ResearchPad - diabetic-endocrinology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Less physical activity and more varied and disrupted sleep is associated with a less favorable metabolic profile in adolescents]]> https://www.researchpad.co/article/elastic_article_14699 Sleep and physical activity are modifiable behaviors that play an important role in preventing overweight, obesity, and metabolic health problems. Studies of the association between concurrent objective measures of sleep, physical activity, and metabolic risk factors among adolescents are limited.ObjectiveThe aim of the study was to examine the association between metabolic risk factors and objectively measured school day physical activity and sleep duration, quality, onset, and variability in adolescents.Materials and methodsWe measured one school week of free-living sleep and physical activity with wrist actigraphy in 252 adolescents (146 girls), aged 15.8±0.3 years. Metabolic risk factors included body mass index, waist circumference, total body and trunk fat percentage, resting blood pressure, and fasting glucose and insulin levels. Multiple linear regression adjusted for sex, parental education, and day length was used to assess associations between metabolic risk factors and sleep and activity parameters.ResultsOn average, participants went to bed at 00:22±0.88 hours and slept 6.2±0.7 hours/night, with 0.83±0.36 hours of awakenings/night. However, night-to-night variability in sleep duration was considerable (mean ± interquartile range) 0.75±0.55 hours) and bedtime (0.64±0.53 hours) respectively. Neither average sleep duration nor mean bedtime was associated with any metabolic risk factors. However, greater night-to-night variability in sleep duration and bedtime was associated with higher total body and trunk fat percentage, and less physical activity was associated with higher trunk fat percentage and insulin levels.ConclusionGreater nightly variation in sleep duration and in bedtime and less physical activity were associated with a less favorable metabolic profile in adolescents. These findings support the idea that, along with an adequate amount of physical activity, a regular sleep schedule is important for the metabolic health of adolescents. ]]> <![CDATA[Ethnic disparities in initiation and intensification of diabetes treatment in adults with type 2 diabetes in the UK, 1990–2017: A cohort study]]> https://www.researchpad.co/article/elastic_article_14688 In the UK, ethnic minority populations, particularly of South Asian and black African/Caribbean descent, have a higher risk of type 2 diabetes mellitus (T2DM) and related adverse outcomes, such as cardiovascular disease, than the white population.Timely and appropriate diabetes treatment can substantially reduce risk of adverse outcomes associated with T2DM.We sought to quantify ethnic differences in time to initiation and intensification of diabetes treatment among individuals newly diagnosed with T2DM to assess whether these clinically modifiable factors may contribute to ethnic differences in outcomes.What did the researchers do and find?We used routinely recorded data from general practices across the UK to identify people newly diagnosed with T2DM and compared how long it took to initiate and intensify diabetes treatment, comparing people of white, South Asian, and black ethnicity.We found that South Asian and black groups initiated diabetes treatment more quickly than white groups but were slower to intensify to second- and third-line treatment regimes.What do these findings mean?Although time to initial treatment of type 2 diabetes was appropriate, ethnic disparities in subsequent longer-term treatment may contribute to the worse outcomes seen in ethnic minority populations in the UK.Interventions to improve timely and appropriate intensification of diabetes treatment are key to reducing disparities in the downstream adverse outcomes of T2DM. ]]> <![CDATA[Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus]]> https://www.researchpad.co/article/elastic_article_14643 Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM).Materials and methodsWe have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1–2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum.ResultsAfter adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567–6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = −5.478, 95% CI: -8.315 to −2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = −6.319, 95% CI: −9.466 to −3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes.ConclusionsThis study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results. ]]> <![CDATA[LoAdaBoost: Loss-based AdaBoost federated machine learning with reduced computational complexity on IID and non-IID intensive care data]]> https://www.researchpad.co/article/Na533cb35-b26a-447b-bd62-8e125a165db4

Intensive care data are valuable for improvement of health care, policy making and many other purposes. Vast amount of such data are stored in different locations, on many different devices and in different data silos. Sharing data among different sources is a big challenge due to regulatory, operational and security reasons. One potential solution is federated machine learning, which is a method that sends machine learning algorithms simultaneously to all data sources, trains models in each source and aggregates the learned models. This strategy allows utilization of valuable data without moving them. One challenge in applying federated machine learning is the possibly different distributions of data from diverse sources. To tackle this problem, we proposed an adaptive boosting method named LoAdaBoost that increases the efficiency of federated machine learning. Using intensive care unit data from hospitals, we investigated the performance of learning in IID and non-IID data distribution scenarios, and showed that the proposed LoAdaBoost method achieved higher predictive accuracy with lower computational complexity than the baseline method.

