Key Metabolic Parameters Research Articles

Assessment of Glecaprevir/Pibrentasvir Treatment’s Influence on Biochemical and Metabolic Markers in Patients with Chronic Hepatitis

Background/Objectives: Liver function tests (LFT) are essential for diagnosing and monitoring liver status in patients with chronic hepatitis. In addition, tracking the systemic implications reflected in the changes in metabolic parameters is essential for correctly managing the cases. This study addresses the critical gap in the literature by evaluating the effects of glecaprevir/pibrentasvir on key liver function markers (AST, ALT, GGT, TB) and metabolic parameters (TC, TG, HbA1c) in patients with chronic hepatitis C (CHC). Moreover, this study will evaluate the impact of glecaprevir/pibrentasvir on A2MG, which provides insights into its effects on liver fibrosis. Awareness of these effects is critical for the optimal management of patients during and following antiviral therapy to ensure that therapeutic success does not come at the expense of overall liver and metabolic health. These parameters should be monitored as they supply clinicians with essential data, informing treatment more accurately and ensuring a holistic approach in CH patients. Methods: This study consists of 104 patients with chronic hepatitis C treated with glecaprevir/pibrentasvir and monitored from January to June 2024. Assessments comprised standard liver markers, lipid profiles, glycated hemoglobin, and alpha-2-macroglobulin, as well as specific non-invasive tests of liver injury. Results: 95.2% of the patients experienced a sustained virologic response. Biochemical markers and total cholesterol values were significantly decreased with glecaprevir/pibrentasvir therapy. Non-significant elevations in total bilirubin and glycated hemoglobin support the drug’s favorable tolerability profile. Conclusions: In the treatment of chronic hepatitis C patients, glecaprevir/pibrentasvir therapy leads to normalization in biochemical markers (AST, ALT, and GGT), as well as in total cholesterol.

Calcification in sea urchin larvae is associated with low metabolic costs.

The energetic costs to generate calcium carbonate skeletons and shells in marine organisms remain largely speculative due to the scarcity of empirical data. However, this information is critical to estimate energetic limitations of marine calcifiers that can explain their sensitivities to changes in sea water carbonate chemistry in past, present and future marine systems. The cost of calcification was evaluated using larval stages of the purple sea urchin, Strongylocentrotus purpuratus. We developed a skeleton re-mineralization assay, in which the skeleton was dissolved in live larvae followed by a re-mineralization over a few days. During skeleton re-mineralization, energetic costs were estimated through the measurement of key metabolic parameters including whole animal metabolic rates, citrate synthase (CS) enzyme activities and mRNA expression as well as mitochondrial densities in the calcifying primary mesenchyme cells (PMCs). Minor increases in a CS activity and a 10-15% increase in mitochondrial densities in PMCs were observed in re-mineralizing larvae as compared to control larvae. Re-mineralization under three different pH conditions (pH 8.1, pH 7.6 and pH 7.1) decreased with decreasing pH accompanied by pronounced increases in CS expression levels and increased mitochondrial densities in PMCs at pH 7.6. Despite a prominent increase in mitochondrial density of primary mesenchyme cells, particularly in the calcifying cohort of this cell type, this work demonstrated a low overall metabolic response to increased mineralization rates on the whole animal level under both, high and low pH conditions. We conclude that calcification in sea urchin larvae is compromised under low pH conditions, associated with low energetic efforts to fuel compensatory processes.

