Access to essential medicines for diabetes care: availability, price, and affordability in central Ethiopia.

BACKGROUND: Diabetes is a major global public health burden. Effective diabetes management is highly dependent on the availability of affordable and quality-assured essential medicines (EMs) which is a challenge especially in low-and-middle-income countries such as Ethiopia. This study aimed to assess the accessibility of EMs used for diabetes care in central Ethiopia's public and private medicine outlets with respect to availability and affordability parameters. METHODS: A cross-sectional study was conducted in 60 selected public and private medicine outlets in central Ethiopia from January to February 2022 using the World Health Organization/Health Action International (WHO/HAI) standard tool to assess access to EMs. We included EMs that lower glucose, blood pressure, and cholesterol as these are all critical for diabetes care. Availability was determined as the percentage of surveyed outlets per sector in which the selected lowest-priced generic (LPG) and originator brand (OB) products were found. The number of days' wages required by the lowest paid government worker (LPGW) to purchase a one month's supply of medicines was used to measure affordability while median price was determined to assess patient price and price markup difference between public procurement and retail prices. RESULTS: Across all facilities, availability of LPG and OB medicines were 34.6% and 2.5% respectively. Only two glucose-lowering (glibenclamide 5 mg and metformin 500 mg) and two blood pressure-lowering medications (nifedipine 20 mg and hydrochlorothiazide 25 mg) surpassed the WHO's target of 80% availability. The median price based on the least measurable unit of LPG diabetes EMs was 1.6 ETB (0.033 USD) in public and 4.65 ETB (0.095 USD) in private outlets. The cost of one month's supply of diabetes EMs was equivalent to 0.3 to 3.1 days wages in public and 1.0 to 11.0 days wages in private outlets, respectively, for a typical LPGW. Thus, 58.8% and 84.6% of LPG diabetes EMs included in the price analysis were unaffordable in private and public outlets, respectively. CONCLUSIONS: There are big gaps in availability and affordability of EMs used for diabetes in central Ethiopia. Policy makers should work to improve access to diabetes EMs. It is recommended to increase government attention to availing affordable EMs for diabetes care including at the primary healthcare levels which are more accessible to the majority of the population. Similar studies are also recommended to be conducted in different parts of Ethiopia.

Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.

Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain 2H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-2H glucose. Time-resolved whole brain 2H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) 2H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for 2H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for 2H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.

Phytochemical Profiling and Assessment of Antidiabetic Activity of Curcuma Angustifolia Rhizome Methanolic Extract: An In Vitro and In Silico Analysis.

Curcuma angustifolia Roxb. is a plant with medicinal potential, traditionally used to treat different diseases. The present study aimed to determine the antidiabetic activity of C. angustifolia rhizome in vitro and in silico. The methanolic extract of C. angustifolia rhizome was analyzed by FTIR and GC-MS to determine the phytochemicals present. The antidiabetic potential of the extract was evaluated by different assays in vitro. The extract inhibited both α-amylase and α-glucosidase enzymes and the glucose diffusion through the dialysis membrane in a concentration-dependent manner with IC50 values of 530.39±0.09, 293.75±0.11, and 551.74±0.3 µg/ml respectively. The methanolic extract also improved yeast cell's ability to take up glucose across plasma membranes and the adsorption of glucose. The findings were supported by molecular docking studies. The results showed that the methanol extract of C. angustifolia rhizome has significant antidiabetic activity and thus can be also studied to isolate the potential compound with antidiabetic activities.

Assessment of the impact of a personalised nutrition intervention in impaired glucose regulation over 26 weeks: a randomised controlled trial.