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<![CDATA[Readiness to prescribe: Using educational design to untie the Gordian Knot]]> https://www.researchpad.co/article/Nd54ed6a5-cf2b-4df7-b723-1be3eaed6fb5

Introduction

Junior residents routinely prescribe medications for hospitalised patients with only arms-length supervision, which compromises patient safety. A cardinal example is insulin prescribing, which is commonplace, routinely delegated to very junior doctors, difficult, potentially very dangerous, and getting no better. Our aim was to operationalise the concept of ‘readiness to prescribe’ by validating an instrument to quality-improve residents’ workplace prescribing education.

Methods

Guided by theories of behaviour change, implementation, and error, and by empirical evidence, we developed and refined a mixed-methods 24-item evaluation instrument, and analysed numerical responses from Foundation Trainees (junior residents) in Northern Ireland, UK using principal axis factoring, and conducted a framework analysis of participants’ free-text responses.

Results

255 trainees participated, 54% women and 46% men, 80% of whom were in the second foundation year. The analysis converged on a 4-factor solution explaining 57% of the variance. Participants rated their capability to prescribe higher (79%) than their capability to learn to prescribe (69%; p<0.001) and rated the support to their prescribing education lower still (43%; p<0.001). The findings were similar in men and women, first and second year trainees, and in different hospitals. Free text responses described an unreflective type of learning from experience in which participants tended to 'get by' when faced with complex problems.

Discussion

Operationalising readiness to prescribe as a duality, comprising residents’ capability and the fitness of their educational environments, demonstrated room for improvement in both. We offer the instrument to help clinical educators improve the two in tandem.

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<![CDATA[Lower plasma insulin levels during overnight closed-loop in school children with type 1 diabetes: Potential advantage? A randomized cross-over trial]]> https://www.researchpad.co/article/5c8c197ad5eed0c484b4d740

Background

Studies have shown that overnight closed-loop insulin delivery can improve glucose control and reduce the risk of hypoglycemia and hence may improve metabolic outcomes and reduce burden for children with type 1 diabetes and their families. However, research so far has not reported insulin levels while comparing closed-loop to open-loop insulin delivery in children. Therefore, in this study we obtained glucose levels as well as plasma insulin levels in children with type 1 diabetes to evaluate the efficacy of a model—based closed-loop algorithm compared to an open-loop administration.

Methods

Fifteen children with type 1 diabetes, 6–12 years, participated in this open-label single center study. We used a randomized cross over design in which we compared overnight closed-loop insulin delivery with sensor augmented pump therapy for two nights in both the hospital and at home (i.e., 1 night in-patient stay and at home per treatment condition). Only during the in-patient stay, hourly plasma insulin and blood glucose levels were assessed and are reported in this paper.

Results

Results of paired sample t-tests revealed that although plasma insulin levels were significantly lower during the closed-loop than in the open-loop (Mean difference 36.51 pmol/l; t(13) = 2.13, p = .03, effect size d = 0.57), blood glucose levels did not vary between conditions (mean difference 0.76 mmol/l; t(13) = 1.24, p = .12, d = 0.37). The administered dose of insulin was significantly lower during the closed-loop compared with the open-loop (mean difference 0.10 UI; t(12) = 2.45, p = .02, d = 0.68).

Conclusions

Lower insulin doses were delivered in the closed-loop, resulting in lower plasma insulin levels, whereby glucose levels were not affected negatively. This suggests that the closed-loop administration is better targeted and hence could be more effective.

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<![CDATA[Comparison of triglyceride glucose index, and related parameters to predict insulin resistance in Korean adults: An analysis of the 2007-2010 Korean National Health and Nutrition Examination Survey]]> https://www.researchpad.co/article/5c990272d5eed0c484b97e62

