type 2 diabetes. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two three-week interventions: 1) KD and 2) standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2 kg weight loss, increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.

Exercise intensities and metabolic health: Targeting blood glucose, insulin, and C-peptide levels in adults with prediabetes in the postprandial state

ObjectiveExercise improves postprandial glycemia and insulin sensitivity in individuals with prediabetes, but the optimal intensity for this metabolic regulation remains unclear. The current study explored the impact of various exercise intensities on blood glucose, insulin, and C-peptide levels in prediabetic individuals to identify the optimal intensity for improving these metabolic indicators. MethodsIn this crossover study, 25 individuals with prediabetes participated in exercise sessions at four different intensities 50 %, 60 %, 70 %, and 80 % of their predicted maximum heart rate using a treadmill. Each session lasted 30 min, including a 5-min warm-up and 5-min cool-down period. Blood samples were collected at four time points: during fasting, immediately before exercise, and 30 and 60 min post-exercise. These samples were analyzed for glucose, insulin, and C-peptide levels. The effects of exercise intensity on these parameters were evaluated using repeated measures analysis of variance (ANOVA), with post hoc tests conducted to determine specific differences between the intensities. ResultsThe participants had an average age of 34.88 years, mean height of 170 cm, and body mass index of 30.34 kg/m2. A significant reduction in insulin and glucose levels post-exercise was observed at 70 % intensity (p ≤ 0.001). Despite high fasting blood glucose levels (110–115 mg/dL), significant reductions were noted at 30 and 60 min post-exercise (p ≤ 0.001). Insulin levels approached near baseline at 70 % intensity, from fasting (26.74 ± 20.83) to 60 min post-exercise (28.47 ± 20.79), indicating a positive response at this intensity. C-peptide levels also showed significant changes, with 70 % intensity exercise bringing them closest to fasting levels by 60 min post-exercise. ConclusionThis study highlights the importance of exercise intensities in enhancing metabolic parameters in individuals with prediabetes. Specifically, 70 % of the predicted maximum heart rate was beneficial, optimizing insulin sensitivity and potentially reducing the risk of progressing from prediabetes to diabetes.

Effects of 12-Week Supplementation with Coffee Diterpene Cafestol in Healthy Subjects with Increased Waist Circumference: A Randomized, Placebo-Controlled Trial.

Background: Coffee consumption is inversely associated with type 2 diabetes. Cafestol, a bioactive compound in coffee, has demonstrated glucose-lowering and insulin-secretory properties in cell and animal studies. The acute effects of cafestol on glucose metabolism in humans have only been briefly investigated, and longer-term effects have not been explored. This study aimed to assess the effects of purified cafestol on insulin sensitivity and other metabolic parameters in healthy individuals with increased waist circumference at risk of developing type 2 diabetes. Methods: A 12-week randomized, placebo-controlled, parallel trial was conducted with 40 participants. Insulin suppression tests, mixed meal tests, and MRI scans were performed before and after the intervention. Results: Administering 6 mg of cafestol twice daily did not alter insulin sensitivity or glucose tolerance but led to significant reductions in body weight (2%), visceral fat volume (5%), and gamma-glutamyl transferase levels (15%) compared to the placebo. Conclusions: Cafestol may hold promise for weight and visceral fat reduction. Cafestol did not improve insulin sensitivity or glucose tolerance in this study but might still contribute to the observed inverse association between coffee consumption and type 2 diabetes. Future research should explore higher dosages and longer treatment durations, particularly in individuals with impaired glucose metabolism and type 2 diabetes.

Will melatonin supplementation become a new form of obesity treatment? A review of recent literature.