Dietary interventions can reduce progression to type 2 diabetes mellitus (T2DM) in people with non-diabetic hyperglycaemia. In this study we aimed to determine the impact of a DNA-personalised nutrition intervention in people with non-diabetic hyperglycaemia over 26 weeks. ASPIRE-DNA was a pilot study. Participants were randomised into three arms to receive either (i) Control arm: standard care (NICE guidelines) (n = 51), (ii) Intervention arm: DNA-personalised dietary advice (n = 50), or (iii) Exploratory arm: DNA-personalised dietary advice via a self-guided app and wearable device (n = 46). The primary outcome was the difference in fasting plasma glucose (FPG) between the Control and Intervention arms after 6 weeks. 180 people were recruited, of whom 148 people were randomised, mean age of 59 years (SD = 11), 69% of whom were female. There was no significant difference in the FPG change between the Control and Intervention arms at 6 weeks (- 0.13 mmol/L (95% CI [- 0.37, 0.11]), p = 0.29), however, we found that a DNA-personalised dietary intervention led to a significant reduction of FPG at 26 weeks in the Intervention arm when compared to standard care (- 0.019 (SD = 0.008), p = 0.01), as did the Exploratory arm (- 0.021 (SD = 0.008), p = 0.006). HbA1c at 26 weeks was significantly reduced in the Intervention arm when compared to standard care (- 0.038 (SD = 0.018), p = 0.04). There was some evidence suggesting prevention of progression to T2DM across the groups that received a DNA-based intervention (p = 0.06). Personalisation of dietary advice based on DNA did not result in glucose changes within the first 6 weeks but was associated with significant reduction of FPG and HbA1c at 26 weeks when compared to standard care. The DNA-based diet was effective regardless of intervention type, though results should be interpreted with caution due to the low sample size. These findings suggest that DNA-based dietary guidance is an effective intervention compared to standard care, but there is still a minimum timeframe of adherence to the intervention before changes in clinical outcomes become apparent.Trial Registration: www.clinicaltrials.gov.uk Ref: NCT03702465.

Comprehensive assessment of the effects of concurrent strength and endurance training on lipid profile, glycemic control, and insulin resistance in type 2 diabetes: A meta-analysis.

BACKGROUND: To investigate the effect of concurrent strength combined with endurance training on the lipid and glucose profile of type 2 diabetes mellitus (T2DM) using Meta-analysis. METHODS: The literature was searched from PubMed, Web of Science, EBSCO, and China National Knowledge Infrastructure(CNKI) databases for relevant randomized controlled trials with dates from the date of establishment to June 2023, and the included studies were individually assessed according to the Cochrane Risk of Bias tool in the Cochrane Systematic Assessor's Handbook, and the data were analyzed using RevMan 5.4 analysis software to analyze and process the data. RESULTS: A total of 9 articles were included, including 589 subjects, including 308 in the experimental group and 281 in the control group. The results of Meta analysis showed that concurrent strength combined with endurance training improved TC (SMD = -1.12, 95% CI = [-1.81, -0.44], P < 0.01), TG (SMD = -0.46, 95% CI = [-0.85, -0.07], P < 0.05), LDL-C (SMD = -1.3, 95% CI = [-2.09, -0.50], P < 0.01), HDL-C (SMD = 0.61, 95% CI = [0.05, 1.17], P < 0.05), FBG (SMD = -0.65, 95% CI = [-1.27, -0.04], P < 0.05), HOMA-IR (SMD = -1.23, 95% CI = [-2.40, -0.06], P < 0.05). CONCLUSION: Concurrent strength combined with endurance training has a positive effect on the improvement of lipid and glucose profile in patients with type 2 diabetes.

Sex and age disparities in multi-metal mixture exposure and cognitive impairment in urban elderly individuals: The mediation effect and biological function of metabolites.

Studies on the relationships between metal mixtures exposure and cognitive impairment in elderly individuals are limited, particularly the mechanism with metabolite. Few studies are available on the potential sex and age specific associations between metal exposure, metabolites and cognitive impairment. We examined plasma metal and blood metabolite concentrations among 1068 urban elderly participants. Statistical analysis included a battery of variable selection approaches, logistic regression for metal/metabolite associations, and Bayesian kernel machine regression (BKMR) to identify mixed effects of metals/metabolites on cognitive impairment risk. Our results showed that As was positively associated with cognitive impairment in the female (OR 95 % CI = 2.21 (1.36, 3.57)) and 60- to 70-year-old (OR 95 % CI = 2.60 (1.54, 4.41)) groups, Cr was positively associated with cognitive impairment in the male (OR 95 % CI = 2.15 (1.27, 3.63)) and 60- to 70-year-old (OR 95 % CI = 2.10 (1.24, 3.57)) groups, and Zn was negatively associated with cognitive impairment, especially in the female (OR 95 % CI = 0.46 (0.25, 0.84)), 60- to 70-year-old (OR 95 % CI =0.24 (0.12, 0.45)) and ≥ 80-year-old (OR 95 % CI = 0.19 (0.04, 0.86)) groups. Positive associations were observed between combined metals (Cr, Cu and As) and cognitive impairment, but Zn alleviated this tendency, especially in elderly individuals aged ≥80 years. Negative associations were observed between metabolites and cognitive impairment, especially in male, female and 60-70 years old groups. The mediation effects of metabolites on the association between metal exposure and cognitive impairment were observed, and the percentages of these effects were 15.60 % (Glu-Cr), 23.00 % (C5:1-Cu) and 16.36 % (Glu-Zn). Cr, Cu, and Zn could increase cognitive impairment risk through the "Malate-Aspartate Shuttle", "Glucose-Alanine Cycle", etc., pathways. Overall, we hypothesize that metabolites have mediation effects on the relationship between multi-metal exposure and cognitive impairment and that there are sex and age differences.