The triglyceride glucose (TyG) index, a product of triglyceride and fasting glucose, is a reliable marker for insulin resistance (IR). Obesity is also known to be closely related with IR. Recently, the efficiency of TyG-related markers that combine obesity markers with TyG index has been studied; however, earlier studies were limited in number and the results were inconsistent. Therefore, in this study, we investigated the efficiency of several combinations of TyG index and obesity indices, namely, body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR), in reflecting IR. Data were obtained from the Korean National Health and Nutrition Examination Survey from 2007–2010. A total of 11,149 subjects (4,777 men and 6,372 women) were included. IR was defined as the homeostasis model assessment for IR (HOMA-IR) of above the 75th percentile for each gender. Logistic regression analysis was performed after adjusting for confounding factors, to compare and identify the associations of the 4 parameters (TyG index, TyG-BMI, TyG-WC, and TyG-WHtR) with IR. For each parameter, odds ratios (OR) and 95% confidence intervals (CIs) of quartiles 2–4 were calculated and compared with quartile 1 as a reference. A receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of each parameter to predict IR. The adjusted ORs of quartile 4 in comparison with quartile 1 (95% CIs) for IR were 7.60 (6.52–8.87) for TyG index, 12.82 (10.89–15.10) for TyG-BMI, 16.29 (13.70–19.38) for TyG-WC, and 14.86 (12.53–17.62) for TyG-WHtR. The areas under the ROC curve for each parameter were 0.690 for TyG index, 0.748 for TyG-BMI, 0.731 for TyG-WC, and 0.733 for TyG-WHtR. In conclusion, TyG-BMI was found to be superior to other parameters for IR prediction. We propose TyG-BMI as an alternative marker for assessing IR in clinical settings.

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<![CDATA[Brief communication: β-cell function influences dopamine receptor availability]]> https://www.researchpad.co/article/5c8c1952d5eed0c484b4d3f2

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a β-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for β-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity.

Clinical Trial Registration Number: NCT00802204

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<![CDATA[Utilization patterns of insulin for patients with type 2 diabetes from national health insurance claims data in South Korea]]> https://www.researchpad.co/article/5c89775bd5eed0c4847d2ad6

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires long-term therapy and regular check-ups to prevent complications. In this study, insurance claim data from the National Health Insurance Service (NHIS) of Korea were used to investigate insulin use in T2DM patients according to the economic status of patients and their access to primary physicians, operationally defined as the frequently used medical care providers at the time of T2DM diagnosis. A total of 91,810 participants were included from the NHIS claims database for the period between 2002 and 2013. The utilization pattern of insulin was set as the dependent variable and classified as one of the following: non-use of antidiabetic drugs, use of oral antidiabetic drugs only, or use of insulin with or without oral antidiabetic drugs. The main independent variables of interest were level of income and access to a frequently-visited physician. Multivariate Cox proportional hazards analysis was performed. Insulin was used by 9,281 patients during the study period, while use was 2.874 times more frequent in the Medical-aid group than in the highest premium group [hazard ratio (HR): 2.874, 95% confidence interval (CI): 2.588–3.192]. Insulin was also used ~50% more often in the patients managed by a frequently-visited physician than in those managed by other healthcare professionals (HR: 1.549, 95% CI: 1.434–1.624). The lag time to starting insulin was shorter when the patients had a low income and no frequently-visited physicians. Patients with a low level of income were more likely to use insulin and to have a shorter lag time from diagnosis to starting insulin. The likelihood of insulin being used was higher when the patients had a frequently-visited physician, particularly if they also had a low level of income. Therefore, the economic statuses of patients should be considered to ensure effective management of T2DM. Utilizing frequently-visited physicians might improve the management of T2DM, particularly for patients with a low income.

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<![CDATA[Use of non-insulin diabetes medicines after insulin initiation: A retrospective cohort study]]> https://www.researchpad.co/article/5c6dc9a1d5eed0c484529f41

Background

Clinical guidelines recommend that metformin be continued after insulin is initiated among patients with type 2 diabetes, yet little is known regarding how often metformin or other non-insulin diabetes medications are continued in this setting.

Methods

We conducted a retrospective cohort study to characterize rates and use patterns of six classes of non-insulin diabetes medications: biguanides (metformin), sulfonylureas, thiazolidinediones (TZDs), glucagon-like peptide 1 receptor agonists (GLP1 receptor agonists), dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors), and sodium-glucose co-transporter inhibitors (SGLT2 inhibitors), among patients with type 2 diabetes initiating insulin. We used the 2010–2015 MarketScan Commercial Claims and Encounters data examining 72,971 patients with type 2 diabetes aged 18–65 years old who initiated insulin and had filled a prescription for a non-insulin diabetes medication in the 90 days prior to insulin initiation. Our primary outcome was the proportion of patients refilling the various non-insulin diabetes medications during the first 90 days after insulin initiation. We also used time-to-event analysis to characterize the time to discontinuation of specific medication classes.

