Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects

Background: Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects.Subjects and Measurements: In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal (n = 68), pre-diabetes (n = 33), T2D less than (good control; n = 31), and greater than HbA1c 7% (poor control; n = 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression.Results: Serum HN concentrations were lower in T2D (p < 0.0001) and negatively correlated with age (p < 0.0001), HbA1c (p < 0.0001), glucose (p < 0.0001), triglycerides (p < 0.003), ALT (p < 0.004), and TG/HDL ratio (p < 0.001). Circulating HN levels were positively correlated to cholesterol (p < 0.017), LDL (p < 0.001), and HDL (p < 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls (p < 0.007). Circulating MOTS-c positively correlated with BMI (p < 0.035), total cholesterol (p < 0.0001), and LDL (p < 0.001) and negatively correlated with age (p < 0.002), HbA1c (p < 0.001), and glucose (p < 0.002). Serum ADP concentrations were lower in T2D (p < 0.002) and negatively correlated with HbA1c (p < 0.001), weight (p < 0.032) TG (p < 0.0001), and ALT (p < 0.0001); and positively correlated with HDL (p < 0.0001) and HN (p < 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c.Conclusion: The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide an additional evidence that mitochondrial dysfunction contributes to glycemic dysregulation and metabolic defects in T2D

Electrochemical measurement of antibody­‐antigen recognition biophysics: thermodynamics and kinetics of human chorionic gonadotropin (hCG) binding to redox-­tagged antibodies

The thermodynamics and kinetics of antigen binding under diffusive conditions to an electrode surface modified with ferrocene-tagged antibodies is studied within this work, and realised experimentally for the case of human chorionic gonadotropin (hGC) as the antigen with monoclonal anti-hCG antibodies immobilised on an electrode surface via a molecular wire platform. The formation of the antigen-antibody complex is monitored through the blocking of the ferrocene voltammetry, thereby enabling the fractional coverage of the electrode binding sites to be unravelled as a function of time. It is found that, at low antigen concentrations, a Frumkin adsorption isotherm fits the data, with repulsive interactions between bound antigens playing a significant rôle, with an affinity constant that is an order of magnitude larger than in the case of an untagged antibody, suggesting that the chemical hydrophobicity of the redox tag may encourage stronger binding. Comparison of the experimental temporal data with relevant diffusion-adsorption models under activation control allows for the extraction of the kinetic parameters; at zero coverage, the rate constants for adsorption and desorption are, respectively, larger and smaller than the untagged antibody. The kinetic study enables the confirmation that this type of platform may be utilised for rapid (15 min) and quantitative electroimmunoassay. This is validated through proof-of-concept analytical measurements, yielding a limit of detection around 25 mIU mL−1 (corresponding to 2.7 ng mL−1) – a value used clinically for urine hCG measurements corresponding to around four weeks of gestational age

Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects

Objective: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder associated with mitochondrial dysfunction and insulin resistance (IR). MOTS-c, a mitochondrial peptide, promotes insulin sensitivity (IS) through activating AKT and AMPK-dependent pathways. The current study was designed to examine the response of MOTS-c to lipids (intralipid) followed by insulin in PCOS and healthy subjects. Methods: All subjects underwent 5-hour intralipid/saline infusion with a hyperinsulinemic-euglycaemic clamp in the final 2 hours. Plasma samples were collected to measure circulating MOTS-c using a commercial ELISA kit. Subsequently, this was repeated following an eight-week exercise intervention. Results: Intralipid significantly increased plasma MOTS-c both in controls and PCOS subjects, whilst the insulin infusion blunted the intralipid-induced response seen for both lipids and MOT-c. Intralipid elevated plasma MOTS-c to 232±124% of basal in control (P < 0.01) and to 349 ± 206% of basal in PCOS (P < 0.001) subjects. Administration of insulin suppressed intralipid-induced MOTS-c from 232 ± 124% to 165 ± 97% (NS) in control and from 349 ± 206% to 183 ± 177% (P < 0.05) in PCOS subjects, respectively. Following exercise, intralipid elevated plasma MOTS-c to 305 ± 153% of basal in control (P < 0.01) and to 215 ± 103% of basal in PCOS (P < 0.01) subjects; insulin suppressed intralipid-induced MOTS-c only in controls.ConclusionsIn conclusion, this is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human. Further, eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels in healthy controls and in women with PCOS

