Changes In Insulin Sensitivity Research Articles

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.

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).

Improvement in insulin sensitivity after switching from an integrase inhibitor-based regimen to doravirine/tenofovir disoproxil fumarate/lamivudine in people with significant weight gain.

We performed an observational, retrospective, cohort study to assess changes in insulin sensitivity after a switch from dolutegravir/lamivudine (DOL/3TC) or bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) to doravirine/tenofovir disoproxil fumarate/3TC (DOR/TDF/3TC) in virologically suppressed people living with HIV with recent significant weight gain. All non-diabetic patients with HIV treated with DOL/3TC or BIC/F/TAF for ≥12 months, with HIV RNA <20 copies/mL, and with a weight increase ≥3 kg in the last year, who underwent a switch to DOR/TDF/3TC were enrolled into the study. Serum levels of glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were evaluated every 6 months during a 12-month follow-up. Overall, 81 patients were enrolled: 41 were treated with DOL/3TC and 40 with BIC/F/TAF. At baseline, median HOMA-IR index was 3.18 and insulin resistance (HOMA-IR index >2.5) was present in 49 subjects (60%). At 12 months after the switch to DOR/TDF/3TC, change in mean serum glucose concentration was not significant, but the reduction in median concentration of insulin was significant (-3.54 mcrUI/L [interquartile range -4.22 to -2.87]; p = 0.012), associated with a significant reduction in mean HOMA-IR index (-0.54 [interquartile range -0.91 to -0.18]; p = 0.021). A significant reduction in total and low-density lipoprotein cholesterol was also reported, whereas decreases in mean body weight and mean body mass index were not significant. In our retrospective study in virologically suppressed people living with HIV treated with DOL/3TC or BIC/F/TAF and with recent weight gain, the switch to DOR/TDF/3TC led to a significant improvement in insulin sensitivity and plasma lipids, with a trend to decreased body weight.

Modelling the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity in a cohort of Australian adults

Dietary guidelines are increasingly promoting plant-based diets, limits on red meat consumption, and plant-based sources of protein for health and environmental reasons(1). It is unclear how the resulting food substitutions associate with insulin resistance, a risk factor for type 2 diabetes. Here, we modelled the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity. We included 783 participants (55% female) from the Childhood Determinants of Adult Health (CDAH) study, a population-based cohort of Australians. In adulthood, diet was assessed at three time points using food frequency questionnaires: CDAH-1 (2004–06), CDAH-2 (2009–11), and CDAH-3 (2017–19). The median follow-up duration was 13 years. The cumulative average intake of each food group was calculated to reflect habitual consumption. Insulin sensitivity (%) was estimated from fasting glucose and insulin concentrations at CDAH-3 (aged 39–49 years) using homeostasis model assessment. Applying the partition model(2), we simulated the replacement of one food group with another by including both in the model simultaneously (e.g., red meat and legumes), along with potential confounders and energy intake. The difference between parameter estimates (i.e., regression coefficients and variances) and their covariance were used to estimate the “substitution” effect. We report the simulated percentage point change in log-transformed insulin sensitivity for a 1 serve/day lower intake of one food group with a 1 serve/day higher intake of another food group. Replacing red meat with a combination of plant-based alternatives was associated with higher insulin sensitivity (β = 0·10, 95% CI 0·04–0·16). Adjustment for waist circumference attenuated this association by 61·4%. On an individual basis, replacing red meat with legumes (β = 0·12, 95% CI 0·02–0·21), nuts and seeds (β = 0·15, 95% CI 0·06–0·23), or whole grains (β = 0·11, 95% CI 0·04–0·17) was likewise associated with higher insulin sensitivity. Point estimates were similar when replacing processed meat with plant-based alternatives, but more uncertain due to wide confidence intervals. Our modelling suggests that habitually replacing red meat, and possibly processed meat, with plant-based alternatives may associate with higher insulin sensitivity, and thus, a lower risk of type 2 diabetes. Abdominal adiposity was identified as a potentially important mediator in this relationship. In relation to insulin sensitivity, our findings support the recommendation to choose plant-based sources of protein at the expense of red meat consumption.