Results

Metformin was the most common non-insulin medication used prior to insulin initiation (N = 53,017, 72.7%), followed by sulfonylureas (N = 25,439, 34.9%) and DPP4 inhibitors (N = 8,540, 11.7%). More than four out of five patients (N = 65,902, 84.7%) refilled prescriptions for any non-insulin diabetes medications within 90 days after insulin initiation. Within that period, metformin remained the most common medication with the highest continuation rate of 84.6%, followed by SGLT2 inhibitors (81.9%) and TZDs (79.3%). Sulfonylureas were the least likely medications to be continued (73.6% continuation) though they remained the second most common medication class used after insulin initiation. The median time to discontinuation varied by therapeutic class from the longest time to discontinuation of 26.4 months among metformin users to the shortest (3.0 months) among SGLT2 inhibitor users.

Conclusion

While metformin was commonly continued among commercially insured adults starting insulin, rates of continuation of other non-insulin diabetes medications were also high. Further studies are needed to determine the comparative effectiveness and safety of continuing insulin secretagogues and newer diabetes medications after insulin initiation.

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<![CDATA[Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts]]> https://www.researchpad.co/article/5c70673cd5eed0c4847c6c7d

Objective

To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.

Research design and methods

Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.

Results

After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.

Conclusions

Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.

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<![CDATA[Consistency of compact and extended models of glucose-insulin homeostasis: The role of variable pancreatic reserve]]> https://www.researchpad.co/article/5c7067acd5eed0c4847c74a3

Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT’s of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT’s were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.

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<![CDATA[A pilot study of metabolic fitness effects of weight-supported walking in women with obesity]]> https://www.researchpad.co/article/5c76fdecd5eed0c484e5b0c0

Background

This is an exploratory pilot study of novel technology enabling people with mobility disability to walk with minimal effort, in the “sedentary range”. The study’s premise is that impairment of the leading physical activity of daily living, walking, is a major contributor to a dysmetabolic state driving many prevalent “civilization diseases” associated with insulin resistance.

Methods

We explore within-subject changes in standard oral glucose tolerance (OGT) tests including metabotropic molecules after 22 twice-weekly, 30-minute bouts of weight-supported light-moderate physical activity in 16 non-diabetic obese, otherwise healthy, reproductive-age, volunteer women walking on an “anti-gravity” lower-body positive pressure (LBPP) treadmill.

Results

Subjects had reference base-line fasting plasma glucose and triglycerides (TG) but 2-hr OGT insulin levels of 467 ± 276 pmol • liter-1 (mean± S.D.) indicating nascent insulin resistance, compared to post-study 308 ± 179 (p = 0.002). Fasting TG decreased from 0.80 ± 0.30 mmol • liter-1 to 0.71 ± 0.25 (p = 0.03). Concomitantly plasma total ghrelin decreased from 69.6 ± 41.6 pmol • liter-1 to 56.0 ± 41.3 (p = 0.008). There were no statistically significant changes in body weight or any correlations between weight change and cardiometabolic markers. However, there were robust positive correlations between changes among different classes of peptides including C-reactive protein–Interleukin 6, leptin–adiponectin, β-endorphin–oxytocin and orexin A (r 2 = 0.48–0.88).

Conclusion

We conclude that brief, low-dose physical activity, walking on an anti-gravity LBPP treadmill may improve cardiometabolic risk, exhibiting favorable changes in neuro-regulatory peptides without weight loss in people with problems walking.

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<![CDATA[Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury]]> https://www.researchpad.co/article/5c59feedd5eed0c4841357ce

Insulin provides important information to tissues about feeding behavior and energy status. Defective insulin signaling is associated with ageing, tissue dysfunction, and impaired wound healing. In the liver, insulin resistance leads to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms integrate insulin signals to coordinate an appropriate injury response or how they are affected by insulin resistance. In this study, we demonstrate that insulin resistance impairs local cellular crosstalk between the fibrotic stroma and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions promote epithelial repair and tissue remodeling. Using insulin-resistant mice deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between stromal niche cells and LPCs during chronic injury. We provide a detailed account of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2-IIIb) expression by the two cell compartments, and we describe an insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on the regulation of IRS2 and FGF7 within the fibrotic stroma and show—using a human coculture system—that IRS2 silencing shifts the equilibrium away from paracrine epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight into the contribution of insulin resistance to the pathogenesis of chronic liver disease and propose IRS2 as a positive regulator of communication between cell types and the transition between phases of stromal to epithelial repair.