8261 Achievement of Diabetes Treatment Goals in Mexico from 2016 to 2022

Abstract Disclosure: D. Ramirez Garcia: None. C.A. Fermin Martinez: None. P.N. Mendez Labra: None. N.E. Antonio Villa: None. J.A. Seiglie: None. O.Y. Bello-Chavolla: None. Background: Optimal diabetes care involves achieving goals with treatment in key metabolic parameters including HbA1c, blood pressure (BP), low density lipoprotein cholesterol (LDL-C) levels, and smoking cessation. Evaluation of diabetes care in Mexico has been incomplete, with previous studies focusing primarily on glycemic control, but not on a comprehensive analysis of combined treatment targets. Objective: To estimate achievement of diabetes treatment goals (HbA1c [A], BP [B], LDL-C [C], smoking cessation [N], and combined targets [AB, BC, AC, ABC, ABCN]) using data from nationally representative surveys from 2016-2022 among individuals with diagnosed diabetes in Mexico. Methods: We analyzed serial cross-sectional National Health and Nutrition Surveys from 2016-2022. A total of 2,689 adults with diagnosed diabetes ≥20 years were identified amongst 21,248 adults ≥20 years. Weighted prevalence estimates were obtained for glycemic control (HbA1c <7% in those <65 years, and <7.5% in those ≥65 years), BP control (<130/80 mmHg), LDL-C control (<70 mg/dL), smoking cessation, and combined targets. We also fitted logistic regression models to estimate the odds of achieving treatment targets according to age, sex, educational level, indigenous identity, and survey cycle. Results: In 2022, the prevalence of HbA1c, BP, and LDL-C control among individuals with diagnosed diabetes in Mexico was 41.2% (95% CI 30.5-52.0%), 46.0% (95% CI 36.5-55.5%), and 17% (95% CI 10.2-25.2%), respectively. Non-smoking prevalence was 92.4% (95% CI 88.6-96.2%). Combined target achievement was low, with a prevalence of 10.8% (95%CI 6.2-15.5%) for BC and 4% (95% CI 1.7-6.3%) for ABCN. The proportion of goal achievement was relatively stable across 2016-2022 for every parameter analyzed, except for LDL-C. LDL-C had the lowest proportion of control across all cycles, although a gradual increase was observed: 8.1% (95% CI 4-12.3%) in 2016 to 17% (95% CI 10.2-25.2%) in 2022. The increase in LDL-C control coincides with greater prevalence of statin use across survey cycles. Men had lower odds of achieving ABCN combined control (OR 0.49, 95%CI 0.45-0.54) than women. Similarly, compared with individuals <45 years, participants 45-64 years (OR 0.36, 95%CI 0.32-0.40) and ≥65 years (OR 0.41 95%CI 0.35-0.47) had lower odds of achieving composite control. Conclusions: Achievement of diabetes treatment goals in Mexico is suboptimal. Less than half of individuals with diagnosed diabetes achieve HbA1c or BP goals, less than a fifth achieve LDL-C control, and only 1 in 20 individuals achieve ABCN control. Greater efforts are needed to the improve the comprehensive care of individuals with diabetes in Mexico. Presentation: 6/3/2024

Association between COVID-19 and the incidence of type 1 diabetes in Portugal – a registry study

BackgroundViral respiratory infections may precipitate type 1 diabetes (T1D). A possible association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, and the incidence of T1D is being determined. This study was carried out using Portuguese registries, aiming at examining temporal trends between COVID-19 and T1D.MethodsHospital data, comparing the incidence before and during the COVID-19 pandemic, from children and young adults diagnosed with new-onset T1D, was acquired beginning in 2017 and until the end of 2022. Data was obtained from nine different Portuguese hospital units. The impact of the COVID-19 pandemic, beginning in March 2020, was assessed comparing the annual numbers of new-onset T1D cases. The annual median levels of glucose, glycated hemoglobin (HbA1c) and fasting C-peptide at T1D diagnosis were compared. The annual number of diabetic ketoacidosis (DKA) episodes among new T1D cases was also assessed at two centers.ResultsIn total, data from 574 newly diagnosed T1D patients was analyzed, including 530 (92.3%) children. The mean ages for child and adult patients were 9.1 (SD 4.4) and 32.8 (SD 13.6) years, respectively. 57.8% (331/573) were male, one patient had unknown sex. The overall median (25–75 percentiles) levels of glucose, HbA1c and fasting C-peptide at diagnosis were 454 mg/dL (356–568), 11.8% (10.1–13.4) and 0.50 µg/L (0.30–0.79), respectively. DKA at T1D diagnosis was present in 48.4% (76/157). For eight centers with complete 2018 to 2021 data (all calendar months), no overall significant increase in T1D cases was observed during the COVID-19 pandemic, i.e. 90 cases in 2018, 90 cases in 2019, 112 in 2020 and 100 in 2021 (P for trend = 0.36). Two of the centers, Faro (CHUA) and Dona Estefânia (CHULC) hospitals, did however see an increase in T1D from 2019 to 2020. No significant changes in glucose (P = 0.32), HbA1c (P = 0.68), fasting C-peptide (P = 0.20) or DKA frequency (P = 0.68) at the time of T1D diagnosis were observed over the entire study period.ConclusionThe T1D incidence did not increase significantly, when comparing the years before and during the COVID-19 pandemic, nor did key metabolic parameters or number of DKA episodes change.