Lower Insulin Sensitivity Through 36 Months of Life With in Utero HIV and Antiretroviral Exposure in Botswana: Results From the Tshilo Dikotla Study.

There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure. The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders. A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms. In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life.

Semaglutide 6-months therapy of type 2 diabetes mellitus restores adipose progenitors potential to develop metabolically active adipocytes

BackgroundNowadays type 2 diabetes mellitus (T2DM) leads to population mortality growth. Today glucagon-like peptide type 1 receptor agonists (GLP-1 RA) are one of the most promising glucose-lowered drugs with anorexigenic and cardioprotective effects. The present study aims to determine the effects of GLP-1 RA semaglutide 6-month therapy on T2DM patient metabolic parameters and adipose progenitor cell health. MethodsT2DM patients (N = 8) underwent clinical characterization and subcutaneous fat biopsy at start point and after semaglutide 6-month therapy. Adipose-derived stem cells (ADSC) were isolated by enzymatic method. Cell proliferation analysis was performed by MTT and immunocytochemistry. White and beige adipogenesis was analyzed by BODIPY493/503 staining and confocal microscopy. Adipocyte’s metabolic properties were estimated by 3H- and 14C-based metabolic assays. Thermogenesis analysis was performed by ERthermAC staining and confocal microscopy. Protein markers were assessed by Western blotting. ResultsSemaglutide 6-month therapy demonstrated significant anorexigenic and glucose-lowering effects. However, insulin sensitivity (HOMA-IR and M-index) was unchanged after therapy. Semaglutide 6-month therapy increased ADSC proliferation and white and beige adipogenesis. Moreover, lipid droplets fragmentation was observed in beige adipocytes. Both white and beige adipocytes after semaglutide therapy demonstrated 2–3 fold growth of glucose uptake without changes in insulin sensitivity. Newly formed white adipocytes demonstrated glucose utilization for active ATP synthesis, whereas beige adipocytes for canonical thermogenesis. ConclusionsOur study has revealed that semaglutide 6-month therapy has not only systemic anorexigenic effects, but can markedly improve adipose tissue health. We have demonstrated critical restoration of ADSC renewal functions, which potentially can be involved in semaglutide based weight loss.

A Diabetes Pregnancy Technology Roadmap: The 2023 Norbert Freinkel Award Lecture.

Norbert Freinkel emphasized the need for "more aggressive therapy with exogenous insulin" during type 1 diabetes (T1D) pregnancy. Recent advances in diabetes technology, continuous glucose monitoring (CGM), and hybrid closed-loop (HCL) insulin delivery systems allow us to revisit Freinkel's observations from a contemporary perspective. The Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) led to international recommendations that CGM be offered to all pregnant women with T1D to help them meet their pregnancy glucose targets and improve neonatal outcomes. However, despite CGM use, only 35% of trial participants reached the pregnancy glucose targets by 35 weeks' gestation, which is too late for optimal obstetric and neonatal outcomes. The constant vigilance to CGM data and insulin dose adjustment, with perpetual worry about the impact of hyperglycemia on the developing fetal structures, leave many pregnant women feeling overwhelmed. HCL systems that can adapt to marked gestational changes in insulin sensitivity and pharmacokinetics may help to bridge the gap between the nonpregnant time in range glycemic targets (70-180 mg/dL) and the substantially more stringent pregnancy-specific targets (TIRp) (63-140 mg/dL) required for optimal obstetric and neonatal outcomes. Use of HCL (CamAPS FX system) was associated with a 10.5% higher TIRp, 10.2% less hyperglycemia, and 12.3% higher overnight TIRp. Clinical benefits were accompanied by 3.7 kg (8 lb) less gestational weight gain and consistently achieved across a representative patient population of insulin pump or injection users, across trial sites, and across maternal HbA1c categories. Working collaboratively, women, HCL technology, and health care teams achieved improved glycemia with less worry, less work, and more positive pregnancy experiences.