Metabolic health tracking using Ultrahuman M1 continuous glucose monitoring platform in non- and pre-diabetic Indians: a multi-armed observational study.

Continuous glucose monitoring (CGM) device adoption in non- and pre-diabetics for preventive healthcare has uncovered a paucity of benchmarking data on glycemic control and insulin resistance for the high-risk Indian/South Asian demographic. Furthermore, the correlational efficacy between digital applications-derived health scores and glycemic indices lacks clear supportive evidence. In this study, we acquired glycemic variability (GV) using the Ultrahuman (UH) M1 CGM, and activity metrics via the Fitbit wearable for Indians/South Asians with normal glucose control (non-diabetics) and those with pre-diabetes (N = 53 non-diabetics, 52 pre-diabetics) for 14 days. We examined whether CGM metrics could differentiate between the two groups, assessed the relationship of the UH metabolic score (MetSc) with clinical biomarkers of dysglycemia (OGTT, HbA1c) and insulin resistance (HOMA-IR); and tested which GV metrics maximally correlated with inflammation (Hs-CRP), stress (cortisol), sleep, step count and heart rate. We found significant inter-group differences for mean glucose levels, restricted time in range (70-110 mg/dL), and GV-by-SD, all of which improved across days. Inflammation was strongly linked with specific GV metrics in pre-diabetics, while sleep and activity correlated modestly in non-diabetics. Finally, MetSc displayed strong inverse relationships with insulin resistance and dysglycemia markers. These findings present initial guidance GV data of non- and pre-diabetic Indians and indicate that digitally-derived metabolic scores can positively influence glucose management.

Self-Buffering system for Cost-Effective production of lactic acid from glucose and xylose using Acid-Tolerant Issatchenkia orientalis.

This study presents a cost-effective strategy for producing organic acids from glucose and xylose using the acid-tolerant yeast, Issatchenkia orientalis. I. orientalis was engineered to produce lactic acid from xylose, and the resulting strain, SD108XL, successfully converted sorghum hydrolysates into lactic acid. In order to enable low-pH fermentation, a self-buffering strategy, where the lactic acid generated by the SD108XL strain during fermentation served as a buffer, was developed. As a result, the SD108 strain produced 67 g/L of lactic acid from 73 g/L of glucose and 40 g/L of xylose, simulating a sugar composition of sorghum biomass hydrolysates. Moreover, techno-economic analysis underscored the efficiency of the self-buffering strategy in streamlining the downstream process, thereby reducing production costs. These results demonstrate the potential of I. orientalis as a platform strain for the cost-effective production of organic acids from cellulosic hydrolysates.

Missing Data Statistics Provide Causal Insights into Data Loss in Diabetes Health Monitoring by Wearable Sensors.

BACKGROUND: Data loss in wearable sensors is an inevitable problem that leads to misrepresentation during diabetes health monitoring. We systematically investigated missing wearable sensors data to get causal insight into the mechanisms leading to missing data. METHODS: Two-week-long data from a continuous glucose monitor and a Fitbit activity tracker recording heart rate (HR) and step count in free-living patients with type 2 diabetes mellitus were used. The gap size distribution was fitted with a Planck distribution to test for missing not at random (MNAR) and a difference between distributions was tested with a Chi-squared test. Significant missing data dispersion over time was tested with the Kruskal-Wallis test and Dunn post hoc analysis. RESULTS: Data from 77 subjects resulted in 73 cleaned glucose, 70 HR and 68 step count recordings. The glucose gap sizes followed a Planck distribution. HR and step count gap frequency differed significantly (p < 0.001), and the missing data were therefore MNAR. In glucose, more missing data were found in the night (23:00-01:00), and in step count, more at measurement days 6 and 7 (p < 0.001). In both cases, missing data were caused by insufficient frequency of data synchronization. CONCLUSIONS: Our novel approach of investigating missing data statistics revealed the mechanisms for missing data in Fitbit and CGM data.

A comparative analysis of energy expenditure and substrate metabolism in male university students with overweight/obesity: Tabata vs HIIT and MICT.