Background: In 2020, the World Health Organization (WHO) estimated that 650 million adults worldwide are obese, and 2.8 billion individuals struggle with overweight. Obesity is associated with an increased risk of cardiovascular diseases, type 2 diabetes, heart disease, adverse effects on mental health, the development of certain cancers, and other conditions. In recent years, there has been growing interest in the role of melatonin, which has therapeutic potential in the treatment of obesity. Studies suggest that melatonin supplementation may lead to weight reduction and improvement in metabolic parameters, significantly reduce cardiovascular disease risk factors, and enhance insulin sensitivity in obese individuals. Aim of study: This review aims to present the latest scientific findings on the impact of melatonin supplementation on the development of obesity and its complications. We focus primarily on the mechanisms of melatonin's action in the context of obesity, particularly on potential pathways that have not yet been thoroughly explored. Our aim is to provide deeper insights into research on obesity and its prevention. Materials and Methods: Search was conducted using PubMed and Google Scholar databases, utilizing the keywords "obesity," "melatonin," and "weight loss" in various configurations. The review primarily considers studies published after 2016 that are available online. Summary Melatonin supplementation leads to a statistically significant reduction in blood glucose levels and an increase in cellular insulin sensitivity. Its promising properties in the treatment of obesity have been demonstrated through the reduction of oxidative stress, indicating a potential adjunct for weight loss. Based on the cited studies, the beneficial effects of melatonin supplementation on cardiovascular risk factors have been confirmed. Melatonin could be considered as an adjunctive therapy for obese individuals who do not respond to other treatment modalities.

An examination of exercise intensity and its impact on the acute release of irisin across obesity status: a randomized controlled crossover trial.

Limited data exist regarding the impact of exercise intensity on irisin release and its association with insulin sensitivity in individuals of differing obesity status. The objective of this study was to investigate the impact of exercise intensity on the acute release of irisin in healthy-weight individuals and individuals with obesity, and whether irisin release during acute exercise was associated with greater insulin sensitivity across obesity status. A randomized controlled crossover study was conducted on 26 non-overweight/obese (non-OW/OB) (BMI: 22.2±1.5 kg/m2) and 26 overweight/obese (OW/OB) (BMI: 33.9±6.5 kg/m2) adults who performed an acute bout of moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), and rest. Irisin was quantified via ELISA and western blotting, and insulin sensitivity (Si) was estimated using the Matsuda index. OW/OB displayed a significantly lower level of circulating irisin and protein expression compared to non-OW/OB (p<0.01). Insulin sensitivity was positively correlated with irisin release during MICT and HIIT in non-OW/OB (all p<0.05), but not in OW/OB. Regarding irisin expression, non-OW/OB with high Si had a 2.03-fold (p<0.05) increase during HIIT, while OW/OB with high Si had only a 1.54-fold increase (p<0.05). These results suggest that irisin is released differently according to obesity status and varying exercise intensities. OW/OB individuals have a blunted irisin response to acute exercise and lower baseline irisin concentrations compared to non-OW/OB individuals. Although exercise stimulates irisin release in non-OW/OB individuals, only a greater exercise intensity stimulates irisin release in OW/OB individuals. These findings are clinically relevant, as irisin is associated with greater insulin sensitivity. This trial was registered at clinicaltrials.gov (NCT03514238).

Pre-Prediabetes: Insulin Resistance is Associated with Cardiometabolic Risk in Non-obese Patients (STOP DIABETES).

To examine if insulin resistance is associated with markers of glycemic, cardiometabolic and atherosclerotic risk in non-obese, non-prediabetic individuals compared to insulin sensitive subjects matched for BMI, gender, and age. Of 1860 patients from STOP DIABETES study, 624 had normal fasting plasma glucose, body mass index < 30, and HbA1c < 5.7%. All received oral glucose tolerance test (OGTT). Insulin sensitivity was quantitated using Matsuda index: <25th percentile = Insulin Resistant (IR) (n=151) and ≥ 25th percentile = Insulin Sensitive (IS) (n=473). Measures of dysglycemia and cardiometabolic risk were compared between insulin resistant subjects (n=151) and subset of insulin sensitive individuals who were matched for BMI, gender, age (n=151). Carotid intima media thickness (CIMT) and carotid plaque were measured in 65 IR and 76 IS individuals. Compared to matched insulin sensitive patients, insulin resistant non-obese subjects demonstrated increased indicators of glycemic and cardiometabolic risk including: increased 60-minute plasma glucose and percentage of patients with 60-minute plasma glucose > 155mg/dL; increased 120-minute plasma glucose; unrecognized impaired glucose tolerance (IGT) and type 2 diabetes (T2D), decreased disposition index; increased systolic and diastolic blood pressure; elevated plasma triglycerides; reduced HDL cholesterol; increased triglyceride/HDL ratio and hs-CRP. The presence, size, and number of carotid plaques was greater in the insulin resistant group. Approximately 1 in 4 non-obese patients in this population with normal fasting glucose and HbA1c were insulin resistant. In these non-obese subjects, insulin resistance was associated with multiple indicators of dysglycemia and cardiometabolic risk.