Serum afamin and its implications in adult growth hormone deficiency: a prospective GH-withdrawal study.

Adult growth hormone deficiency (AGHD) is associated with a high prevalence of metabolic syndrome (MS), which contributes to the unfavorable cardiovascular risk profile in these patients. Insulin like growth factor-1 (IGF-1) is a widely used biomarker, however it does not always reflect the cardiometabolic risk and has a poor relationship with clinical efficacy endpoints. Consequently, there is an unmet need for biomarkers to monitor responses to GH-replacement. Afamin is a hormone-like glycoprotein, expressed in the liver. Higher afamin levels are strongly associated with MS and insulin resistance (IR). Although both MS and IR are very common in AGHD, afamin has not been investigated in these patients. To investigate afamin as a potential biomarker in patients with AGHD. Participants included 20 AGHD patients (11 GH-substituted and 9 GH-unsubstituted) and 37 healthy controls. Subjects underwent routine laboratory examinations, anthropometric measurements, body composition analysis using multi-frequency bioelectrical impedance analysis (InBody720) and measurement of serum afamin concentrations. In GH-substituted subjects, GH-substitution was withdrawn for 2 months. Measurements were carried out right before GH-withdrawal, at the end of the 2-month withdrawal period, and 1 month after reinstituting GH-replacement therapy (GHRT). GH-unsubstituted patients demonstrated higher afamin levels compared to controls (p=0.03). Afamin positively correlated with skeletal muscle mass, bone mineral content, total body water, extracellular- and intracellular water content, insulin (all, p<0.01), HOMA-IR (p=0.01) and C-peptide (p=0.03) levels in AGHD but not in healthy controls. In GH-substituted patients 2-month of GH-withdrawal caused significant changes in body composition, including decreased fat-free mass, skeletal muscle mass, total body water, and intracellular water content (all, p<0.01); but these changes almost fully recovered 1 month after reinstituting GHRT. Unexpectedly, afamin levels decreased after GH-withdrawal (p=0.03) and increased with reinstitution (p<0.01). Changes of afamin levels during GH-withdrawal positively correlated with changes of HOMA-IR (r=0.80; p<0.01) and changes of insulin (r=0.71; p=0.02). Higher afamin levels in unsubstituted AGHD patients might indicate severe metabolic dysregulation. Significant changes accompanying GH-withdrawal and reinstitution, along with strong correlations with measures of IR, suggest that afamin could be a promising biomarker to monitor GHRT-associated changes of insulin sensitivity.

Bushenhuoluo Decoction improves polycystic ovary syndrome by regulating exosomal miR-30a-5p/ SOCS3/mTOR/NLRP3 signaling-mediated autophagy and pyroptosis

BackgroundPolycystic ovary syndrome (PCOS) is a frequent and complicated endocrine disease that remains a major reason for infertility. Bushenhuoluo Decotion (BSHLD) has been validated to exhibit curative effects on PCOS. This study was aimed to explore the potential mechanism underlying the therapeutic action of BSHLD.MethodsPCOS rat model was induced by dehydroepiandrosterone (DHEA). Serum hormone and cytokines levels and ovarian pathological alterations were measured to assess ovarian function. Exosomes (Exos) were identified by Transmission electron microscopy and Nanoparticle Tracking Analysis. RT-qPCR, Western blotting, immunohistochemical staining, and immunofluorescence staining were performed to detect molecule expressions. Proliferation and pyroptosis of granulosa cells (GCs) were evaluated by CCK-8 and flow cytometry, respectively. The binding relationship between miR-30a-5p and suppressor of cytokine signaling 3 (SOCS3) was verified by dual luciferase reporter and RIP assays.ResultsBSHLD treatment improved serum hormone abnormality, insulin sensitivity, and ovarian morphologic changes of PCOS rats. Moreover, BSHLD treatment restrained the excessive autophagy and pyroptosis in ovarian tissues of PCOS rats. Moreover, BSHLD reduced the expression of miR-30a-5p in serum, serum-derived Exos, and ovarian tissues, thus inhibiting autophagy and NLRP3-mediated pyroptosis in GCs. Mechanistically, SOCS3 was proved as a target of miR-30a-5p and could activate mTOR/P70S6K pathway to repress autophagy. The inhibitory effect of miR-30a-5p deficiency on autophagy and pyroptosis of GCs was attenuated by rapamycin.ConclusionCollectively, BSHLD suppressed autophagy and pyroptosis to improve POCS by regulating exosomal miR-30a-5p/SOCS3/mTOR signaling.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial.

Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707. DERR1-10.2196/53092.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of β- cell function and insulin sensitivity in patients with transfusion-dependent β- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate β-cell response, and the ability of β-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent β-thalassemia (β-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for β-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with β-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

Short-term induced hyperinsulinaemia and dexamethasone challenge do not affect circulating total adiponectin concentrations in insulin-sensitive ponies.

Hypoadiponectinaemia is a risk factor for endocrinopathic laminitis, but the directionality and nature of its association with insulin dysregulation is unclear. To investigate the effects of short-term induced hyperinsulinaemia and dexamethasone challenge on circulating [total adiponectin] and whole blood expression of adiponectin (AdipoR1 and AdipoR2), insulin, and insulin-like growth factor 1 (IGF-1) receptors in insulin-sensitive ponies. In vivo experiment. Six never-laminitic, insulin-sensitive, native-breed UK ponies first underwent a dexamethasone challenge (0.08 mg/kg i.v.) with blood samples collected every 15 min over 3 h. After a 14-day washout period, hyperinsulinaemia was induced for 9 h via a euglycaemic-hyperinsulinaemic clamp (EHC), with blood samples collected every 30 min. Serum [insulin], plasma [total adiponectin], and plasma [IGF-1] were measured using validated assays and receptor gene expression was assessed via quantitative polymerase chain reaction (qPCR). Finally, whole blood was incubated with 10-1000 ng/mL dexamethasone for 3 h at 37°C to investigate its direct effects on gene expression. There were no adverse effects observed during either protocol. Dexamethasone challenge did not alter circulating [insulin] or [total adiponectin] at any time-point, but significantly upregulated AdipoR1 and IGF-1R expression at 150 and 180 min. Ex vivo incubation of whole blood with dexamethasone did not alter expression of the genes examined. There was no change in [total adiponectin] or expression of the genes examined associated with EHC-induced hyperinsulinemia. This was a small sample size that included only native-breed ponies; total adiponectin was measured rather than high-molecular-weight adiponectin. Short-term induced hyperinsulinaemia and dexamethasone challenge did not affect circulating [total adiponectin] in insulin-sensitive ponies. However, dexamethasone administration was associated with upregulation of two receptors linked to adiponectin signalling, suggesting that a physiological response occurred possibly to counteract dexamethasone-associated changes in tissue insulin sensitivity.

THU314 Diagnosis Performance Of Insulin Surrogate Indices For Predicting Insulin Resistance In Young Men Defining As Reference The Matsuda Index - An Exploratory Case-Control Study Conducted In Latin America Population

