Changes In Insulin Sensitivity Research Articles

Association of METS-IR index with psoriasis in US adults: a cross-sectional study.

Psoriasis is linked to insulin resistance (IR). Nevertheless, the applicability of the METS-IR index, a new IR evaluation tool, for evaluating changes in insulin sensitivity in psoriasis populations is currently unknown. This study aimed to investigate the relationship between the METS-IR index and psoriasis in a US adult population. This cross-sectional study utilized data from adults aged 20 to 80 years from the U.S. National Health and Nutrition Examination Survey (NHANES) spanning 2003-2006 and 2009-2014. The associations between the METS-IR index and psoriasis were examined using multivariate logistic regression and smoothed curve fitting. Subgroup analyses and interaction tests were conducted to verify the stability of the association within the population. This study included 5,966 participants, of whom 182 had psoriasis. In the fully adjusted model, the METS-IR index was positively associated with psoriasis, showing a 1.7% increase in psoriasis prevalence for each one-unit increase in the METS-IR index (Model 2: OR 1.017, 95% CI 1.006-1.028). Participants in the highest quartile group were 91.9% more likely to develop psoriasis compared to those in the lowest quartile group (OR = 1.919, 95% CI 1.180-3.118). Smooth curve fitting revealed a nonlinear association between the METS-IR index and psoriasis, with an inflection point of 41.675. This positive association was more pronounced in females, non-obese individuals, those with light alcohol consumption, comorbid coronary heart disease and hyperlipidemia, non-hypertensive and non-diabetic individuals. The results of the study suggest that higher METS-IR scores are associated with an increased likelihood of psoriasis among U.S. adults. The METS-IR index is specifically recommended as a clinical indicator for the management and treatment of psoriasis in women, non-obese individuals, light alcohol consumers, individuals with comorbid coronary artery disease andhyperlipidemia, non-hypertensive and non-diabetic individuals. However, Considering the many known and unknown covariates that may be associated with psoriasis and influence theresults of the study, we remain cautious about the results obtained and look forward to the addition of subsequent studies.

NMDA Receptors in POMC Neurons Connect Exercise With Insulin Sensitivity.

Increased arcuate proopiomelanocortin (POMC) neuron activity improves glucose metabolism and reduces appetite, facilitating weight loss. We recently showed that arcuate POMC neurons are activated by exercise. However, the role of excitatory glutamatergic input in these neurons and the metabolic outcomes of exercise remains undefined. To investigate this, we developed a mouse model with NMDA receptors (NMDARs) selectively deleted from POMC neurons of adult mice. We performed metabolic assessments, including the monitoring of body weight, body composition analysis, and glucometabolic tolerance tests. We also examined the metabolic outcomes of these mice in response to exercise, including changes in arcuate POMC neuronal activity and insulin sensitivity. Loss of NMDARs in POMC neurons failed to alter body weight or body composition. Notably, however, we did observe a marked impairment in glucose tolerance and insulin sensitivity. Additionally, exercise resulted in activation of arcuate POMC neurons and a sustained improvement in insulin sensitivity, an effect that was abrogated in mice deficient for NMDARs in POMC neurons when compared with their respective sedentary controls. This underscores an important link among exercise, hypothalamic neuron function, and metabolic health. Moreover, this highlights an underappreciated role of hypothalamic POMC neurons in mediating beneficial effects of exercise on glucose metabolism.

Type 1 Diabetes and Pregnancy: Challenges in Glycemic Control and Maternal-Fetal Outcomes.

Managing type 1 diabetes during pregnancy presents significant challenges due to physiological and hormonal changes. These factors contribute to major changes in insulin sensitivity, complicating efforts to achieve and sustain optimal blood glucose levels. Poorly controlled glucose levels during pregnancy can result in diabetic embryopathy and elevate the risks of maternal complications such as hypertensive disorders and diabetic ketoacidosis. Fetal complications may include preterm birth, fetal demise, and admission to neonatal intensive care units. It is essential to recognize that there is no universal approach to managing glycemic control in pregnant women with T1DM and care should be individualized. Effective management requires a multidisciplinary approach involving regular monitoring, adjustments in insulin therapy, dietary modifications, and consistent prenatal care. Continuous glucose monitoring has emerged as a valuable tool for real-time glucose monitoring, facilitating tighter glycemic control. Education and support for self-management are important in addressing these challenges. Future developments in technology and personalized approaches to care show promising potential for advancing diabetes management during pregnancy. This provides a comprehensive overview of current literature on the challenges with the management of T1DM during pregnancy, focusing on its impact on maternal and neonatal outcomes and highlighting effective strategies for achieving optimal glycemic control.