The Ex-Timing trial: evaluating morning, afternoon, and evening exercise on the circadian clock in individuals with type 2 diabetes and overweight/obesity—a randomized crossover study protocol

BackgroundExercise is known to provide multiple metabolic benefits such as improved insulin sensitivity and glucose control in individuals with type 2 diabetes mellitus (T2DM) and those at risk. Beyond the traditional exercise dose, exercise timing is perceived as a contemporary hot topic, especially in the field of T2DM; however, the number of intervention studies assessing exercise timing and glucose metabolism is scarce. Our aim is to test the effect of exercise timing (i.e., morning, afternoon, or evening) on the inter-individual response variability in glycemic control and related metabolic health parameters in individuals with T2DM and those at risk during a 12-week intervention.MethodsA randomized crossover exercise intervention will be conducted involving two groups: group 1, individuals with T2DM; group 2, age-matched older adults with overweight/obesity. The intervention will consist of three 2-week blocks of supervised post-prandial exercise using high-intensity interval training (HIIT). Between each training block, a 2-week washout period, where participants avoid structured exercise, will take place. Assessments will be conducted in both groups before and after each exercise block. The primary outcomes include the 24-h area under the curve continuous glucose monitoring-based glucose. The secondary outcomes include body composition, resting energy expenditure, insulin response to a meal tolerance test, maximal aerobic capacity, peak power output, physical activity, sleep quality, and insulin and glucose levels. All primary and secondary outcomes will be measured at each assessment point.DiscussionOutcomes from this trial will provide us additional insight into the role of exercise timing on the inter-individual response variability in glycemic control and other related metabolic parameters in two distinct populations, thus contributing to the development of more effective exercise prescription guidelines for individuals with T2DM and those at risk.Trial registrationClinicalTrials.gov NCT06136013. Registered on November 18, 2023.

Unveiling a Novel Frontier: Exploring Creatine Applications in Diabetes Management

In the dynamic realm of diabetes management, the quest for innovative strategies continually evolves. This article embarks on an exploration of a groundbreaking frontier, introducing a new approach that extends beyond conventional paradigms. We delve into the intriguing intersection of creatine applications and diabetes care, unveiling a novel perspective that holds potential to redefine how we approach the multifaceted challenges posed by this metabolic condition. Traditionally renowned for its role in enhancing muscular energy metabolism, creatine has emerged from the realms of sports nutrition to captivate the attention of researchers and practitioners alike in the field of diabetes management. This paradigm shift invites us to reconsider the scope of creatine supplementation, moving beyond its established association with athletic performance to explore its nuanced impact on glucose regulation and insulin sensitivity in individuals grappling with diabetes. As we navigate this uncharted territory, this article aims to provide a comprehensive overview of the intricate interplay between creatine and diabetes, weaving together current research findings, emerging treatment trends, and the potential synergies that could shape the future of diabetes care. From the molecular intricacies of energy metabolism to the broader landscape of contemporary diabetes treatments, our exploration seeks to illuminate a path towards a more holistic and personalized approach to diabetes management.

Novel Proteome Targets Marking Insulin Resistance in Metabolic Syndrome.

In order to better understand which metabolic differences are related to insulin resistance in metabolic syndrome (MetSyn), we used hyperinsulinemic-euglycemic (HE) clamps in individuals with MetSyn and related peripheral insulin resistance to circulating biomarkers. In this cross-sectional study, HE-clamps were performed in treatment-naive men (n = 97) with MetSyn. Subjects were defined as insulin-resistant based on the rate of disappearance (Rd). Machine learning models and conventional statistics were used to identify biomarkers of insulin resistance. Findings were replicated in a cohort with n = 282 obese men and women with (n = 156) and without (n = 126) MetSyn. In addition to this, the relation between biomarkers and adipose tissue was assessed by nuclear magnetic resonance imaging. Peripheral insulin resistance is marked by changes in proteins related to inflammatory processes such as IL-1 and TNF-receptor and superfamily members. These proteins can distinguish between insulin-resistant and insulin-sensitive individuals (AUC = 0.72 ± 0.10) with MetSyn. These proteins were also associated with IFG, liver fat (rho 0.36, p = 1.79 × 10-9) and visceral adipose tissue (rho = 0.35, p = 6.80 × 10-9). Interestingly, these proteins had the strongest association in the MetSyn subgroup compared to individuals without MetSyn. MetSyn associated with insulin resistance is characterized by protein changes related to body fat content, insulin signaling and pro-inflammatory processes. These findings provide novel targets for intervention studies and should be the focus of future in vitro and in vivo studies.