Abstract Disclosure: V.M. Soriano: None. C. Espinel Pachon: None. Diagnosis performance of insulin surrogate indices for predicting insulin resistance in young men defining as reference the Matsuda index – An exploratory case-control study conducted in Latin America population Víctor Antonio Malagón – Soriano1, Álvaro Javier Burgos – Cárdenas1, Maria Fernanda Garcés2, Cristian Felipe Espinel – Pachon1, Roberto Franco – Vega3, Jorge Andres Rubio – Romero4, Sofia Alexandra Caminos – Cepeda5, Ezequiel Lacunza6, Ariel Iván Ruiz – Parra4, Jorge Eduardo Caminos2 1Department of Internal Medicine, 2Department of Physiology, 3Endocrinology Unit - Department of Internal Medicine, 4Department of Obstetrics &amp; Gynecology, School of Medicine Universidad Nacional de Colombia, Bogotá 11001, Colombia. 5School of Medicine, Universidad Pompeu Fabra; Barcelona 08002, Spain.6Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina. Correspondence: Jorge Eduardo Caminos, MSc. PhD., Department of Physiology, School of Medicine, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Edificio 471 Oficina 406, Bogotá, Colombia, E-mail: jecaminosp@unal.edu.coRunning title: Diagnosis performance of Insulin Surrogate Indices using as reference the Matsuda index. Key words: Insulin surrogate indices, diagnosis performance, Matsuda index, healthy and insulin resistant young men Abstract Insulin plays an essential role in glucose and lipid homeostasis. Changes in insulin sensitivity in adipose tissue, liver and muscle occur in the course of different metabolic disorders, and have been proposed to be a potential contributor to obesity and type 2 diabetes. The euglycemic-hyperinsulinemic clamp technique is the gold standard approach for assessing insulin sensitivity in humans, with the disadvantages of being expensive, labor intensive, and time consuming. Therefore, this study aimed to investigate the diagnosis performance of insulin surrogate indices using as reference the Matsuda index, in healthy and insulin resistant young men in Latin America population. Thus, the current cross-sectional study was conducted in healthy (n=48) and insulin resistant (n=45) young adult men (18–31 year old) using the Matsuda index cut-off value as reference to determine insulin sensitivity/resistance. Receivers operating characteristic curves (ROC) were used to determine the cut-off, sensitivity, and specificity values for QUICKI, HOMA-IR, TG/HDL-C, TyG, TyG-WC, TyG-BMI, LAP and VAI. TyG-WC (AUC=1.0) and TyG-BMI (AUC=1.0) indices showed the highest diagnostic performance with high sensitivity and specificity to predict insulin resistance in young men. In addition, TyG-BMI index showed a statistically significant stronger correlation with waist circumference (WC), when compared with HOMA-IR, Matsuda and QUICKY indices. In conclusion, we were able to diagnose insulin resistance with high sensitivity and specificity in young individuals -supposedly metabolically healthy- who do not meet the criteria for metabolic syndrome diagnosis, using widely available, low-cost, and reliable surrogate indices. Additionally, the TyG-WC and TyG-BMI indices were the better predictors of insulin resistance. The cut-off values used to define insulin resistance in our Latin America population studied were similar to recent studies in the United States population, despite clinical and racial/ethnic differences. Presentation: Thursday, June 15, 2023

FRI664 The Impact Of Prediabetes Diagnosis On The Prevalence Of Postbariatric Hypoglycemia