8413 Skeletal Muscle Mass, Insulin Sensitivity, And Beta-Cell Function In The Development Of Type 2 Diabetes: A 16-Year Prospective Cohort Study

Abstract Disclosure: H. Mun: None. S. Lee: None. S. Kim: None. S. Yoo: None. J. Son: None. Background: The relationship of relative muscle mass with beta-cell dysfunction and insulin resistance in the development of type 2 diabetes is unclear. We therefore aimed to evaluate longitudinal changes in glycemia, insulin sensitivity, and beta-cell function according to muscle mass. Methods: We prospectively evaluated 7090 middle-aged and older participants without diabetes at baseline every 2 years with oral glucose tolerance tests for 16 years in the Korean Genome Epidemiology Study. Weight-adjusted appendicular skeletal muscle mass was used to derive the muscle mass index (MMI). Using linear mixed-effect models, we assessed trajectories of fasting and 2-hour post-load glucose (2hPG), the composite insulin sensitivity index (ISIcomp), the 60-minute insulinogenic index (IGI60), and the disposition index (DI) according to sex-specific MMI tertiles before diagnosis with type 2 diabetes or the completion of follow-up. Results: During a median follow-up of 13.9 years, 1742 (24.5%) participants were diagnosed with type 2 diabetes. The risk of developing type 2 diabetes gradually increased as MMI decreased (multivariable-adjusted hazard ratio 1.36; 95% CI 1.29; 1.44 per SD decline in MMI). After age- and sex adjustment, significant differences were found in fasting and 2hPG trajectories between low and high MMI tertiles during follow-up (p < 0.001 for group-by-time interaction). The low MMI tertile showed significantly lower ISIcomp and DI at baseline compared to the high MMI tertile. The rate of increase in IGI60 was significantly lower in the low MMI tertile than in the high MMI tertile (0.0021 vs. 0.0191; p < 0.001) despite a progressive decline in ISIcomp during follow-up. The rate of decrease in DI was significantly greater in the low MMI tertile than in the high MMI tertile (-0.0228 vs. -0.006; p < 0.001). Conclusion: Sufficient muscle mass in middle-aged and older adults could protect against incident type 2 diabetes by preserving beta-cell function to compensate for aging-induced reductions in insulin action, independent of obesity. Presentation: 6/1/2024

Rationale and Design of the Study to Investigate the Metabolic Action of Imeglimin on Patients with Type2 Diabetes Mellitus (SISIMAI).

Imeglimin is a first-in-class, novel, oral glucose-lowering agent for the treatment of type2 diabetes mellitus. The efficacy and safety of imeglimin as an antidiabetic agent have been investigated in clinical trials. However, its metabolic effects in humans have not yet been fully elucidated. The Study to InveStIgate the Metabolic Action of Imeglimin on patients with type2 diabetes mellitus (SISIMAI) is a single-arm intervention study. In this study, we have recruited 25 patients with type2 diabetes to receive 2000mg/day imeglimin for 20weeks. We perform a 75-g oral glucose tolerance test (OGTT) with double-glucose tracers, a two-step hyperinsulinemic-euglycemic clamp with glucose tracer, ectopic fat measurement by proton magnetic resonance spectroscopy, visceral/subcutaneous fat area measurement by magnetic resonance imaging, muscle biopsy, and evaluation of fitness level by cycle ergometer before and after imeglimin administration. The primary outcome is the change in area under the curve of glucose levels during the OGTT after 20weeks of imeglimin treatment. We also calculate the endogenous glucose production, rate of oral glucose appearance, and rate of glucose disappearance from the data during the 75-g OGTT and compare them between pre- and post-treatment. Additionally, we will compare other parameters, such as the changes in tissue-specific insulin sensitivity, ectopic fat accumulation, visceral/subcutaneous fat area accumulation, and fitness level between each point. This is the first study to investigate the organ-specific metabolic action of imeglimin in patients with type2 diabetes mellitus using the 75-g OGTT with the double tracer method. The results of this study are expected to provide useful information for drug selection based on the pathophysiology of individual patients with type2 diabetes mellitus. jRCTs031210600.

Sex-Specific Skeletal Muscle Gene Expression Responses to Exercise Reveal Novel Direct Mediators of Insulin Sensitivity Change.

Understanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise. The study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount. In women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.