Introduction: Exploring the energy expenditure and substrate metabolism data during exercise, 10-minute recovery, and 20-minute recovery phases in Tabata, HIIT(High-Intensity Interval Training), and MICT(Moderate-Intensity Continuous Training). This study explores the scientific aspects of weight reduction strategies, examining energy expenditure and substrate metabolism from various training perspectives. The aim is to establish a theoretical foundation for tailoring targeted exercise plans for individuals within the population with overweight/obesity. Methods: This study used an experimental design with fifteen male university students with overweight/obesity. Participants underwent random testing with Tabata, HIIT, and MICT. Tabata involved eight sets of 20 seconds exercise and 10 seconds rest, totaling 4 minutes. HIIT included four sets of power cycling: 3 minutes at 80% VO2max intensity followed by 2 minutes at 20% VO2max. MICT comprised 30 minutes of exercise at 50% VO2max intensity. Gas metabolism indices were continuously measured. Subsequently, fat and glucose oxidation rates, along with energy expenditure, were calculated for each exercise type. Results: During both the exercise and recovery phases, the Tabata group exhibited a significantly higher fat oxidation rate of (0.27 ± 0.03 g/min) compared to the HIIT group (0.20 ± 0.04 g/min, p<0.05) and the MICT group (0.20 ± 0.03g/min, p<0.001). No significant difference was observed between the HIIT and MICT groups (p=0.854). In terms of energy expenditure rate, the Tabata group maintained a substantially elevated level at 5.76 ± 0.74kcal/min compared to the HIIT group (4.81 ± 0.25kcal/min, p<0.01) and the MICT group (3.45 ± 0.25kcal/min, p<0.001). Additionally, the energy expenditure rate of the HIIT group surpassed that of the MICT group significantly (p<0.001). Conclusion: The study finds that male college students with overweight/obesity in both exercise and recovery, Tabata group has lower fat and glucose oxidation rates, and energy expenditure compared to HIIT and MICT groups. However, over the entire process, Tabata still exhibits significantly higher rates in these aspects than HIIT and MICT. Despite a shorter exercise duration, Tabata shows a noticeable "time-efficiency" advantage. Tabata can be used as an efficient short-term weight loss exercise program for male college students with overweight/obesity.

Formation mechanism of α particles in glycogen: Testing the budding hypothesis by Monte-Carlo simulation.

Glycogen, a complex branched glucose polymer and a blood-sugar reservoir in animals, comprises small ß particles joined together into composite α particles. In diabetic animals, α particles fragment more easily than those in healthy animals. Finding evidence for or against postulated mechanisms for α-particle formation is thus important for diabetes research. Insight into this is obtained here using Monte-Carlo simulations, including addition and loss of glucose monomer, branching and debranching, based on earlier simulations which were in acceptable agreement with experiment [Zhang et al., Int J Biol Macromolecules 2018, 116, 264]. One postulated mechanism for α-particle formation is "budding": occasionally a glucan chain temporarily protrudes from the particle, and if its growing end is sufficiently far from its parent particle, it propagates to a new linked particle. We tested this by simulations in which an "artificial" bud (a chain extending well outside the average particle radius) is added to a glycogen molecule in a dynamic steady state, and the system allowed to evolve. In some simulations, the particle reached a new steady state having an irregular dumbbell shape: a rudimentary α particle. Thus 'budding' is a possible mechanism for α particles to form. If no simulations had shown this behaviour, it would have refuted the postulate.

The Determination of Diabetes Utilities, Costs, and Effects Model: A Cost-Utility Tool Using Patient-Level Microsimulation to Evaluate Sensor-Based Glucose Monitoring Systems in Type 1 and Type 2 Diabetes: Comparative Validation.

OBJECTIVES: To assess the accuracy and validity of the Determination of Diabetes Utilities, Costs, and Effects (DEDUCE) model, a Microsoft-Excel-based tool for evaluating diabetes interventions for type 1 and type 2 diabetes. METHODS: The DEDUCE model is a patient-level microsimulation, with complications predicted based on the Sheffield and Risk Equations for Complications Of type 2 diabetes models for type 1 and type 2 diabetes, respectively. For this tool to be useful, it must be validated to ensure that its complication predictions are accurate. Internal, external, and cross-validation was assessed by populating the DEDUCE model with the baseline characteristics and treatment effects reported in clinical trials used in the Fourth, Fifth, and Ninth Mount Hood Diabetes Challenges. Results from the DEDUCE model were evaluated against clinical results and previously validated models via mean absolute percentage error or percentage error. RESULTS: The DEDUCE model performed favorably, predicting key outcomes, including cardiovascular disease in type 1 diabetes and all-cause mortality in type 2 diabetes. The model performed well against other models. In the Mount Hood 9 Challenge comparison, error was below the mean reported from comparator models for several outcomes, particularly for hazard ratios. CONCLUSIONS: The DEDUCE model predicts diabetes-related complications from trials and studies well when compared with previously validated models. The model may serve as a useful tool for evaluating the cost-effectiveness of diabetes technologies.