Kisspeptins centrally modulate food intake and locomotor activity in mice independently of gonadal steroids in a sexually dimorphic manner.

Kisspeptins are essential regulators of the reproductive axis, with capacity to potently activate gonadotropin-releasing hormoneneurons, acting also as central conduits for the metabolic regulation of fertility. Recent evidence suggests that kisspeptins per se may also modulate several metabolic parameters, including body weight, food intake or energy expenditure, but their actual roles and site(s) of action remain unclear. We present herein a series of studies addressing the metabolic effects of central and peripheral administration of kisspeptin-10 (Kp-10; 1 nmol and 3 nmol daily, respectively) for 11 days in mice of both sexes. To assess direct metabolic actions of Kp-10 versus those derived indirectly from its capacity to modulate gonadal hormone secretion, kisspeptin effects were tested in adult male and female mice gonadectomized and supplemented with fixed, physiological doses of testosterone or 17β-estradiol, respectively. Central administration of Kp-10 decreased food intake in male mice, especially during the dark phase (~50%), which was accompanied by a reduction in total and nocturnal energy expenditure (~16%) and locomotor activity (~70%). In contrast, opposite patterns were detected in female mice, with an increase in total and nocturnal locomotor activity (>65%), despite no changes in food intake or energy expenditure. These changes were independent of body weight, as no differences were detected in mice of both sexes at the end of Kp-10 treatments. Peripheral administration of Kp-10 failed to alter any of the metabolic parameters analyzed, except for a decrease in locomotor activity in male mice and a subtle increase in 24 h food intake in female mice, denoting a predominant central role of kisspeptins in the control of energy metabolism. Finally, glucose tolerance and insulin sensitivity were not significantly affected by central or peripheral treatment with Kp-10. In conclusion, our data reveal a potential role of kisspeptins in the control of key metabolic parameters, including food intake, energy expenditure and locomotor activity, with a preferential action at central level, which is sex steroid-independent but sexually dimorphic.

Longitudinal observation of tRNA-derived fragments profiles in gestational diabetes mellitus and its diagnostic value.

Gestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health. Current diagnostic methods based on glucose tolerance tests have limitations for early detection. tRNA-derived small RNAs (tsRNAs) have emerged as potential molecular regulators in various diseases, including metabolic disorders. However, the diagnostic value of tsRNAs in plasma for early GDM or postpartum remains unclear. This longitudinal study profiled the expression of tsRNAs across different gestational stages and postpartum in women with GDM (n = 40) and healthy control gestational women (HCs, n = 40). High-throughput small RNA sequencing identified candidate tsRNAs, which were then validated and correlated with clinical biochemical markers such as fasting blood glucose (FBG), HOMA-IR, and GHbA1c. tRF-1:32-Val-AAC-1-M6, tRF-1:31-Glu-CTC-1-M2, and tRF-1:30-Gly-CCC-1-M4 were consistently upregulated in the GDM group compared to HCs during the second trimester (p < 0.05). Only tRF-1:31-Glu-CTC-1-M2 was highly expressed during the first trimester, and tRF-1:30-Gly-CCC-1-M4 increased during postpartum. tRF-1:31-Glu-CTC-1-M2 showed a significant correlation with FBG levels in the first trimester (R = 0.317, p = 0.047). The expression of tRF-1:30-Gly-CCC-1-M4 was significantly correlated with HOMA-IR (r = 0.65, p < 0.001) and GHBA1c (r = 0.33, p = 0.037) during postpartum. A joint diagnostic model incorporating tsRNAs expression and clinical markers demonstrated enhanced predictive power for GDM (ROC AUC = 0.768). Our results revealed distinct expression patterns of specific tsRNAs in GDM, showcasing their correlation with key metabolic parameters. This underscores their promising role as biomarkers for early prediction and diagnosis of GDM. The integration of tRFs into a composite biomarker panel holds the potential to improve clinical outcomes by enabling personalized risk assessment and targeted interventions.

Higher haemoglobin levels are associated with impaired periodontal status.

