Metabolic Control Research Articles

Subcutaneous Insulin Infusion Versus Multiple Administrations of Insulin Analogs: Is Either Method Associated with Better Quality of Life in Pediatric Patients with Type 1 Diabetes Mellitus?

Objectives − Type 1 Diabetes Mellitus (DM1) requires demanding treatment in order to achieve good metabolic control. Our aim was to assess whether either method of insulin administration (multiple daily administrations of insulin analogues (MDIA) or continuous subcutaneous insulin infusion (CSII)) is associated with better health-related quality of life (HRQoL).Methods − We conducted a cross-sectional study. Patients aged 10-18 years with a disease duration of at least six months were included. HRQoL was assessed by having patients and their caregivers complete the DISABKIDS-37 questionnaire.Results − Of the 40 patients included, 22 (55%) had CSII. There were no statistically significant differences between subscale scores and overall HRQoL between patients or between parents of patients with CSII or MDIA. CSII patients and parents scored better on all subscales and on the total scale, although without statistically significant differences. There were no statistically significant differences in the subscale scores and overall HRQoL reported by the patients and their parents, but there was a strong correlation between the children’s and parents’ scores (R=0.770; P<0.01), which was similar in patients with CSII or MDIA (R=0.735 vs R=0.790).Conclusion − Although we did not identify statistically significant differences, there was a trend towards a better HRQoL associated with the use of CSII, both from the perspective of the adolescents and their parents. This could influence therapeutic choice. Consistency between the assessments of adolescents and their carers was observed. The choice between MDIA and CSII should be based on individual preferences in order to optimize the HRQoL of adolescents with DM1.

Lipophilic index of serum phospholipids in patients with type 2 diabetes and atherosclerotic cardiovascular disease: links with metabolic control, vascular inflammation and platelet activation.

Little is known about the mechanisms underlying the association of the serum phospholipid lipophilic index (LI) with atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes (T2D). Therefore, we investigated whether the LI is associated with glucometabolic control, meta-inflammation, thrombin generation, fibrin clot properties, endothelial function and platelet activation in T2D patients with angiographically documented ASCVD. We studied 74 T2D patients with ASCVD, aged 65.6 ± 6.8 years, with a median diabetes duration of 10 years and median HbA1c of 7.0%. Serum phospholipid fatty acids (FAs) were measured by gas chromatography. The serum phospholipid LI was calculated as the sum of the products of the proportion (% of total FAs) with the melting points (°C) of each individual FA, divided by the sum of the proportions of all FAs. Levels of HbA1c, insulin, leptin, adiponectin, lipid profiles, inflammatory markers (hsCRP, interleukin-6, TNF-α), Lp-PLA2 (a biomarker of vascular inflammation), endothelial function (sICAM-1, sVCAM-1, FMD, NMD), thrombin generation, fibrin clot properties and platelet activation, measured by light transmission aggregometry with arachidonic acid [AA] and adenosine diphosphate [ADP], were assessed. Patients with LI > 16.9°C (median) had higher HbA1c concentrations by 5.9% compared to the remaining subjects (p = 0.035). In this group, HbA1c levels ≥ 7.0% were found more often than in individuals with LI ≤ 16.9°C (62.2 vs. 35.1%; p = 0.020). Subjects with LI > 16.9°C had higher levels of TCh by 17.1% (p = 0.012), LDL-Ch by 29.4% (p = 0.003), interleukin-6 by 22.2% (p = 0.031) and Lp-PLA2 by 32.4% (p = 0.040), compared to the remaining patients. Moreover, they had increased maximal platelet aggregation induced by AA (p = 0.045), but not by ADP. Serum phospholipid LI correlated with HbA1c (r = 0.24; p = 0.037), TCh (r = 0.36; p = 0.002), LDL-Ch (r = 0.38; p < 0.001), interleukin-6 (r = 0.27; p = 0.020) and Lp-PLA2 (r = 0.26; p = 0.026). There were no intergroup differences in endothelial function, thrombin generation and fibrin clot properties. Regression analysis showed that HbA1c ≥ 7.0% and serum levels of LDL-Ch, interleukin-6 and Lp-PLA2 were predictors of LI > 16.9°C in adjusted models. In well-controlled T2D patients with ASCVD, the higher serum phospholipid LI is associated with worse glucometabolic control, enhanced vascular inflammation and higher platelet reactivity during aspirin treatment at cyclooxygenase-1-selective doses.