Production and characterization of polyhydroxybutyrate bioplastic precursor from Parageobacillus toebii using low-cost substrates and its potential antiviral activity.

There is an increasing desire for bioplastics produced from renewable resources as an alternative to their petrochemical counterparts. These biopolymers have long-unnoticed antiviral properties. This study aimed to produce and characterize bioplastics by Parageobacillus toebii using low-cost substrates and determine their antiviral activity against coxsackievirus B4. Seven low-cost substrates (bagasse, water hyacinth, rice straw, rice water, sesame husks, molasses, and corn syrup) were compared with glucose for bioplastic precursor production. The highest bioplastic produced was from water hyacinth and glucose, followed by molasses, rice straw, rice water, sesame husks, and bagasse. Water hyacinth and glucose media were further optimized to increase the bioplastic precursor yield. The optimization of the media leads to increases in bioplastic precursor yields of 1.8-fold (3.456 g/L) and 1.496-fold (2.768 g/L), respectively. These bioplastics were further characterized by thermogravimetric analysis (TGA), Fourier-transformed infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR), and gas chromatography-mass spectrometry (GC-MS). They are thermostable, and their characterizations confirm the presence of polyhydroxybutyrate. The antiviral assay showed reasonable antiviral effects for bioplastics from water hyacinth (80.33 %) and glucose (55.47 %) media at 250 µg/mL maximum non-toxic concentrations (MNTC). The present investigation demonstrates a low-cost model for producing polyhydroxybutyrate bioplastic precursor for antiviral applications.

Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling.

OBJECTIVE: Obesity is a global health concern with management strategies encompassing bariatric surgery and anti-obesity drugs; however, concerns regarding complexities and side effects persist, driving research for more effective, low-risk strategies. The promotion of white adipose tissue (WAT) browning has emerged as a promising approach. Moreover, alisol B 23-acetate (AB23A) has demonstrated efficacy in addressing metabolic disorders, suggesting its potential as a therapeutic agent in obesity management. Therefore, in this study, we aimed to investigate the therapeutic potential of AB23A for mitigating obesity by regulating metabolic phenotypes and lipid distribution in mice fed a high-fat diet (HFD). METHODS: An obesity mouse model was established by administration of an HFD. Glucose and insulin metabolism were assessed via glucose and insulin tolerance tests. Adipocyte size was determined using hematoxylin and eosin staining. The expression of browning markers in WAT was evaluated using Western blotting and quantitative real-time polymerase chain reaction. Metabolic cage monitoring involved the assessment of various parameters, including food and water intake, energy metabolism, respiratory exchange rates, and physical activity. Moreover, oil red O staining was used to evaluate intracellular lipid accumulation. A bioinformatic analysis tool for identifying the molecular mechanisms of traditional Chinese medicine was used to examine AB23A targets and associated signaling pathways. RESULTS: AB23A administration significantly reduced the weight of obese mice, decreased the mass of inguinal WAT, epididymal WAT, and perirenal adipose tissue, improved glucose and insulin metabolism, and reduced adipocyte size. Moreover, treatment with AB23A promoted the expression of browning markers in WAT, enhanced overall energy metabolism in mice, and had no discernible effect on food intake, water consumption, or physical activity. In 3T3-L1 cells, AB23A inhibited lipid accumulation, and both AB23A and rapamycin inhibited the mammalian target of rapamycin-sterol regulatory element-binding protein-1 (mTOR-SREBP1) signaling pathway. Furthermore, 3-isobutyl-1-methylxanthine, dexamethasone and insulin, at concentrations of 0.25 mmol/L, 0.25 µmol/L and 1 µg/mL, respectively, induced activation of the mTOR-SREBP1 signaling pathway, which was further strengthened by an mTOR activator MHY1485. Notably, MHY1485 reversed the beneficial effects of AB23A in 3T3-L1 cells. CONCLUSION: AB23A promoted WAT browning by inhibiting the mTOR-SREBP1 signaling pathway, offering a potential strategy to prevent obesity. Please cite this article as: Han LL, Zhang X, Zhang H, Li T, Zhao YC, Tian MH, Sun FL, Feng B. Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling. J Integr Med. 2024; 22(1): 83-92.