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<![CDATA[Resilient hepatic mitochondrial function and lack of iNOS dependence in diet-induced insulin resistance]]> https://www.researchpad.co/article/5c61e8b8d5eed0c48496f037

Obesity-derived inflammation and metabolic dysfunction has been related to the activity of the inducible nitric oxide synthase (iNOS). To understand the interrelation between metabolism, obesity and NO., we evaluated the effects of obesity-induced NO. signaling on liver mitochondrial function. We used mouse strains containing mitochondrial nicotinamide transhydrogenase activity, while prior studies involved a spontaneous mutant of this enzyme, and are, therefore, more prone to oxidative imbalance. Wild-type and iNOS knockout mice were fed a high fat diet for 2, 4 or 8 weeks. iNOS knockout did not protect against diet-induced metabolic changes. However, the diet decreased fatty-acid oxidation capacity in liver mitochondria at 4 weeks in both wild-type and knockout groups; this was recovered at 8 weeks. Interestingly, other mitochondrial functional parameters were unchanged, despite significant modifications in insulin resistance in wild type and iNOS knockout animals. Overall, we found two surprising features of obesity-induced metabolic dysfunction: (i) iNOS does not have an essential role in obesity-induced insulin resistance under all experimental conditions and (ii) liver mitochondria are resilient to functional changes in obesity-induced metabolic dysfunction.

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<![CDATA[Prospective evaluation of a dynamic insulin infusion algorithm for non critically-ill diabetic patients: A before-after study]]> https://www.researchpad.co/article/5c58d61bd5eed0c48403163c

Introduction

Insulin infusion is recommended during management of diabetic patients in critical care units to rapidly achieve glycaemic stability and reduce the mortality. The application of an easy-to-use standardized protocol, compatible with the workload is preferred. Glycaemic target must quickly be reached, therefore static algorithms should be replaced by dynamic ones. The dynamic algorithm seems closer to the physiological situation and appreciates insulin sensitivity. However, the protocol must meet both safety and efficiency requirements. Indeed, apprehension from hypoglycaemia is the main deadlock with the dynamic algorithms, thus their application remains limited. In contrary to the critical care units, to date, no prospective study evaluated a dynamic algorithm of insulin infusion in non-critically ill patients.

Aim

This study primarily aimed to evaluate the efficacy of a dynamic algorithm of intravenous insulin therapy in non-critically-ill patients, and addressed its safety and feasibility in different departments of our university hospital.

Methods

A "before-after" study was conducted in five hospital departments (endocrinology and four “non-expert” units) comparing a dynamic algorithm (during the "after" period-P2) to the static protocol (the “before” period-P1). Static protocol is based on determining insulin infusion according to an instant blood glycaemia (BG) level at a given time. In the dynamic algorithm, insulin infusion rate is determined according to the rate of change of the BG (the previous and actual BG under a specific insulin infusion rate). Additionally, two distinct glycaemic targets were defined according to the patients’ profile: 100–180 mg/dl (5.5–10 mmol/l) for vigorous patients and 140–220 mg/dl (7.8–12.2 mmol/l) for frail ones. Different BG measurements for each patient were collected and recorded in a specific database (e-CRF) in order to analyse the rates of hypo- and hyperglycaemia. A satisfaction survey was also performed. A study approval was obtained from the institutional revision board before starting the study.

Results

Over 8 months, 72 and 66 patients during P1 and P2 were respectively included. The dynamic algorithm was more efficient, with reduced time to control hyperglycaemia (P1 vs P2:8.3 vs 5.3 hours; HR: 2.02 [1.27; 3.21]; p<0.01), increased the number of in-target BG measurements (P1 vs P2: 37.0% vs 41.8%; p<0.05), and reduced the glycaemic variability related to each patient (P1 vs P2, %CV: 40.9 vs 38.2;p<0.05, Index Correlation Class:0.30 vs 0.14; p<0.05). In patients after the first event of hypoglycemia after having started the infusion, new events were lower (P1 vs P2: 19.4 vs 11.4; p<0.001) thanks to an earlier reaction to hypoglycaemia (8.3% during P1 vs 44.3% during P2; p = 0.004). With the dynamic algorithm, the percentage of recurrence of mild hypoglycaemia was significantly lower in frail patients (20.5% vs 10.2%; p<0.001), and in patients managed in the non-expert units (18 vs 7.1%, p<0.001). The %CV was significantly improved in frail patients (36.9%). Mean BG measurements for each patient/day were 5.5±1.1 during P1 and 6.0±1.6 during P2 (p = 0.6). The threat from hypoglycaemia and the difficulty in using dynamic algorithm are barriers for nurses’ adherence.