Abstract Disclosure: J.R. Shariff: None. L. Funk: None. A. Zaveri: None. D.B. Davis: None. Bariatric surgery is not only a mainstay of obesity treatment, but it can result in remission of metabolic conditions, such as Type 2 diabetes. Post-operatively however, patients can develop postbariatric hypoglycemia (PBH), which is thought to be due to changes in insulin sensitivity and hypersecretion after eating. It has been suggested that prior type 2 diabetes can protect against PBH as decreased β-cell function prevents hyperinsulinemia. Patients with prediabetes may not have deterioration of β-cell function resulting in increased insulin production in response to glycemic excursion and subsequent hypoglycemia. The study aimed to assess the prevalence and severity of PBH in patients with prediabetes compared to those without prediabetes prior to bariatric surgery. We conducted a retrospective cohort study of patients 18 years and older who underwent either Roux-en-Y gastric bypass or sleeve gastrectomy between 2014 and 2021 and did not have a history of type 1 or type 2 diabetes mellitus at a single academic medical center. A history of PBH (hypoglycemia reported or documented after eating, symptoms of hypoglycemia, and resolution of symptoms after eating) and prediabetes (defined as A1c 5.7-6.4%, fasting glucose of 100-125mg/dL, or oral glucose tolerance testing with 2-hour glucose 140-199mg/dL) was determined based on medical record review. 14 patients developed PBH out of 539 (2.6%). 110 patients had prediabetes (20.4%). Of these 110 patients, 4 had PBH (3.6%). Of the 429 patients without prediabetes, 10 patients had PBH (2.3%). There was a greater post-operative weight loss, on average, in patients with PBH (19.5%) than in those without PBH (15.9%), although it should be noted that all PBH patients had Roux en Y gastric bypass. Interestingly, only 15% of the PBH population appeared to be on pharmacologic treatment, despite 21.5% being hospitalized or in the emergency room for hypoglycemic events. Most PBH patients (64.3%) developed symptoms between 1 to 3 years post-operatively, which is consistent with other studies on this topic. There was no association between prediabetes and PBH in our dataset (p=0.46), however our data set was quite small and it may be difficult to draw significant conclusions. A larger scale study done in a prospective manner would be useful for further research. Presentation: Friday, June 16, 2023

FRI417 An Interdisciplinary Program Promoting The Adoption Of A Healthy Lifestyle Increases Insulin Sensitivity In Women With Obesity And Infertility

Abstract Disclosure: A. Forget-Renaud: None. M. Belan: None. F. Jean-Denis: None. M. Pesant: None. J. Baillargeon: Grant Recipient; Self; Ferring Pharmaceuticals, JPB received an unrestricted investigator-initiated grant from Ferring Canada, which was not for the reported study. Introduction Obesity increases the risk of ovulatory and anovulatory infertility in women, mainly through the development of polycystic ovary syndrome (PCOS). Insulin resistance contributes to the pathogenesis of PCOS and may play a role in the infertility of PCOS and non-PCOS women with overweight or obesity. Lifestyle modifications are recommended as a first-line therapy in women with PCOS or those with obesity and infertility, as it was associated with improvement in menstrual pattern and fertility outcomes. We therefore hypothesized that a lifestyle intervention may increase insulin sensitivity in women with obesity and infertility. Methods Women with obesity and infertility were randomly allocated to usual fertility care (control group, CG) or to an interdisciplinary intervention promoting the adoption of a healthy lifestyle (LSG) alone for 6 months and then combined with usual care. Insulin resistance was estimated during fasting (HOMA-IR) and a 75-g oral glucose test (Matsuda Insulin Sensitivity Index, ISI(M)), and β-cell function was estimated using the Insulin Secretion-Sensitivity Index (ISSI-2) in women not taking medication affecting insulin sensitivity (except metformin). Data were collected at baseline, 6, 12 and 18 months, and as soon as possible when the participant knew she was pregnant. We estimated the integrated change in insulin sensitivity during follow-up using the incremental area-under-the-curve of ISI(M) divided by time (iAUC-ISI(M)/time). Results Among 130 randomized participants, 105 had available data (LSG=51, CG=54). PCOS was diagnosed using the Rotterdam criteria in 63.2% of participants, equally distributed between the groups. As compared to CG, women in the LSG improved significantly more their ISI(M) after 6 months (+0.24 [IQR: -0.48 - +0.94] vs 0.16 [-1.32 - +0.53], p=0.039, n=90), as well as their iAUC-ISI(M)/time during follow-up (+0.18±0.84 vs -0.21±0,93, p=0.035, n=104). All these results remained statistically significant after correction for baseline BMI, age and use of folic acid. Increases in iAUC-ISI(M)/time in the intervention vs control groups were significantly more important (p for interaction=0.045) in participants with baseline ISI(M) above the median (LSG: +0.10±1.13, n=24, vs CG: -0.62±1.13, n=27, p=0.028) than in those below the median (LSG: +0.26±0.48, n=27, vs CG: +0.21±0.35, n=26, p=0.71). Interactions with PCOS status and other subgroups were not statistically significant. There was no impact on HOMA-IR or ISSI-2. Conclusion An interdisciplinary program promoting the adoption of a healthy lifestyle significantly increases whole-body insulin sensitivity in women with infertility and obesity, mainly in those with higher baseline insulin sensitivity. It may be explained in part by the weight loss associated with the intervention and may have a role in improving fertility in this population. Presentation: Friday, June 16, 2023