Cellular oxygen sensing mechanisms have been linked to periodontal condition, and levels of haemoglobin (Hb) (the main carrier of oxygen) can be used as a surrogate measure for hypoxia. We aimed to examine relations between Hb levels and key periodontal health parameters in a general population. The population comprised 1711 (47% male) subjects from the Northern Finland Birth Cohort 1966, for whom an oral health examination was carried out at 46 years of age and whose Hb levels were within the Finnish reference values. Relative risks (RRs) were estimated using Poisson regression models. The low-Hb tertile (mean Hb 133 g/L) had healthier anthropometric, metabolic and periodontal health parameters than the high-Hb tertile (mean Hb 151 g/L). Multivariable regression models adjusted for risk factors showed Hb levels to be positively associated with alveolar bone loss (ABL) and periodontal pocket depth (PPD), although the associations were weaker after adjustment for key metabolic parameters and were strongly influenced by smoking status. Hb levels within the normal variation are positively associated with PPD and ABL. The association between Hb levels and periodontal condition appeared to be more complex than had previously been anticipated.

Interplay Between the American Diabetes Association's ABC Targets for Diabetes, Insulin Resistance Indices, and Dyslipidemia in Indian Type 2 Diabetes Patients.

Background The increasing incidence of type 2 diabetes (T2D) in India underscores the pressing need for effective management strategies. Meeting the American Diabetes Association (ADA) ABC targets for diabetes (glycated hemoglobin (HbA1c), blood pressure, and serum low-density lipoprotein cholesterol (LDL-C)) is crucial for effectively managing T2D, as it reflects the optimal control of key metabolic parameters. Insulin resistance (IR) and impaired beta cell function (BCF) have been found to have a significant impact on glycemic control, lipid metabolism, and hypertension, contributing to the complex cardiovascular risk profile of patients with T2D. This study aimed to explore the association between ABC targets for diabetes, IR, BCF, and dyslipidemia in a cross-sectional cohort of T2D patients. Methods This retrospective study examined data from 681 T2D patients with comorbid hypertension and dyslipidemia. The patients were part of a one-year online lifestyle intervention program for diabetes management at the Freedom from Diabetes Clinic in Pune, India, between January 2021 and December 2022. Baseline data (at the time of enrollment in the program) on medical history and anthropometric and biochemical parameters were retrospectively extracted from medical records and used to assess ABC targets and other clinical parameters. The ABC targets for diabetes include three goals: an HbA1c level of less than 7.0%, a blood pressure level of less than 140/90 mmHg, and an LDL-C level of less than 100 mg/dL. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic Model Assessment of Beta Cell Function (HOMA-B), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated using standard formulas. Results Cross-sectional analysis at baseline showed that 152 (22.3%) participants met all three ABC targets, 306 (45.0%) and 183 (26.8%) participants met two or one targets, respectively, and 40 (5.9%) did not meet any of the ABC targets. Participants meeting all three targets showed significantly lower IR, higher sensitivity (HOMA-IR, median 2.1; QUICKI, median 0.34), higher BCF (HOMA-B, median 62.9), and healthier lipid profiles (mg/dL) (total cholesterol, median 126; triglycerides, median 114; and non-high-density lipoprotein (HDL), median 84) than those who did not meet any of the ABC targets (HOMA-IR, median 3.4; QUICKI, median 0.31; HOMA-B, median 31.7; total cholesterol, median 221; triglycerides, median 187; and non-HDL, median 182) (p < 0.01). A significant association was observed between lower BMI (< 25 kg/m2), lower IR (HOMA-IR <2.5), and meeting all three ABC targets (p < 0.01). No significant association was observed between the duration of diabetes and ABC target status (p > 0.1). Lower IR was identified as a predictor of achievement of all three ABC targets (p < 0.01). Conclusion This study highlights the significance of meeting ABC targets for diabetes in relation to not only a better lipid profile but also lower IR and higher BCF. These preliminary findings provide novel insights into the interplay between IR, BCF, dyslipidemia, and meeting ABC targets in an Indian T2D population. These findings highlight the need for effective diabetes management strategies and improved patient outcomes, considering factors such as BMI and IR indices.

Intensive lifestyle intervention positively affects nonalcoholic fatty liver fibrosis score (NFS) and key metabolic parameters: A retrospective study