Unraveling the metabolic activities of bioactive compounds on cellular models of hepatosteatosis and adipogenesis through docking analysis with PPARs.

Obesity is associated with fatty liver disease. Available therapies show modest efficacy, and nutraceuticals with good effectiveness and safety are largely investigated. We focused on five natural compounds, three plant phenolic compounds (carvacrol, rosmarinic acid, silybin), and two thyroid hormones (T2: 3,5-diiodo-l-thyronine; T3: 3,5,3'-triiodo-L-thyronine) as comparison, to assess their beneficial effects on two cellular models of hepatosteatosis and adipogenesis. All compounds ameliorated the lipid accumulation and oxidative stress in both models, but with different potencies. The peroxisome proliferator-activated receptors (PPARs) are pivotal controllers of adipogenesis and lipid metabolism. For the main isoforms, PPARγ and PPARa, we assessed their possible binding to the compounds by molecular docking calculations, and their expression pattern by real-time PCR. All compounds bind both PPARs with different affinity, while not all compounds affect their expression. The results may clarify the distinctive molecular mechanisms underlying the action of the five compounds in the different cell models with possible applications to treat obesity.

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

Phase angle and body composition in long-term type 1 diabetes in adults: a comparative study in a Brazilian public reference outpatient clinic.

Type 1 Diabetes Mellitus (DM1) affects a small percentage of the population. Nevertheless, its prevalence is currently growing with alarming data on uncontrolled cases. The importance of body composition and Phase Angle (PA), assessed by Bioelectrical Impedance (BIA), in long- term DM1 patients lies in the fact that alterations in cellular integrity and body compartments may affect risk profiles and metabolic control. The objective of this study was to compare PA and body composition parameters between adults with DM1 and healthy controls. A comparative study was carried out in a public university outpatient clinic including a cohort of adult patients of both sexes diagnosed with DM1 and healthy controls matched by age and sex in a 2:1 ratio. Anthropometric measurements included weight, height and BMI. Using the raw BIA data of Resistance and Reactance, fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), fat mass index (FMI), PA and standardized PA (SPA) were calculated. Means or medians were compared between the groups. Regression models were used to identify distinguishing characteristics of the groups and associations within the DM1 group (i.e. glycated hemoglobin (HbA1c), disease duration, presence of microvascular complications, capillary blood glucose, BMI and FMI). 88 patients with DM1and 46 healthy controls were evaluated. PA (6.05 vs. 6.85, p = 0.000) and SPA (-1.47 vs. -0,37, p = 0.000) were lower in patients with DM1 compared to healthy controls. People with DM1 displayed higher adiposity (%FM = 29.6 vs. 27.6, p = 0.016; FMI = 7.00 vs. 6.33, p = 0.016) and lower %FFM compared to healthy controls. Most of the differences were maintained after sex stratification; however, men with DM1 showed a lower FFMI than male controls (18.2 vs. 20.16, p = 0.029). Patients with DM1 present lower PA than healthy controls, which may be related to worse cell membrane integrity. Significant body composition differences between the groups and between sexes were identified, with data showing greater adiposity in women with DM1 and men displaying lower muscle mass. These findings suggest the importance of including PA and body composition evaluations in the follow-up of patients with DM1. The ultimate goal is to obtain a better metabolic control and, consequently, a better prognosis.

BS O01 - Comparison of Roux-en-Y Gastric Bypass(RYGBP) and Laparoscopic Sleeve Gastrectomy(LSG) in patients with obesity and diabetes mellitus: Meta-analysis and systemic review