Abstract 41: SerpinA3N in Leptin Receptor Neurons Regulates Metabolic Homeostasis and Cardiovascular Function

Obesity and associated conditions such as type 2 diabetes are among the most concerning health issues in the U.S. Leptin receptor (LepR) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. SerpinA3N is a serine protease inhibitor which is highly expressed in the arcuate nucleus of the hypothalamus, upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the LepR expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis confirmed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the LepR positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in LepR expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3N fl/fl ) with mice expressing Cre recombinase driven by the LepR (LepRb Cre ). We found that female, but not male, conditional knockout (CKO, LepRb Cre /SerpinA3N fl/fl ) mice have significantly lower body weight when fed HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response to leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but no change in insulin sensitivity. Insulin-induced phosphorylation of AKT was elevated only in skeletal muscleof CKO mice relative to controls. Finally, systolic arterial blood pressure of CKO mice fed HFHSD trend to be lower during dark time compared to controls (142±6.4 vs 127.9±7.1 mmHg, p=0.06), although heart rate was not changed. These results demonstrate that SerpinA3N in LepRb-expressing neurons regulate energy and glucose homeostasis in a sex-dependent manner,and may protect from HFHSD induced hypertension.

Unlocking the Potential: Amylin-Based Therapies as Novel Interventions for Addressing the Nexus of Obesity and Cardiovascular Health

The rising prevalence of obesity and cardiovascular diseases demands innovative therapeutic strategies. This paper explores the potential of amylin-based therapies in addressing the intricate interplay between obesity and cardiovascular health. Amylin, a hormone co-secreted with insulin, regulates glucose metabolism, appetite, and gastric emptying. Despite its established role in diabetes management, recent research highlights its promise in addressing obesity. Pramlintide, a synthetic amylin analog, emerges as a promising intervention for obesity, overcoming limitations of current treatments. Cardiovascular diseases, closely linked to obesity, prompt exploration of amylin's potential cardiovascular benefits. The study examines vasodilatory effects, anti-inflammatory properties, and anti-atherosclerotic effects associated with amylin. Amylin-based therapies, including pramlintide and the investigational drug AM833 (cagrilintide), are scrutinized for their impact on blood pressure, lipid profiles, and cardiovascular markers. Beyond weight loss, the study explores changes in body composition, insulin sensitivity, and lipid metabolism. The safety profile of amylin analogs, particularly pramlintide, is discussed, emphasizing their generally well-tolerated nature with manageable gastrointestinal side effects. In conclusion, amylin-based therapies present a novel approach to address the complex connections between obesity and cardiovascular diseases. The study highlights their potential in modifying body composition, improving metabolic parameters, and influencing cardiovascular outcomes. As research progresses, amylin-based strategies may offer innovative approaches to enhance metabolic and cardiovascular health, potentially reducing the global burden of cardiovascular diseases.

Amelioration of Insulin Resistance after Delivery Is Associated with Reduced Risk of Postpartum Diabetes in Women with Gestational Diabetes Mellitus.

Identifying risk factors for postpartum type 2 diabetes in women with gestational diabetes mellitus (GDM) is crucial for effective interventions. We examined whether changes in insulin sensitivity after delivery affects the risk of type 2 diabetes in women with GDM. This prospective cohort study included 347 women with GDM or gestational impaired glucose tolerance, who attended the follow-up visits at 2 months postpartum and annually thereafter. Changes in insulin sensitivity were calculated using the Matsuda index at GDM diagnosis and at 2 months postpartum (ΔMatsuda index). After excluding women with pregestational diabetes or those followed up only once, we analyzed the risk of postpartum type 2 diabetes based on the ΔMatsuda index tertiles. The incidence of type 2 diabetes at the two-month postpartum visit decreased with increasing ΔMatsuda index tertiles (16.4%, 9.5%, and 1.8%, P=0.001). During a 4.1-year follow-up, 26 out of 230 women who attended more than two follow-up visits (11.3%) developed type 2 diabetes. Compared to the lowest tertile, subjects in the highest ΔMatsuda index tertile showed a significantly reduced risk of type 2 diabetes (hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.93; P=0.036) after adjusting for confounders. Improvement in insulin sensitivity after delivery is associated with a reduced risk of postpartum type 2 diabetes in women with GDM. Postpartum changes in insulin sensitivity could be a useful prediction for future type 2 diabetes development in women with GDM.