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women

© Copyright © 2020 Ramanjaneya, Bensila, Bettahi, Jerobin, Samra, Aye, Alkasem, Siveen, Sathyapalan, Skarulis, Atkin and Abou-Samra. Background: The fibroblast growth factors (FGF) 19 subfamily, also referred to as endocrine FGFs, includes FGF19, FGF21, and FGF23 are metabolic hormones involved in the regulation of glucose and lipid metabolism. Fetuin-A is a hepatokine involved in the regulation of beta-cell function and insulin resistance. Endocrine FGFs and fetuin-A are dysregulated in metabolic disorders including obesity, type 2 diabetes, non-alcoholic fatty liver disease and polycystic ovary syndrome (PCOS). Our study was designed to examine the response of endocrine FGFs and fetuin-A to an acute intralipid, insulin infusion and exercise in PCOS and healthy women. Subjects and Measurements: Ten healthy and 11 PCOS subjects underwent 5-h saline infusions with a hyperinsulinemic-euglycemic clamp (HIEC) performed during the final 2 h. One week later, intralipid infusions were undertaken with a HIEC performed during the final 2 h. After an 8 week of exercise intervention the saline, intralipid, and HIEC were repeated. Plasma levels of endocrine FGFs and fetuin-A were measured. Results: Baseline fetuin-A was higher in PCOS women but FGF19, FGF21, and FGF23 did not differ and were unaffected by exercise. Insulin administration elevated FGF21 in control and PCOS, suppressed FGF19 in controls, and had no effects on FGF23 and fetuin-A. Intralipid infusion suppressed FGF19 and increased FGF21. Insulin with intralipid synergistically increased FGF21 and did not have effects on lipid-mediated suppression of FGF19 in both groups. Conclusion: Our study provides evidence for insulin and lipid regulation of endocrine FGFs in healthy and PCOS women, suggesting that FGF family members play a role in lipid and glucose metabolism. Clinical Trial Registration: www.isrctn.org, Identifier: ISRCTN42448814

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes.

OBJECTIVE: The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS: This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA(1c) = 7-11%) or previously on basal insulin ± OAD(s) (HbA(1c) = 7-10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA(1c) reduction after 26 weeks. RESULTS: After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex - IGlar OD]: 0.04% points [-0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS: The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety

Effect of Moderate Aerobic Exercise on Complement Activation Pathways in Polycystic Ovary Syndrome Women

Background: The complement system is pivotal in host defense mechanisms, protecting against pathogenic infection by regulating inflammation and cell immunity. Complement-related protein activation occurs through three distinct pathways: classical, alternative, and lectin-dependent pathways, which are regulated by cascades of multiple proteins. Complement activation is recognized in polycystic ovary syndrome (PCOS) to be associated with obesity and insulin sensitivity. Exercise reduces insulin resistance and may help reduce obesity, and therefore, this study was undertaken to determine the effect of exercise on the activation of complement-related proteins in PCOS and control women. Subjects and Measurements: In this study, 10 controls and 11 PCOS subjects who were age- and weight-matched underwent an 8-week supervised exercise program at 60% maximal oxygen consumption. Weight was unchanged though insulin sensitivity was increased in PCOS subjects and controls. Fasting baseline and post-exercise samples were collected and 14 complement-related proteins belonging to classical, alternative, and lectin-dependent pathways were measured. Results: Baseline levels of complement C4b and complement C3b/iC3b were higher in PCOS (P < 0.05) compared with controls. Exercise reduced complement C1q (P < 0.05), C3 (P < 0.001), C4 (P < 0.01), factor B (P < 0.01), factor H (P < 0.01), and properdin (P < 0.05) in controls, but not in PCOS women. Conclusion: Exercise induced complement changes in controls that were not seen in PCOS subjects, suggesting that these pathways remain dysregulated even in the presence of improved insulin sensitivity and not improved by moderate aerobic exercise. Clinical Trial Registration: ISRCTN registry, ISRCTN42448814