Abstract Background Laparoscopic Sleeve gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) are the two procedures used to treat patients with obesity and type 2 diabetes mellitus(T2DM). However, it is still unclear which of the two procedures is better for T2DM remission. This study aims to compare the effectiveness of LSG and RYGB considering important comparison outcomes including diabetes remission, and overall glycemic and metabolic control. Method We conducted a comprehensive search of Medline, PubMed, the Cochrane Library, Scopus, the Web of Science, Clinical Key, Ovid, and Wiley from their inceptions through August 2022 for randomized controlled trials (RCTs) comparing LSG with RYGB for patients with morbid obesity and T2DM. The data were extracted and pooled using Review Manager software (RevMan5.4). Results Eighteen RCTs including 1360 patients were found. After one year, two years, and five years, the RYGB group's BMI was significantly lower than the LSG group's as follows respectively (MD = -1.58, P &amp;lt; 0.0001), (MD = -1.64, P=0.03), and (MD = -2.26, P= 0.0004). Moreover, the LSG group had a higher incidence of diabetes remission than the RYGP group after five years. Although there was no significant difference in terms of safety outcomes between both groups, GERD was significantly higher in the LSG group, and dumping syndrome was significantly higher in the RYGB group. Conclusion RYGB is more effective in achieving weight loss and reducing BMI, while LSG shows better improvement in diabetes remission, notably for those with high BMI. Both surgeries have similar complication rates, but RYGB has a higher incidence of dumping syndrome and lower rates of GERD compared to LSG.

Investigating the Role of Inositol: Myo-inositol and D-Chiro-inositol in Diabetes: A Review

The sugar alcohol known as inositol and its derivatives are becoming more and more interesting in metabolism-related research studies due to its physiological roles. Inositol derivatives mainly myoinositol and d-chiroinositol have gained so much attention these days in the context of managing and treating metabolic issues such as diabetes and polycystic ovarian syndrome. For a long time, it was considered as the vitamin B, but later we got to know it is produced from glucose so considered non-essential. Nowadays rising rates of obesity which are further linked with diabetes and polycystic ovarian syndrome have fuelled demand for artificial sweeteners. Many people are searching for options to maintain their weight, which has led to the widespread usage of sucrose and fructose substitutes in the food industry. Sugar alcohols such as myoinositol and d chiroinositol (which are not been commonly used) in particular can be metabolized without the need for insulin control and have little effect on blood sugar levels. These sugar substitutes have the potential to provide sweetness without raising blood sugar levels and adding calories. These have half of the sweetness of sucrose. This paper aims to thoroughly investigate and understand the various roles played by inositol in the complex field of managing metabolic diseases. To find out the eligible papers for review paper screening has been performed through PubMed, Science Direct, Web of Science and Google Scholar. Different sets of keywords such as inositol, d chiro inositol, myo-inositol, insulin-resistance, diabetes, insulin sensitivity, DCI and type 2 diabetes mellitus were used. Studies which full text article were present used for the review. Research articles have been included the studies specifically to find out the relation between myoinositol and diabetes or any metabolic disease. The development of many diseases, such as PCOS and diabetes, is linked with inositol deficiency. Myoinositol is derived from the food we eat as well as from within. The low levels of MI can be the result of several factors, including decreased dietary intake, increased catabolism, alterations in the gut and reduced biosynthesis. These two forms, myoinositol and d-chiroinositol play significant roles in regulating lipid metabolism and glycaemic control. glycaemic metabolism and this are also supported by many research studies. Therefore, it can be a possible treatment or management option for people suffering from metabolic issues such as diabetes and PCOS. Future studies should focus on how we can increase the intake of myoinositol through diet and dietary food products.

Light-Induced Nanobody-Mediated Targeted Protein Degradation for Metabolic Flux Control.

In metabolic engineering, increasing chemical production usually involves manipulating the expression levels of key enzymes. However, limited synthetic tools exist for modulating enzyme activity beyond the transcription level. Inspired by natural post-translational mechanisms, we present targeted enzyme degradation mediated by optically controlled nanobodies. We applied this method to a branched biosynthetic pathway, deoxyviolacein, and observed enhanced product specificity and yield. We then extend the biosynthesis pathway to violacein and show how simultaneous degradation of two target enzymes can further shift production profiles. Through the redirection of metabolic flux, we demonstrate how targeted enzyme degradation can be used to minimize unwanted intermediates and boost the formation of desired products.