Maintaining Stabilization of Blood Sugar Levels in Diabetes Mellitus Patients with Foot Exercises: Case Report

The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs. Physical activity is one of the factors that affect glycemic management. This case study aims to maintain the stability of blood sugar levels in DM patients by applying leg exercises. The design of this research is a case report with a nursing process approach carried out on Diabetes Mellitus patients with nursing problems of unstable blood sugar levels. Nursing care was carried out for seven days at the Muhammadiyah Ponorogo General Hospital. The intervention implemented is foot exercises. The results of the case study are presented in the form of nursing documentation. The case study results showed that the patient's blood sugar levels tended to be stable starting on the second day of the intervention.Exercise-induced glycemic control is mostly explained by an increase in whole-body insulin sensitivity. The long-term advantages of frequent exercise on glycemic control appear to be related to the cumulative effect of transitory gains in insulin sensitivity and glycemic control after each bout of exercise, rather than structural changes in insulin sensitivity. Keywords: blood sugar level; diabetes mellitus; foot exercise

Role of Vitamin D in Management of Diabetes and Unresolved Cardiovascular Diseases.

Vitamin D deficiency is becoming a widely recognized global health issue. Serum values of 25-(OH) vitamin D (<20 ng/ml) are used to identify vitamin D deficiency. By prompting vascular endothelial cells to activate their nuclear receptor in cardio-myocytes, Vitamin D regulates obesity, Renin-angiotensin system (RAS), energy consumption, and pancreatic cell function. Vitamin D deficiency has been associated with diabetes, asthma, hyperlipidaemia, and pulmonary hypertension in humans. PubMed and Google Scholar databases were utilised to search the literature on vitamin D and related diseases. It is also linked to an elevated risk of death and heart disease. On the other hand, metaanalyses of vitamin D intervention and trials have found no substantial changes in insulin sensitivity, lipid markers, or blood pressure, which result in the association between deficiency of vitamin D and cardiovascular disease. In this review, we present the most recent research on the effects of Vitamin D therapy on various cardiovascular diseases and diabetes, and explain the underlying mechanisms.

Intra-Individual Variations in How Insulin Sensitivity Responds to Long-Term Exercise: Predictions by Machine Learning Based on Large-Scale Serum Proteomics.

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise ("non-responders"). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40-65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes.

Reducing cardiometabolic risk with semaglutide in type 1 diabetes (RESET1): Study protocol of a phase 2double-blinded randomised placebo-controlled trial.

Premature cardiovascular disease is the leading cause of death in people living with type 1 diabetes. Therapies are urgently needed to address cardiovascular risk in this group. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, has been shown to reduce cardiovascular events and improve weight and glycaemia in type 2 diabetes. Semaglutide may offer cardioprotective and metabolic benefits in type 1 diabetes. We will study 60 adults aged 25-70 years with type 1 diabetes of duration at least 2 years, body mass index ≥25 kg/m2, HbA1c ≥7% and at least one cardiovascular risk factor (microalbuminuria, hypertension or anti-hypertensive treatment, hyperlipidemia or lipid lowering therapy, current smoking). Participants will receive semaglutide up to 1.0 mg weekly or matched placebo for 26 weeks. The primary outcome is carotid femoral pulse wave velocity, a measure of arterial stiffness, as a surrogate marker of cardiovascular risk. Potential mechanisms for metabolic changes will be explored including change in insulin sensitivity determined by hyperinsulinaemic-euglycaemic clamp; and incretin and pancreatic hormone action measured during mixed meal tolerance test. The REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes study will investigate whether semaglutide, a long acting glucagon-like peptide receptor agonist, can improve markers of cardiometabolic health in T1D. Underlying mechanisms predicting response, including insulin resistance and incretin hormone status, will also be explored.

Insulin sensitivity, body composition and bone mineral density after testosterone treatment in transgender youth with and without prior GnRH agonist therapy