To date lifestyle intervention is the only proven therapy to treat nonalcoholic fatty liver disease (NAFLD). In this study, we retrospectively analyze the influence of a structured, multimodal 52-week lifestyle intervention program on NAFLD fibrosis score (NFS) as a marker for liver fibrosis. At baseline, 16/47 subjects (34.0%) in our cohort displayed elevated NFS levels suggestive for advanced stages of liver fibrosis. Already after the initial 12-week hypocaloric fasting phase with a formula diet, this number decreased significantly and continued to decrease until the end of the program to 10/47 (21.3%). At baseline, 48.9% of the participants had impaired glucose metabolism, as defined by impaired fasting glucose, elevated HbA1c, or overt type 2 diabetes mellitus. This proportion reduced markedly to 31.9% by the end of the program. The proportion of advanced stages of liver fibrosis was especially high in the subgroup of participants with impaired glucose metabolism. This group particularly benefited from the lifestyle intervention program in terms of their NFS. The present study demonstrates that participants of structured multimodal lifestyle intervention programs with formula diets can significantly improve their metabolic parameters, such as body weight, fasting glucose, HbA1c, and lipids, and substantially reduce their risk of advanced liver fibrosis. Primary care providers must be aware of the close link between impaired glucose metabolism and increased liver-related risk and refer their metabolically ill patients to effective programs.

Hepatic GRK2 is dispensable for glucose homeostasis and other key metabolic parameters in mice

ObjectiveG-protein-coupled receptor (GPCR) kinases (GRKs) abrogate GPCR signaling by promoting receptor desensitization and internalization. Accumulating evidence suggests that GRK2 represents an important regulator of GPCR-mediated effects on systemic glucose metabolism, obesity, and insulin resistance. Despite the key role of the liver in maintaining euglycemia, the potential metabolic relevance of hepatic GRK2 has yet to be examined. Thus, the goal of this study was to explore the potential role of hepatic GRK2 in maintaining glucose homeostasis and other key metabolic functions. MethodsTo address this question, we generated mice that showed a ∼90% reduction in GRK2 protein expression selectively in hepatocytes (Hep-GRK2-KO mice) and subjected these mice, together with their control littermates, to systematic metabolic phenotyping studies. ResultsWe found that Hep-GRK2-KO mice maintained on regular chow did not differ significantly from their control littermates in glycemia, glucose tolerance, insulin sensitivity, in vivo gluconeogenesis, and glucagon-induced hyperglycemia. We obtained similar findings when we analyzed Hep-GRK2-KO mice and control littermates consuming an obesogenic high-fat diet. Likewise, plasma levels of insulin, glucagon, free fatty acids, and ketone bodies remained unaffected by the lack of hepatocyte GRK2. The same was true when we examined the expression levels of key genes regulating hepatic glucose and fatty acid metabolism. ConclusionIn summary, our data suggest that hepatocyte GRK2 is dispensable for systemic glucose homeostasis and other key metabolic functions in both lean and obese mice. This finding suggests that drug development efforts aimed at inhibiting GRK2 to improve impaired glucose homeostasis and insulin sensitivity need to focus on other metabolically important tissues.

Portable optical spectroscopic assay for non-destructive measurement of key metabolic parameters on in vitro cancer cells and organotypic fresh tumor slices.

To enable non-destructive metabolic characterizations on in vitro cancer cells and organotypic tumor models for therapeutic studies in an easy-to-access way, we report a highly portable optical spectroscopic assay for simultaneous measurement of glucose uptake and mitochondrial function on various cancer models with high sensitivity. Well-established breast cancer cell lines (MCF-7 and MDA-MB-231) were used to validate the optical spectroscopic assay for metabolic characterizations, while fresh tumor samples harvested from both animals and human cancer patients were used to test the feasibility of our optical metabolic assay for non-destructive measurement of key metabolic parameters on organotypic tumor slices. Our optical metabolic assay captured that MCF-7 cells had higher mitochondrial metabolism, but lower glucose uptake compared to the MDA-MB-231 cells, which is consistent with our microscopy imaging and flow cytometry data, as well as the published Seahorse Assay data. Moreover, we demonstrated that our optical assay could non-destructively measure both glucose uptake and mitochondrial metabolism on the same cancer cell samples at one time, which remains challenging by existing metabolic tools. Our pilot tests on thin fresh tumor slices showed that our optical assay captured increased metabolic activities in tumors compared to normal tissues. Our non-destructive optical metabolic assay provides a cost-effective way for future longitudinal therapeutic studies using patient-derived organotypic fresh tumor slices through the lens of tumor energetics, which will significantly advance translational cancer research.