Prevalence of Autoimmune Thyroiditis Among Children with Type 1 Diabetes

A single-stage cross-sectional study was conducted on the basis of the National Center for Maternal Health in the Kyrgyz Republic, children aged 0 to 18 years were examined. To study the prevalence of autoimmune thyroid disease with type 1 diabetes mellitus to improve the compensation of carbohydrate metabolism in children and adolescents with type 1 diabetes. Autoimmune thyroiditis often accompanies and interferes with type 1 diabetes mellitus in children and adolescents. Thyroid dysfunction in children with type 1 diabetes mellitus can negatively affect various areas of metabolic control. This study included 60 children with type 1 diabetes mellitus and autoimmune thyroiditis, 24 of them girls (40.0%), 36 boys (60%). The average value of ±SD for their age at the time of examination was 11.6±4.1 years, ranging from 1 to 17 years. Of the children with type 1 diabetes mellitus who tested positive for antibodies to thyroid peroxidase, 30 children (50%) had obvious hypothyroidism. Of the thirty children with normal TSH levels, 4 children (13.3%) showed signs of subclinical hypothyroidism, while 26 children (86.7%) had euthyroidism.

A Nutritional Strategy Based on Multiple Components for Glycemic Control in Type 2 Diabetes: A Multicenter Randomized Controlled Clinical Trial

Background/Objectives: The optimal dietary approach for managing glycemic and metabolic control in type 2 diabetes (T2D) is still uncertain, though it should be tailored for clinical settings. Therefore, we sought to assess the impact of a multicomponent nutritional strategy on glycemic control in T2D patients within a public health system. Methods: NUGLIC was an open-label, parallel-group, superiority, multicenter randomized controlled trial. Participants aged 30 and older with poorly controlled T2D were randomly assigned to either (1) a personalized dietary prescription (control group, n = 185) or (2) a strategy involving targeted nutritional advising, mindfulness techniques, and short message services (NUGLIC [intervention] group, n = 186). The primary outcomes were glycated hemoglobin (HbA1c, %) measured after 24 weeks and glycemic control, defined as having an HbA1c &gt; 7% at baseline and achieving ≤7% after follow-up, or having HbA1c ≤ 7% at baseline and reducing the use of glucose-lowering medications post-follow-up. The secondary outcomes included cardiometabolic features, self-care practices, diet quality, and quality of life. Results: A total of 371 participants were included in an intention-to-treat analysis for the primary outcomes. At six months, both groups exhibited a reduction in HbA1c levels compared to the baseline (NUGLIC group: −0.6% [95% confidence interval (CI) −0.9; −0.3], p &lt; 0.001; control group: −0.5% [95% CI −0.7; −0.3], p &lt; 0.001). However, no significant differences were observed between the groups in terms of HbA1c after follow-up (intervention group: 8.1%; control group: 8.3%; difference: −0.2% [95% CI −0.5; 0.1], p = 0.30) or glycemic control (NUGLIC group: 19.9%; control group: 18.9%; odds ratio 0.96 [95% CI 0.56; 1.67], p = 0.89). While the control group showed an improvement in overall diet quality, no significant differences emerged between the groups by the end of this study (p = 0.13). There were also no significant differences in other secondary outcomes nor in the use of glucose-lowering medications and adverse events after follow-up. Conclusions: The multicomponent nutritional strategy did not demonstrate superiority over personalized dietary prescriptions in achieving glycemic control for participants with poorly managed T2D. In this sense, both nutritional interventions could be used in clinical practice to improve HbA1c levels, considering the profile and preferences of individuals.

Wavelet Phase Coherence Analysis of Oxyhemoglobin and DeoxyHemoglobin Oscillations to Investigate the Relationship Between Cups of Cupping Therapy.

Research has not demonstrated whether multiple cups of negative pressure cupping therapy would induce interactions of hemodynamic responses between different areas. A multichannel near-infrared spectroscopy (NIRS) was used to assess oxyhemoglobin and deoxyhemoglobin oscillations in response to cupping therapy. Wavelet transform and wavelet phase (WPC) coherence were used to quantify NIRS signals. Three levels of negative pressure (-75, -225, and -300 mmHg) were applied to the gastrocnemius in 12 healthy adults. Oxyhemoglobin coherence between the two inside-cup areas was higher at -75 mmHg compared to -300 mmHg in both metabolic (WPC = 0.80 ± 0.11 vs. 0.73 ± 0.13) and neurogenic (WPC = 0.70 ± 0.11 vs. 0.60 ± 0.17) controls. Deoxyhemoglobin coherence was also higher at -75 mmHg compared to -300 mmHg in both metabolic (WPC = 0.78 ± 0.11 vs. 0.66 ± 0.14) and neurogenic (WPC = 0.67 ± 0.11 vs. 0.58 ± 0.13) controls. Our study provides first evidence on the interaction of hemodynamic responses between the two cups of cupping therapy using WPC analysis of NIRS signals.