Myofiber-specific lipidomics unveil differential contributions to insulin sensitivity in individuals of African and European ancestry

AimsIndividuals of African ancestry (AA) present with lower insulin sensitivity compared to their European counterparts (EA). Studies show ethnic differences in skeletal muscle fiber type (lower type I fibers in AA), muscle fat oxidation capacity (lower in AA), whilst no differences in total skeletal muscle lipids. However, skeletal muscle lipid subtypes have not been examined in this context. We hypothesize that lower insulin sensitivity in AA is due to a greater proportion of type II (non-oxidative) muscle fibers, and that this would result in an ancestry-specific association between muscle lipid subtypes and peripheral insulin sensitivity. To test this hypothesis, we examined the association between insulin sensitivity and muscle lipids in AA and EA adults, and in an animal model of insulin resistance with muscle-specific fiber types. MethodsIn this cross-sectional study, muscle biopsies were obtained from individuals with a BMI ranging from normal to overweight with AA (N = 24) and EA (N = 19). Ancestry was assigned via genetic admixture analysis; peripheral insulin sensitivity via hyperinsulinaemic–euglycemic clamp; and myofiber content via myosin heavy chain immunohistochemistry. Further, muscle types with high (soleus) and low (vastus lateralis) type I fiber content were obtained from high-fat diet-induced insulin resistant F1 mice and littermate controls. Insulin sensitivity in mice was assessed via intraperitoneal glucose tolerance test. Mass spectrometry (MS)-based lipidomics was used to measure skeletal muscle lipid. ResultsCompared to EA, AA had lower peripheral insulin sensitivity and lower oxidative type 1 myofiber content, with no differences in total skeletal muscle lipid content. Muscles with lower type I fiber content (AA and vastus from mice) showed lower levels of lipids associated with fat oxidation capacity, i.e., cardiolipins, triacylglycerols with low saturation degree and phospholipids, compared to muscles with a higher type 1 fiber content (EA and soleus from mice). Further, we found that muscle diacylglycerol content was inversely associated with insulin sensitivity in EA, who have more type I fiber, whereas no association was found in AA. Similarly, we found that insulin sensitivity in mice was associated with diacylglycerol content in the soleus (high in type I fiber), not in vastus (low in type I fiber).Conclusions; Our data suggest that the lipid contribution to altered insulin sensitivity differs by ethnicity due to myofiber composition, and that this needs to be considered to increase our understanding of underlying mechanisms of altered insulin sensitivity in different ethnic populations.

Beta2-agonist impairs muscle insulin sensitivity in persons with insulin resistance.

Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance. To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects. In a cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, two hours into and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques. We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. While both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen. Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist.

Insulin-related traits and prostate cancer: A Mendelian randomization study

Investigating the causal relationship between insulin secretion and prostate cancer (PCa) development is challenging due to the multifactorial nature of PCa, which complicates the isolation of the specific impact of insulin-related factors. We conducted a Mendelian randomization (MR) study to investigate the associations between insulin secretion-related traits and PCa. We used 36, 60, 56, 23, 48, and 49 single nucleotide polymorphisms (SNPs) as instrumental variables for fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals, individuals with diabetes, and individuals receiving exogenous insulin, respectively. These SNPs were selected from various genome-wide association studies. To clarify the causal relationship between insulin-related traits and PCa, we utilized a multivariable MR analysis to adjust for obesity and body fat percentage. Additionally, two-step Mendelian randomization was conducted to assess the role of insulin-like growth factor 1 (IGF-1) in the relationship between proinsulin and PCa. Two-sample MR analysis revealed strong associations between genetically predicted fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals and the development of PCa. After adjustment for obesity and body fat percentage using multivariable MR analysis, proinsulin remained significantly associated with PCa, whereas other factors were not. Furthermore, two-step MR analysis demonstrated that proinsulin acts as a negative factor in prostate carcinogenesis, largely independent of IGF-1. This study provides evidence suggesting that proinsulin may act as a negative factor contributing to the development of PCa. Novel therapies targeting proinsulin may have potential benefits for PCa patients, potentially reducing the need for unnecessary surgical treatments.