Berberine as a Natural Modifier of Gut Microbiota to Promote Metabolic Status in Animal Studies and Clinical Trials: A Systematic Review

As a phytochemical, berberine can modulate metabolic parameters via altering gut flora. However, findings are conflicting. In the present systematic review, we aimed to summarize the effects of berberine on gut microbiota in the models of metabolic disorders in both animal studies and clinical trials. Publications in five electronic databases including PubMed, Scopus, Embase, Web of Science, and Cochrane Library were searched systematically up to 31 May 2021 to find relevant articles with English language. Out of 4102 studies (including 2125 duplicates), 35 studies were included. In animal studies, various effects of berberine on beneficial and harmful microbiota were reported. However, findings also indicated that berberine can decrease the Firmicutes to Bacteroidetes (F/B) ratio. Three out of five studies showed positive effects of berberine on the production of short-chain fatty acids (SCFA), particularly butyrate. In three animal studies, lipopolysacaride (LPS) concentrations decreased with berberine administration. In clinical trials (n=3) positive effects on microbiota and metabolic status were also reported. However, the quality of clinical trials was mainly low. The present systematic review showed that berberine can modulate key metabolic parameters through improving the balance of intestinal microbiome, decreasing the abundance of harmful microbiota and LPS concentrations, and increasing the production of SCFAs, particularly butyrate in animal models. However, there are limited high-quality evidence regarding the effects of berberine on gut flora in clinical trials. Although berberine can be an effective prebiotic supplement to modulate metabolic parameters, further high-quality clinical trials are needed to confirm this potential.

Adding a ketogenic dietary intervention to IVF treatment in patients with polycystic ovary syndrome improves implantation and pregnancy

Patients with polycystic ovary syndrome (PCOS) on a high-carbohydrate diet intrinsically suffer from exacerbated glucotoxicity, insulin resistance (IR), and infertility. Lowering the carbohydrate content has improved fertility in patients with IR and PCOS; however, the effects of a well-controlled ketogenic diet on IR and fertility in PCOS patients undergoing in vitro fertilization (IVF) have not been reported. Twelve PCOS patients with a previous failed IVF cycle and positive for IR (HOMA1-IR>1.96) were retrospectively evaluated. Patients followed a ketogenic diet (50 g of total carbohydrates/1800 calories/day). Ketosis was considered when urinary concentrations were > 40 mg/dL. Once ketosis was achieved, and IR diminished, patients underwent another IVF cycle. The nutritional intervention lasted for 14 ± 11 weeks. Carbohydrate consumption decreased from 208 ± 50.5 g/day to 41.71 ± 10.1 g/day, which resulted in significant weight loss (−7.9 ± 1.1 kg). Urine ketones appeared in most patients within 13.4 ± 8.1 days. In addition, there was a decrease in fasting glucose (−11.4 ± 3.5 mg/dl), triglycerides (−43.8 ± 11.6 mg/dl), fasting insulin (−11.6 ± 3.7 mIU/mL), and HOMA-IR (−3.28 ± 1.27). All patients underwent ovarian stimulation, and compared to the previous cycle, there was no difference in oocyte number, fertilization rate, and viable embryos produced. However, there was a significant improvement in the implantation (83.3 vs. 8.3 %), clinical pregnancy (66.7 vs. 0 %), and ongoing pregnancy/live birth rates (66.7 vs. 0 %). Here, restriction in carbohydrate consumption in PCOS patients induced ketosis, improved key metabolic parameters, and decreased IR. Even though this did not affect oocyte or embryo quality or quantity, the subsequent IVF cycle significantly improved embryo implantation and pregnancy rates.

Time trajectories of key cardiometabolic parameters and of cardiovascular risk in subjects with diabetes in a real world setting

Background and aimsDiabetes is associated with increased cardiovascular risk. Glycated haemoglobin (HbA1c), lipid parameters and blood pressure are known risk factors for adverse outcome. The aim of the study was to explore the time trajectories of these key parameters and of the associated cardiovascular risk. MethodsWe linked the diabetes electronic health records to the laboratory information system so as to investigate the trajectories of key metabolic parameters from 3 years prior to the diagnosis of diabetes to 10 years after diagnosis. We calculated the cardiovascular risk at the different time points during this period using the United Kingdom Prospective Study (UKPDS) risk engine. ResultsThe study included 21,288 patients. The median age at diagnosis was 56 years and 55.3% were male. There was a sharp decrease in HbA1c after diagnosis of diabetes, but there was a progressive rise thereafter. All lipid parameters after diagnosis also improved in the year of diagnosis, and these improvements persisted even up to 10 years post-diagnosis. There was no discernible trend in mean systolic or diastolic blood pressures following diagnosis of diabetes. There was a slight decrease in the UKPDS-estimated cardiovascular risk after diagnosis of diabetes followed by a progressive increase. Estimated glomerular filtration rate declined at an average rate of 1.33 ml/min/1.73 m2/year. ConclusionsOur data suggest that lipid control should be tightened with increasing duration of diabetes since this is more readily achievable than HbA1c lowering and since other factors such as age and duration of diabetes are unmodifiable.