Background1.8% of youth identify as transgender; a growing proportion are transgender male (female sex, male gender identity). Many receive gonadotropin releasing hormone agonist (GnRHa) therapy to suppress endogenous puberty and/or will start testosterone to induce secondary sex characteristics that align with gender identity. Objective(s)To determine the effects of 12 months of testosterone on cardiometabolic health among transgender youth, including insulin sensitivity, body composition, and bone mineral density and whether changes in outcomes differ based on prior GnRHa treatment. MethodsParticipants (n = 19, baseline age 15.0 ± 1.0 years) were examined prior to and 12 months after testosterone therapy in a longitudinal observational study. Fasted morning blood draw, a 2-hour 75-gram oral glucose tolerance test, body composition and bone mineral density (dual-energy X-ray absorptiometry) were assessed at baseline and 12 months. Insulin sensitivity was estimated by HOMA-IR and Matsuda index. Changes were compared with mixed linear regression models evaluating time (baseline, 12 months), group (GnRHa treatment yes/no), and their interaction. ResultsIn the entire cohort, fasted insulin decreased (median [25,75 %ile]: −3 [-5, 0] mIU/L, p = 0.044) and 2-hour glucose increased (mean ± standard deviation): +18.5 ± 28.9 mg/dL, p = 0.013 from baseline after 12 months of testosterone therapy. There were no significant changes in HOMA-IR (p = 0.062) or Matsuda index (p = 0.096), nor by GnRHa status. Absolute (+6.2 [4.7, 7.5] kg, p = 0.016) and percent fat-free mass increased (+7.3 [5.4, 9.1] %, p = 0.003) and percent fat mass declined (−7.4 [-9.3, 5.3]%, p = 0.005) for the entire cohort. There were time*group interactions for absolute (p = 0.0007) and percent fat-free mass (p = 0.033). There were time*group interactions for bone mineral content (p = 0.006). ConclusionsTwelve months of testosterone in transgender adolescents resulted in changes in body composition and bone mineral density, with baseline differences between the +/-GnRHa group and convergence after 12 months. There were no changes in insulin sensitivity over time or between groups.

Model predictive control of blood glucose in critically ill patients using Gaussian processes

Abstract Stress-induced hyperglycemia and high glycemic variability are common in intensive care patients. Several clinical studies show the benefits of tight blood glucose control, including lower mortality. This article presents an algorithm for blood glucose control in the intensive care unit. An Unscented Kalman Filter is developed to estimate the glucose metabolism state and time-varying insulin sensitivity from blood glucose measurements. Gaussian Processes are used to predict future insulin sensitivity changes based on previous measurements. A model predictive controller is designed to estimate optimal insulin infusion based on current state, predicted insulin sensitivity and planned nutrition. The developed control algorithm allows individualized blood glucose control with reduced glycemic variability and reduced risk of hypoglycemia in the intensive care unit.

SerpinA3N in Leptin Receptor Neurons Regulates Metabolic and Glucose Homeostasis

Obesity and associated conditions such as type 2 diabetes are among the most concerning issues for health in the U.S. Leptin receptor signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. High fat diet induces inflammation within the hypothalamus, leading to leptin insensitivity which contribute to obesity. Previous studies have shown that a novel gene SerpinA3N, a serine protease inhibitor, which is highly expressed in the arcuate nucleus of the hypothalamus, where the leptin receptor is also highly expressed, is upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the leptin receptor expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis showed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Upregulation of hypothalamic SerpinA3N in HFHSD fed mice was confirmed by Western blot. This increase in hypothalamic SerpinA3N appears to be caused by excess of nutrient as we found that exposure to fatty acid significantly increased SerpeinA3N promoter activity in mouse hypothalamic N39 cells. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the leptin receptor positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in leptin receptor expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3Nfl/fl) with mice expressing Cre recombinase in leptin receptor cells (LepRCre). We found that female, but not male, conditional knockout (CKO, LepRCre/SerpinA3Nfl/fl) mice have significantly lower body weight when fed normal chow or HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response following leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but not change in insulin sensitivity, only when fed HFHSD. Finally, insulin-induced phosphorylation of AKT was elevated in skeletal muscle, but not in liver and white adipose tissue, of CKO mice relative to controls. These results demonstrate that SerpinA3N in leptin receptor-expressing neurons regulate body weight and glucose homeostasis in a sex-dependent manner. NIH and VA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of environmentally relevant concentrations of florfenicol on the glucose metabolism system, intestinal microbiome, and liver metabolome of zebrafish