Effect of high-intensity interval training compared to moderate-intensity continuous training on body composition and insulin sensitivity in overweight and obese adults: A systematic review and meta-analysis

ObjectiveTo compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on adults with overweight and obesity. Outcomes, including changes in insulin sensitivity, weight, body mass index (BMI), waist circumference, and body fat, were analyzed. MethodsA systematic literature review was conducted. This review is registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42021281899. Clinical trials involving individuals who are overweight and obese and comparing HIIT with MICT effects on insulin sensitivity, weight, BMI, body fat percentage, and waist circumference were included. PubMed, Web of Science, Embase, and Scopus databases were searched using controlled vocabulary and free-text terms related to HIIT, obesity, and overweight. The search included studies published until September 2022. The Rob2 tool was used to assess the risk of bias. The results were presented through meta-analyses that provided summary estimators and confidence intervals. Subgroup analyses were conducted to assess the effect of the risk of bias on the outcomes. This research did not receive any specific funding. ResultsOf the 2534 articles, 30 met the eligibility criteria. The intervention duration ranged from 4 to 16 weeks. The observed effects for each outcome were as follows: insulin sensitivity (p = 0.02), weight (p = 0.58), BMI (p = 0.53), waist circumference (p = 0.87), body fat percentage (p = 0.07), body fat mass in kilograms (p = 0.39). The level of evidence obtained was moderate except for waist circumference, which was rated as low. Limitations included heterogeneity in training protocols, measurements, and study duration. Additionally, a risk of bias was identified in these studies. ConclusionHIIT and MICT did not significantly differ in their effects on weight, BMI, waist circumference, or body fat mass in adults with overweight and obesity. However, a moderate beneficial effect of HIIT was observed on insulin sensitivity. Therefore, further evidence is required to confirm these findings.

Effect of Bariatric Surgery on Plasma Cell-Free Mitochondrial DNA, Insulin Sensitivity and Metabolic Changes in Obese Patients.

While improvement of mitochondrial function after bariatric surgery has been demonstrated, there is limited evidence about the effects of bariatric surgery on circulatory cell-free (cf) mitochondrial DNA (mtDNA) and intracellular mtDNA abundance. Plasma and peripheral blood mononuclear (PBM) cells were isolated from healthy controls (HC) and bariatric surgery patients before surgery and 2 weeks, 3 months, and 6 months after surgery. At baseline, the plasma level of short cf-mtDNA (ND6, ~100 bp) fragments was significantly higher in obese patients compared to HC. But there was no significant variation in mean ND6 values post-surgery. A significant positive correlation was observed between preop plasma ND6 levels and HgbA1c, ND6 and HOMA-IR 2 weeks post-surgery, and mtDNA content 6 months post-surgery. Interestingly, plasma from both HC and obese groups at all time points post-surgery contains long (~8 kb) cf-mtDNA fragments, suggesting the presence of near-intact and/or whole mitochondrial genomes. No significant variation was observed in mtDNA content post-surgery compared to baseline data in both PBM and skeletal muscle samples. Overall, bariatric surgery improved insulin sensitivity and other metabolic parameters without significant changes in plasma short cf-mtDNA levels or cellular mtDNA content. Our study provides novel insights about possible molecular mechanisms underlying the metabolic effects of bariatric surgery and suggests the development of new generalized approaches to characterize cf-mtDNA.