Clinical and Microbiological Periodontal Biofilm Evaluation of Patients with Type I Diabetes

Background/Objectives: The purpose of this study was to assess the microbial composition and density of subgingival plaque samples for periodontal pathogens while correlating the values with glycemic control levels via glycated hemoglobin (HbA1c), a type of hemoglobin that has chemically linked glucose, in type I diabetes individuals who will undergo complex oral rehabilitation through orthodontic treatment and implant surgery. Methods: A cohort of 42 adults with type I diabetes were included in this study. The subjects sustained a comprehensive periodontal clinical examination as well as microbiological assessments of their subgingival plaque samples through quantitative real-time PCR. The samples were collected from the two deepest pockets of each subject. Results: The highest number of periodontopathogenic bacteria was observed in the pockets of 5–7 mm. T. forsythia showed the highest prevalence (20.48%), with decreasing numbers as follows: T. denticola (13.31%), P. gingivalis (11.26%), A. actinomycetemcomitans (7%), and P. intermedia (4.9%). T. denticola and T. forsythia were significantly more commonly observed in individuals with elevated HbA1c serum levels. No correlation was observed between P. gingivalis, A. actinomycetemcomitans, P. intermedia presence, and the HbA1c value. Conclusions: Periodontopathogenic agents’ presence in subgingival biofilm samples varied in accordance with the pocket probing depth and metabolic control of the diabetic individuals. In our study, the appearance of these periodontopathogenic agents was linked to lowered metabolic control in patients with type I diabetes mellitus.

Integrating the new pharmacological standard of care with traditional nutritional interventions in non-dialysis CKD.

Chronic kidney disease (CKD) is widely recognized as a leading and growing contributor to global morbidity and mortality worldwide. Nutritional therapy is the basic treatment for metabolic control, and may contribute to nephroprotection; however, the absence of solid evidence on slowing CKD progression together with poor adherence to dietary prescription limit de facto itsefficacy and prevent itsmore widespread use. Sodium-glucose transport protein 2 inhibitors (SGLT2is) are now considered the new standard of care in CKD; in addition, novel potassium binders, glucagon-like peptide-1 receptor antagonists (GLP1-RAs) and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) show either direct (SGLT2i, GLP1-RA, nsMRA) or indirect (potassium binders that enable the optimal use of renin-angiotensin-aldosterone system inhibitors) nephroprotective effects. These drugs could potentially lead to a more permissive diet, thereby allowing the patient to reap the benefits of this approach. In particular, SGLT2is, and to a lesser extent also GLP1-RAs and nsMRAsin patients with diabetic kidney disease, can counterbalance hyperfiltration as well as the higher protein intake often recorded in obese patients; on the other hand, potassium binders can facilitate following plant-based diets, which are considered healthy because of the high content of essential micronutrients such as antioxidant vitamins, minerals, alkalies, and fibers. In this review paper, we discuss the current pharmacological paradigm shift that places a new, broader standard of care in light of its interaction with nutritional therapy in order to optimize the global approach to patients with CKDnotondialysis.

NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia.

RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.

Long-term safety of photobiomodulation exposure to beta cell line and rat islets in vitro and in vivo

This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm², from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM’s protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy.