Poorly controlled glycemia and worse beta cell function associate with higher resting and total energy expenditure in adults with obesity and type 2 diabetes: A doubly labeled water study.

BACKGROUND: Some studies comparing persons with and without type 2 diabetes (T2DM) show no difference in resting energy expenditure (REE). However, the degree of glycemic control may be a crucial factor in determining energy requirements. Few studies have employed the doubly labeled water (DLW) method in persons with T2DM to objectively measure daily energy expenditure. AIMS: To determine relationships between glycemia, body composition, and energy expenditure in adults with obesity and T2DM. We hypothesized that worse hyperglycemia, insulin resistance, and beta cell function would associate with higher resting and total energy expenditure (TEE). METHODS: Two cohorts age 31-50 years were included: 78 with obesity and T2DM, 19 with normal weight and no chronic disease. Baseline data from clinical biomarkers, intravenous glucose tolerance tests, DXA and MRI for body composition, and dietary intakes were used in multivariable regression models to predict REE and TEE. Additionally, comparisons were made by categorizing participants as having controlled or uncontrolled glycemia based on glucose levels ≥175 mg/dL. RESULTS: REE was higher in participants with T2DM by 534.08 ± 74.35 kcal/d (p < 0.001). Higher fasting glucose and HbA1C levels associated with higher TEE. Abdominal SAT and VAT were also predictors in regression models accounting for 76 % of the variance in REE and 89 % of TEE. Participants with uncontrolled glycemia had 22 % higher adipose/lean ratio, two-fold higher VAT/SAT ratio, 21 % higher HOMA-IR score, and worse beta cell function (mean difference in HOMA2-%ß of 74.09 ± 14.01, p < 0.001) than those with controlled glycemia. Both REE and TEE were significantly higher in uncontrolled glycemia, difference in REE of 154.17 ± 96.28 kcals/day (p = 0.04) and difference in TEE of 480.64 ± 215.45 kcals/day (p = 0.03). CONCLUSIONS: Poor beta cell function and uncontrolled glycemia associate with higher REE and TEE in persons with obesity and T2DM. This study is registered with clinicaltrials.gov identifier: NCT01239550.

Conditional Deletion of ß-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity.

ß-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, ß-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether ß-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female ß-catenin flox mice, to specifically delete ß-catenin expression in the mediobasal hypothalamus (MBH-ß-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-ß-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-ß-cat KO mice were significantly heavier than the control mice in both sexes (p < 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-ß-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for ß-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.

Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Deletion of the mitochondrial calcium uniporter in adipose tissue promotes energy expenditure and alleviates diet-induced obesity.

OBJECTIVE: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. METHODS: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. RESULTS: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. CONCLUSIONS: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.

Pharmacist-driven outreach initiative to increase prescribing of sodium-glucose cotransporter-2 inhibitors in eligible VHA patients with chronic kidney disease: a study protocol.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for multiple adverse events, several of which have been proven to be less likely with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i). As a result, guidelines now recommend SGLT2i be given to those with mild to moderate CKD and type 2 diabetes. The objective of this study is to evaluate if a pharmacist-driven SGLT2i prescribing initiative among eligible patients with CKD and diabetes within the VA could more rapidly improve the adoption of SGLT2i via a pragmatic approach aligned with learning health systems. METHODS: Eligible patients will be identified through an established VA diabetes dashboard. Veterans with an odd social security number (SSN), which is effectively a random number, will be the intervention group. Those with even SSNs will serve as the control while awaiting a second iteration of the same interventional program. The intervention will be implemented in a rolling fashion across one Veterans Integrated Service Network. Our primary outcome is initiation of an SGLT2i. Secondary outcomes will include medication adherence and safety-related outcomes. DISCUSSION: This project tests the impact of a pharmacist-driven medication outreach initiative as a strategy to accelerate initiation of SGLT2i. The results of this work will not only illustrate the effectiveness of this strategy for SGLT2is but may also have implications for increasing other guideline-concordant care. Furthermore, the utilization of SSNs to select Veterans for the first wave of this program has created a pseudo-randomized interventional trial supporting a pragmatic learning health system approach. TRIAL REGISTRATION: ISRCTN12374636.