Effects of different light quality and GA3 concentration on tobacco seedling growth, root characteristics, and carbon and nitrogen metabolism

Light quality and gibberellins affect growth, development and morphogenesis of plants. In order to improve the quality of tobacco seedlings under greenhouse conditions, the influence of different light sources and their interaction with foliar-applied gibberellic acid (GA3) on key growth and metabolic parameters in tobacco were examined. Light sources included white, red and blue lights while GA3 was applied in three concentrations, i.e., 0, 50 and 100 mg L-1. The survival rate of the seedlings was observed after transplanting. Morphological parameters like plant height, stalk diameter, and length, width and number of leaves increased maximally with higher concentration of GA3 under all three light regimes, however, light sources did not show any visible difference. Further, root vitality, chlorophyll content and the activities amylase and nitrate reductase increased significantly due to GA3 application and achieved highest values with blue light + 100 mg L-1 GA3. Supplementation of red and blue light along with foliar application of GA3 significantly increased the growth parameters including seedling height, stem diameter, root-shoot ratio, leaf length and root vitality. The contents of carbon metabolites including starch, soluble sugars, and reducing sugars improved significantly in plants grown under red and blue lights in combination with foliar application of GA3. The results of the present study depict that growing tobacco under blue light and the application GA3 is beneficial in terms of achieving increased growth, root characteristics, carbon and nitrogen metabolism of tobacco seedlings.

Breathe Easy, an automated respiratory data pipeline for waveform characteristic analysis

Whole body barometric flow through plethysmography is used to study respiratory output in adult rodent genetic and disease models. Turn-key commercial and custom systems are both used to gather multiple data streams for a reasonable estimation of tidal volume and key metabolic parameters. Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic, and degenerative diseases. However, such studies produce large amounts of data that are time-consuming and difficult to analyze. The investigator may use cumbersome hand annotation subject to observer bias or a series of software products to manage raw data, calculated data, statistical analysis, and graphing. Commercial software, however, is prohibitively expensive or bundled with turn-key systems limiting options for bespoke respiratory measurement systems. A lack of tools for high-throughput analysis of respiratory datasets remains a major challenge.Here, we present Breathe Easy, a novel open-source pipeline for processing raw recordings and associated metadata into operative outcomes, publication-worthy graphs, and robust statistical analyses including QQ and residual plots for assumption queries and data transformations. This pipeline uses a facile graphical user interface for uploading data files, setting waveform feature thresholds, and defining experimental variables. Behind the scenes we have a fine-tuned, python-based program called BASSPRO that takes the user-settings and selects all quantitatively defined, quality breaths from each period of interest in the signal files. After BASSPRO, STAGG takes those breaths and performs linear mixed effects modeling based on user selections for each dependent variable of interest. Furthermore, our software can integrate non-respiratory experimental outcomes including quantified behavioral or expression data to test for breathing related associations.To validate breath selection and generate optimized default values, results from Breathe Easy were compared to manual selection by experts, which represents the current standard in the field. We show high quality breath selection and a significant reduction in quality of breaths that were rejected by the software. We also demonstrate Breathe Easy’s utility and capacity by examining a 2-year longitudinal study of an Alzheimer’s Disease mouse model to assess contributions of forebrain pathology in disordered breathing (600+ files; 1TB data). We show that, at least with this model of AD, there does not seem to be an association between forebrain pathology and respiratory outcomes.Breathe Easy offers a facile and highly customizable platform for automated handling and analysis of animal respiratory and metabolic data that sets the stage for high-throughput studies and machine learning approaches on large data sets. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2023 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.