Good metabolic control is associated with decreased circulating factor VIIa– antithrombin complexes in type 2 diabetes: a cross-sectional study

BackgroundDiabetes is associated with a prothrombotic state that contributes to cardiovascular (CV) events in type 2 diabetes (T2DM). Activated factor VII (FVIIa)– antithrombin (AT) complexes are indicative of tissue factor (TF) exposure and have been associated with thromboembolic risk in coronary artery disease. To our knowledge there have been no reports on FVIIa-AT complexes in T2DM, therefore we assessed factors that determine FVIIa-AT complexes in this disease and the impact of higher complexes on a prothrombotic state.MethodsIn 108 T2DM patients (mean age 63.8 years, 52.8% men, median HbA1c of 6.9 [interquartile range 6.1–8.2] %) and 83 age- and sex-matched non-diabetic subjects, we measured FVIIa-AT complexes. Metabolic control of T2DM involved fasting glucose, glycated hemoglobin (HbA1c), albumin/creatinine ratio (ACR), and lipid levels. To characterize a prothrombotic state, we determined thrombin generation parameters, fibrinolysis markers, and plasma fibrin clot properties.ResultsFVII-AT complexes in T2DM patients were similar to controls (73.6 [59.4–91.7] vs. 79.6 [59.2–97.1]pM, respectively, p = 0.30). The T2DM patients with FVIIa-AT in the top vs. the bottom quartile had a larger prevalence of active smoking and insulin use, along with higher fasting glucose (+ 36.4%), HbA1c (+ 27.4%), ACR (+ 72.8%), total cholesterol (+ 34.5%), and LDL-cholesterol (+ 80%). FVIIa-AT complexes showed no associations with in vitro thrombin generation potential, plasma fibrin clot properties, or fibrinolysis variables. On multivariable analysis HbA1c, ACR, and total cholesterol remained independently associated with FVIIa-AT complexes in T2DM.ConclusionsThis is the first study to show that in T2DM higher FVIIa-AT complexes are associated with markers of dyslipidemia and glycemia control, indicating that TF-induced coagulation activation could be suppressed by achieving treatment targets.Graphical abstract

Global Co-regulatory Cross Talk Between m6A and m5C RNA Methylation Systems Coordinate Cellular Responses and Brain Disease Pathways.

N6 adenosine and C5 cytosine modification of mRNAs, tRNAs and rRNAs are regulated by the behaviour of distinct sets of writer, reader and eraser effector proteins which are conventionally considered to function independently. Here, we provide evidence of global cross-regulatory and functional interaction between the m6A and m5C RNA methylation systems. We first show that m6A and m5C effector protein transcripts are subject to reciprocal base modification supporting the existence of co-regulatory post-transcriptional feedback loops. Using global mass spectrometry proteomic data generated after biological perturbation to identify proteins which change in abundance with effector proteins, we found novel co-regulatory cellular response relationships between m6A and m5C proteins such as between the m6A eraser, ALKBH5, and the m5C writer, NSUN4. Gene ontology analysis of co-regulated proteins indicated that m6A and m5C RNA cross-system control varies across cellular processes, e.g. proteasome and mitochondrial mechanisms, and post-translational modification processes such as SUMOylation and phosphorylation. We also uncovered novel relationships between effector protein networks including contributing to intellectual disability pathways. Finally, we provided in vitro confirmation of colocalisation between m6A-RNAs and the m5C reader protein, ALYREF, after synaptic NMDA activation. These findings have important implications for understanding control of RNA metabolism, cellular proteomic responses, and brain disease mechanisms.

Comprehensive analysis of glycoprotein profiles and their association with cardiovascular disease-related microRNAs in rheumatoid arthritis, metabolic disorders, and controls

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint pain and disability. The connection between RA and cardiovascular (CV) disease is still being studied. This research aims to explore the relationship between CV-related microRNAs, inflammation, and glycosylated proteins to understand RA’s inflammatory pathophysiology concerning CV disease. The study included 219 RA patients, 82 with metabolic disorders, and 64 controls. Clinical evaluations and blood samples were collected. Quantification of microRNAs (Let7a, 24, 96, 103, 125a, 125b, 132, 146, 191, 223, 425, 451) and measurement of glycoproteins (GlycA, GlycB, GlycF) using proton nuclear magnetic resonance (1 H-NMR) were performed. Multivariate linear models were applied. RA patients showed higher glycoprotein levels than those with metabolic disorders and controls. Significant associations between miRNAs 24, 451, Let7a and glycoprotein levels were found in RA patients, particularly in women. Glycoprotein levels were positively correlated with inflammatory markers, highlighting their role in indicating RA severity. This study highlights elevated glycoprotein levels in RA patients, indicating a severe inflammatory pattern. Moreover, glycoproteins were highly associated with CV-disease-related miRNAs, indicating that glycoproteins are involved in both inflammation and CV disease. Finally, the inflammatory profile of glycoproteins was validated as they were highly associated with inflammatory markers of RA.