Florfenicol, a widely used veterinary antibiotic, has now been frequently detected in various water environments and human urines, with high concentrations. Accordingly, the ecological risks and health hazards of florfenicol are attracting increasing attention. In recent years, antibiotic exposure has been implicated in the disruption of animal glucose metabolism. However, the specific effects of florfenicol on the glucose metabolism system and the underlying mechanisms are largely unknown. Herein, zebrafish as an animal model were exposed to environmentally relevant concentrations of florfenicol for 28 days. Using biochemical and molecular analyses, we found that exposure to florfenicol disturbed glucose homeostasis, as evidenced by the abnormal levels of blood glucose and hepatic/muscular glycogen, and the altered expression of genes involved in glycogenolysis, gluconeogenesis, glycogenesis, and glycolysis. Considering the efficient antibacterial activity of florfenicol and the crucial role of intestinal flora in host glucose metabolism, we then analyzed changes in the gut microbiome and its key metabolite short-chain fatty acids (SCFAs). Results indicated that exposure to florfenicol caused gut microbiota dysbiosis, inhibited the production of intestinal SCFAs, and ultimately affected the downstream signaling pathways of SCFA involved in glucose metabolism. Moreover, non-targeted metabolomics revealed that arachidonic acid and linoleic acid metabolic pathways may be associated with insulin sensitivity changes in florfenicol-exposed livers. Overall, this study highlighted a crucial aspect of the environmental risks of florfenicol to both non-target organisms and humans, and presented novel insights into the mechanistic elucidation of metabolic toxicity of antibiotics.

NAMPT, IL-6, and vaspin gene expressions and serum protein levels in type 2 diabetes mellitus and related complication.

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes and occurs due to insufficient insulin secretion or inability to use existing insulin and the effects of environmental factors. Although there are many studies on the pathophysiology of T2DM, the mechanisms contributing to the pathogenesis of insulin resistance and pancreatic beta-cell dysfunction have not been completely elucidated. Some adipokines secreted from adipose tissue, which are the primary regulators of insulin resistance, affect immune and inflammatory functions. Altered adipokine profiles have been observed in obesity and T2DM, leading to severe metabolic risks and changes in insulin sensitivity. This study used quantitative PCR and ELISA techniques to analyze samples from individuals without diabetes (control group) and with T2DM (macrovascular and microvascular complications and without complications) for at least 10 years. The mRNA expression and protein levels of NAMPT, IL-6, and vaspin genes were determined. While there was no significant difference in NAMPT, IL-6, and vaspin mRNA expression levels between diabetic groups, there was a significant decrease between the patient and control groups (p < 0.001). For serum protein levels, NAMPT protein levels decreased significantly in the uncomplicated group, while IL-6 and vaspin protein levels increased significantly in both microvascular and macrovascular complication groups (p < 0.001). The correlations between gene expressions, clinical parameters, and protein levels are crucial to understanding the implications of the findings.

Impact of detraining on the health of individuals with spinal cord injury: a systematic review

Introduction: Spinal cord injury (SCI) is a debilitating condition that causes motor, physiological, and sensory impairments, potentially leading to permanent disability, increased morbidity, and mortality, ultimately impacting an individual's quality of life (QoL). Physical exercise emerges as an effective alternative to mitigate these consequences and uphold the autonomy and QoL for this population. Detraining (DT), defined as the partial or total loss of adaptations induced by physical training in response to its complete interruption or insufficient stimulus, represents a significant concern. The objective of this systematic review was to conduct a comprehensive literature review regarding the current state of knowledge on the potential impacts of DT on the health of individuals with SCI. Method: The search was conducted on PubMed, Web of Science, Embase, SPORTDiscus, and Cochrane databases using relevant English terms (("Detraining") AND ("Spinal Cord Injury")) and their synonyms. Due to the limited number of studies addressing this topic, no specific time frame was set for study eligibility. Results: The literature search was performed in November 2023, yielding 42 results, from which 15 remained after removing duplicates. Two articles were excluded following title analysis. Thirteen abstracts were reviewed, and 7 were excluded, leaving 6 articles for full analysis. Due to the nature of the studies, a meta-analysis was not conducted. Conclusion: DT resulted in alterations in body composition (BC), including increased body fat and reduced muscle mass, especially following the interruption of testosterone-associated training. Additionally, the cessation of training impacted the metabolic profile, leading to changes in glucose, lipids, and insulin sensitivity. Furthermore, hemodynamic variables, such as blood pressure (BP) and heart rate (HR), underwent changes, elevating the risk of cardiovascular complications. Regarding cardiorespiratory components, there was a decline in peak oxygen consumption (VO2peak) following the DT period. Halting exercise can lead to detrimental health consequences, underscoring the imperative of maintaining consistent physical training for these individuals.

Body composition and body fat distribution in tissue-specific insulin resistance and in response to a 12-week isocaloric dietary macronutrient intervention

BackgroundBody composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity.ObjectivesTo investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet.MethodsThis subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25–40 kg/m2, 40–75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition.ResultsAt baseline, liver fat content was associated with worse liver insulin sensitivity (β [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity.ConclusionsLiver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity.Trial registrationNCT03708419 (clinicaltrials.gov).