364 Beneficial Actions of SGLT2 Inhibition and H2S Therapy in Heart Failure with Preserved Ejection Fraction

OBJECTIVES/GOALS: SGLT2i therapy is currently a cornerstone in heart failure with preserved ejection fraction (HFpEF) therapy. Similarly, H2S has been shown to be beneficial in preclinical models of heart failure. With this in mind, we sought to investigate the effects of the SGLT2i and H2S donor therapy alone or in combination in a rodent model of cardiometabolic HFpEF. METHODS/STUDY POPULATION: Male C57BL/6N mice (9 weeks of age) were fed a high fat, Western diet (HFD) and received L-NG-Nitro arginine methyl ester (L-NAME) in the drinking water (0.5 g/L) to induce HFpEF. At 5 weeks, animals were randomized to either control, H2S donor (SG-1002, 90 mg/kg/d, P.O), Empagliflozin (155 mg/L, P.O), or the combination of SG-1002 and Empagliflozin for an additional 5 weeks while being maintained on HFD and L-NAME. Echocardiography, left ventricular invasive LV and systemic hemodynamics, and exercise capacity testing were performed to assess cardiovascular disease severity. Fasted glucose, circulating triglyceride and cholesterol content were similarly measured to quantify key clinical metabolic parameters. H2S and its metabolite, sulfane sulfur, were quantified to assure adequate H2S donation. RESULTS/ANTICIPATED RESULTS: Administration of SG-1002 restored H2S and sulfane sulfur to normal circulating levels. All treatment groups exhibited similar improvements in LV diastolic dysfunction as measured by E/E’and LVEDP. Combination therapy significantly improved exercise capacity whereas the monotherapy groups did not. Treatment with SG-1002 decreased fasting glucose and circulating cholesterol while all treatment groups displayed decreased circulating triglycerides and body weight compared to HFpEF control. DISCUSSION/SIGNIFICANCE: These data indicate that restoring H2S or treatment with an SGLT2i in this preclinical HFpEF model attenuates pathology. Combination of both drugs exhibited greater benefit than either monotherapy in important HFpEF parameters such as exercise capacity. Further studies are underway to characterize the benefits observed from combination therapy.

Real-Time Analysis of Bioenergetics in Primary Human Retinal Pigment Epithelial Cells Using High-Resolution Respirometry.

Metabolic dysfunction of retinal pigment epithelial cells (RPE) is a key pathogenic driver of retinal diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Since RPE are highly metabolically-active cells, alterations in their metabolic status reflect changes in their health and function. High-resolution respirometry allows for real-time kinetic analysis of the two major bioenergetic pathways, glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), through quantification of the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively. The following is an optimized protocol for conducting high-resolution respirometry on primary human retinal pigment epithelial cells (H-RPE). This protocol provides a detailed description of the steps involved in producing bioenergetic profiles of RPE to define their basal and maximal OXPHOS and glycolytic capacities. Exposing H-RPE to different drug injections targeting the mitochondrial and glycolytic machinery results in defined bioenergetic profiles, from which key metabolic parameters can be calculated. This protocol highlights the enhanced response of BAM15 as an uncoupling agent compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) to induce the maximal respiration capacity in RPE. This protocol can be utilized to study the bioenergetic status of RPE under different disease conditions and test the efficacy of novel drugs in restoring the basal metabolic status of RPE.

Dysregulated systemic metabolism in a Down syndrome mouse model

ObjectiveTrisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS. MethodsTs65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism. ResultsUnder the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism. ConclusionsA combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.

The effect of sun light exposure on prediabetic patients in tamil nadu population

This study examines the impact of sunlight exposure on metabolic health indicators in prediabetic individuals in Tamil Nadu, with a focus on its potential to reduce the risk of Type 2 diabetes mellitus (T2DM). Prediabetes, characterized by elevated glucose levels, is a major risk factor for both T2DM and cardiovascular diseases. With projections that diabetes will affect 380 million people globally by 2025, including 70 million in India, early intervention is critical. Vitamin D, synthesized through sunlight exposure, plays a role in insulin sensitivity and glucose regulation. Vitamin D deficiency has been linked to increased insulin resistance and higher HbA1c levels, particularly among those with obesity, a common risk factor in prediabetes. This retrospective study included 100 prediabetic patients, divided based on sunlight exposure, and followed over three years. Key anthropometric and metabolic parameters such as BMI, blood glucose, HbA1c, and lipid profiles were assessed. Results showed that the sunlight-exposed group had significant improvements in BMI, blood glucose, and HbA1c compared to those with low sunlight exposure, with blood pressure also improving, though HDL and LDL cholesterol changes were not statistically significant. These findings suggest that regular sunlight exposure may help delay or prevent diabetes progression by improving metabolic health, especially when combined with lifestyle modifications and Vitamin D supplementation. Further research is recommended to determine optimal sunlight exposure guidelines for high-risk groups.