Metabolic biomarkers of appetite control in Parkinson's disease patients with and without cognitive impairment

BackgroundAppetite dysregulation in Parkinson’s Disease (PD) appears to be linked to physical and cognitive deterioration. PD patients with and without cognitive impairment (CI) were compared to an age-matched control group to explore predictors of appetite control in fasting and post-prandial conditions. MethodsFifty-five patients were recruited and divided into three groups: twenty controls (age: 74y, BMI: 25.8kg/m2), nineteen PD patients without CI (72.5y, 25.1kg/m2) and sixteen PD patients with CI (74.3y, 24.0kg/m2). Self-reported appetite perception and circulating blood metabolic biomarkers were measured in fasting and over a three-hour post-prandial period. Biomarkers included glucose, insulin, tumour necrosis factor alpha (TNF-α), leptin, acyl-ghrelin, total ghrelin, peptide YY (PYY), glucagon like peptide 1 (GLP-1), insulin growth factor 1 (IGF-1), growth factor (GF) and triglycerides. Patients were then provided with a mixed meal to eat ad libitum with the aim to evaluate links between metabolic biomarkers and control of energy intake. ResultsPD patients with CI had a significant lower protein intake (7.4±2.5g, p=0.01) compared to controls (21.9±3.1g) and PD patients without CI (14.3±3.0g). Post-prandial plasma GLP-1 concentrations were associated with decreased hunger perception (B±SE, -5.3±2.4mm·hour-1, p=0.04). PYY concentrations were significantly associated with GLP-1 in fasting (r=0.40, p=0.005) and post-prandial (r=0.46, p<0.001) conditions. In a multivariate model, post-prandial PYY concentrations were a significant predictor of ad libitum energy intake in all subjects (B±SE, -87.5±34.9kcal, p=0.01) and in patients with PD (B±SE, -106.8±44.9kcal, p=0.04). ConclusionsPYY and GLP-1 appeared to influence appetite control in PD patients and their roles merit further investigation.

Personalized management of hepatic glycogen storage disorders: The role of continuous glucose monitoring.

Glycogen storage disorders (GSD), inherent disorders of carbohydrate metabolism, feature hypoglycemia as a hallmark. Normoglycemia and glucose monitoring are pivotal in disease management. Conventional glucometer-based monitoring may overlook hypoglycemic trends. This study assesses glycemic control in Asian Indian GSD children using continuous glucose monitoring (CGM) and its role in facilitating dietary adjustments. A pre-post study enrolled molecularly confirmed GSDI, GSDIII, GSDVI, and GSDIX patients for baseline dietary compliance and CGM-based glycemic status evaluation. Hypoglycemic patients were stratified into diet-compliant and diet-noncompliant groups. Noncompliant patients received dietary reinforcement; compliant individuals underwent dietary adjustments. Repeat CGM (rCGM) was performed 6 weeks to 6 months postadjustments. Clinical and metabolic parameters were re-evaluated at 6 months. Of the 20 patients assessed at baseline, 11 were diet compliant. Six among these exhibited hypoglycemia, prompting diet adjustments. Among nine noncompliant patients, eight experienced hypoglycemia and received diet reinforcement. rCGM in 10 patients (five GSDI, three GSDIII, and two GSDIXc) showed a significant reduction in hypoglycemia duration in all. An improvement in height and body mass index was observed in all GSDI and GSDIII patients. Triglyceride levels, raised at baseline in two GSDI and one GSDIII, showed a substantial decline in one GSDI patient. Hepatic transaminase levels decreased in both GSDIXc patients. Plasma lactate levels decreased in all GSDI patients. CGM is an efficacious adjunct in the personalized management of hepatic GSD patients, in the Asian Indian population. The study also underscores the need for long-term follow-up to determine the role of glycemic management in growth, general well-being, and metabolic control in the GSD subtypes.