Association between antioxidant metabolites and N-terminal fragment brain natriuretic peptides in insulin-resistant individuals.

Oxidative stress plays a pivotal role in the development of metabolic syndrome, including heart failure and insulin resistance. The N-terminal fragment of brain natriuretic peptide (NT-proBNP) has been associated with heightened oxidative stress in heart failure patients. Yet, its correlation with insulin resistance remains poorly understood. Our objective is to investigate the association between oxidative stress markers and NT-proBNP levels in insulin-resistant individuals. In this cross-sectional study involving 393 participants from the Qatar Biobank, clinical and metabolic data were collected, and the association between NT-proBNP and 72 oxidative stress metabolites was compared between insulin-sensitive and insulin-resistant individuals. Our results showed significantly lower NT-proBNP levels in insulin-resistant individuals (median = 17 pg/ml; interquartile range = 10.3-29) when compared to their insulin-sensitive counterparts (median = 31 pg/ml; interquartile range = 19-57). Moreover, we revealed notable associations between NT-proBNP levels and antioxidant metabolic pathways, particularly those related to glutathione metabolism, in insulin-resistant, but not insulin-sensitive individuals. The significant decrease in NT-proBNP observed in individuals with insulin resistance may be attributed to a direct or indirect enhancement in glutathione production, which is regarded as a compensatory mechanism against oxidative stress. This study could advance our understanding of the interplay between oxidative stress during insulin resistance and cardiovascular risk, which could lead to novel therapeutic approaches for managing cardiovascular diseases. Further investigations are needed to assess the practical utility of these potential metabolites and understand the causal nature of their association with NT-proBNP in the etiology of insulin resistance.

THE EFFECTS OF DOWNHILL WALKING ON INSULIN SENSITIVITY, ARTERIAL HEALTH, MUSCLE STRENGTH AND FUNCTIONAL PHYSICAL FITNESS IN PEOPLE WITH TYPE 2 DIABETES MELLITUS

INTRODUCTION &amp; AIMS Exercise is effective in preventing and managing Type 2 Diabetes Mellitus (T2DM). However, a significant number of people do not exercise as they perceive exercise to be physically challenging. Eccentric exercise, a novel aerobic exercise modality is less metabolically demanding and has been shown to have positive effects on blood glucose levels, cardiovascular fitness, and muscle strength in healthy populations. This research was conducted to explore the impact of eccentric exercise, specifically downhill walking, on insulin sensitivity, arterial health, muscle strength, and physical functional fitness in individuals with T2DM. METHODS A 12-week randomised controlled trial was conducted to investigate the effects of downhill, level, and uphill walking on people with T2DM. Sedentary adult participants with T2DM were randomised to perform downhill walking (DW), level walking (LW), or uphill walking (UW) for 30 minutes twice a week for twelve weeks at a standard speed of 2.5km/hr. The primary outcome measure was glycosylated haemoglobin (HbA1c), while secondary measures included arterial stiffness, strength, and physical fitness. RESULTS A significant reduction in HbA1c between baseline and 12 weeks was observed in the UW group However, per-protocol analysis showed a significant decrease in HbA1c in the DW group post-intervention as well. Central Systolic blood pressure significantly decreased between baseline and post-intervention in the DW group. Participants in DW group and UW group showed significant improvements in distance walked in 6MWT post-intervention. A significant increase in knee extensors isometric strength between baseline and 12 weeks was observed for the DW group only. CONCLUSION DW was as effective as UW for improving insulin sensitivity and more effective than LW and UW for improving central systolic blood pressure, muscle strength and functional physical fitness. DW is a viable option for those seeking a less demanding form of exercise.

Impact of Combined Aerobic Training and Magnesium Supplementation on Serum Biomarkers and microRNA-155 and microRNA-21 Expression in Adipose Tissue of Type 2 Diabetic Rats: An Eight-Week Interventional Study.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance and chronic inflammation. Aerobic training (AT) and magnesium supplementation (Mg) have both been independently shown to have beneficial effects on glucose control and insulin sensitivity in individuals with T2DM. However, the potential synergistic effects of combining AT and Mg supplementation have not been extensively studied. This study aimed to investigate the effects of an 8-week AT and Mg supplementation on serum levels of insulin, glucose, leptin, adiponectin, TNF-α, IL-1β, IL-6, NF-κB, as well as the expression of mir-155 and mir-21 in the visceral adipose tissue (VAT) of rats with T2DM. For this experimental study, 32 male Wistar rats were induced with T2DM by a high-fat diet combined with a low-dose streptozotocin injection. The rats were randomly assigned to four groups: AT and Mg supplementation (AT + Mg), AT (5 days/week for 8 weeks), Mg supplementation (received daily supplementation of Mg chloride), and diabetic control (C). An 8-week AT program was implemented, with gradually increasing the intensity and duration to reach 25m/min and 60min in the 8th week, respectively. The training intensity was set at 50-60% of VO2max. The Mg groups were provided with rat diets containing 1000mg/kg of Mg. The AT + Mg group received both interventions, while the C group served as the untreated control. Serum biomarkers were measured using enzyme-linked immunosorbent assay (ELISA), and VAT samples were collected for gene expression analysis using real-time polymerase chain reaction (PCR). Serum biomarker analysis revealed that the AT + Mg group had a significant decrease in fasting insulin (p = 0.001) and serum glucose (p = 0.001), as well as an increase in adiponectin levels compared to the C group (p = 0.002). Additionally, the AT + Mg group showed a significant reduction in serum leptin, TNF-α, IL-6, IL-1β, and NF-κB, as well as downregulation of mir-155 and mir-21 in the VAT compared to the other groups. The AT group also showed improvements in several parameters, while the Mg group had fewer significant differences compared to the C group. The combination of AT and Mg supplementation provides a synergistic effect that improves serum biomarkers and downregulates pro-inflammatory microRNAs in the VAT of T2DM rats. Meanwhile, Mg supplementation alone does not have a significant effect on pro-inflammatory microRNAs in the VAT. These findings suggest that such combined interventions could be a promising strategy for managing T2DM, potentially ameliorating inflammatory states and improving metabolic health.

Immunometabolic Signatures of Circulating Monocytes in Humans With Obesity and Insulin Resistance.

Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.

Altered extracellular matrix dynamics is associated with insulin resistance in adolescent children with obesity.

The objective of this study was to examine the hypothesis that abdominal and gluteal adipocyte turnover, lipid dynamics, and fibrogenesis are dysregulated among insulin-resistant (IR) compared with insulin-sensitive (IS) adolescents with obesity. Seven IS and seven IR adolescents with obesity participated in a 3-h oral glucose tolerance test and a multi-section magnetic resonance imaging scan of the abdominal region to examine body fat distribution patterns and liver fat content. An 8-week 70% deuterated water (2 H2 O) labeling protocol examined adipocyte turnover, lipid dynamics, and fibrogenesis in vivo from biopsied abdominal and gluteal fat. Abdominal and gluteal subcutaneous adipose tissue (SAT) turnover rates of lipid components were similar among IS and IR adolescents with obesity. However, the insoluble collagen (type I, subunit α2) isoform measured from abdominal, but not gluteal, SAT was elevated in IR compared with IS individuals. In addition, abdominal insoluble collagen Iα2 was associated with ratios of visceral-to-total (visceral adipose tissue + SAT) abdominal fat and whole-body and adipose tissue insulin signaling, and it trended toward a positive association with liver fat content. Altered extracellular matrix dynamics, but not expandability, potentially decreases abdominal SAT lipid storage capacity, contributing to the pathophysiological pathways linking adipose tissue and whole-body IR with altered ectopic storage of lipids within the liver among IR adolescents with obesity.

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

β-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.