Conclusions

This dynamic algorithm for non-critically-ill patients is more efficient and safe than the static protocol, and adapted for frail patients and non-expert units.

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<![CDATA[Effects of HIIT and MICT on cardiovascular risk factors in adults with overweight and/or obesity: A meta-analysis]]> https://www.researchpad.co/article/5c58d62bd5eed0c4840317ea

Objective

The purpose of this study was to evaluate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on cardiovascular disease (CVD) risk factors in adults with overweight and obesity.

Methods

Twenty-two articles were included by searching six databases, the total number of subjects was 620 in these articles. Outcomes were synthesised using a random-effects meta-analysis of the Standardized mean difference (SMD) in CVD risk factors.

Results

HIIT and MICT resulted in statistically significant reductions in Weight, BMI, fat%, total cholesterol(TC), and improvement in VO2max. Compared with MICT, subgroup of durations of HIIT training interval ≥2 min can significantly increase VO2max (SMD = 0.444, 95% CI:0.037~0.851,P = 0.032), subgroup of energy expenditure of HIIT equal to MICT can significantly increase VO2max (SMD = 0.399, 95% CI:0.106~0.692,P = 0.008).

Conclusions

HIIT appears to provide similar benefits to MICT for improving body composition, VO2maxand TC, but HIIT spent less time than MICT by 9.7 min on one session. HIIT is superior to MICT in improving cardiopulmonary fitness when durations of HIIT training interval ≥2 min or energy expenditure of HIIT same as MICT. PROSPERO ID: CRD42016045835.

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<![CDATA[An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z]]> https://www.researchpad.co/article/5c521814d5eed0c48479726d

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. The RNAi screening was utilized to identify genes that modify the intracellular accumulation of ATZ and a novel computational pipeline was developed to make high confidence predictions on repurposable drugs. This approach identified glibenclamide (GLB), a sulfonylurea drug that has been used broadly in clinical medicine as an oral hypoglycemic agent. Here we show that GLB promotes autophagic degradation of misfolded ATZ in mammalian cell line models of ATD. Furthermore, an analog of GLB reduces hepatic ATZ accumulation and hepatic fibrosis in a mouse model in vivo without affecting blood glucose or insulin levels. These results provide support for a drug discovery strategy using simple organisms as human disease models combined with genetic and computational screening methods. They also show that GLB and/or at least one of its analogs can be immediately tested to arrest the progression of human ATD liver disease.

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<![CDATA[Fluorescent labelling of membrane fatty acid transporter CD36 (SR-B2) in the extracellular loop]]> https://www.researchpad.co/article/5c521873d5eed0c484798546

Context

Upon palmitate oversupply, membrane fatty acid-transporter CD36 (SR-B2) permanently translocates from endosomal storage to the sarcolemma, inducing lipotoxicity. CD36 translocation results from endosomal alkalinisation elicited by palmitate-induced disattachment of the cytoplasmic V1-subcomplex from the membrane-integrated V0-subcomplex of vacuolar-type H+-ATPase.

Objective

Develop a CD36 fluorescent labeling technique as initial step towards live cell imaging.

Methods

Three human CD36 (hCD36) mutants were constructed via insertion of a tetracysteine motif at different positions within the extracellular domain. Constructs were lentivirally transduced for subsequent CD36 labeling with fluorescein-arsenical hairpin-binder (FlAsH). Cell imaging was combined with V0/V1 immunostaining and Western blotting.

Results

Transduction of hCD36-wildtype and mutants yielded corresponding proteins in HL-1 cardiomyocytes. Tetracysteine mutant-2 (hCD36-TC2) showed similar fatty acid uptake to wildtype. FlAsH staining revealed a speckled pattern reminiscent of endosomes. We found decreased V1 co-localization with CD36 upon high-palmitate culturing. Conversely, V0 consistently co-localized with CD36.

Conclusion

hCD36-TC2 is a possible candidate for application of biarsenical dyes in live imaging studies pending further investigation. Our data is compatible with V0/V1 disassembly in high-palmitate-treated cells.

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<![CDATA[Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes]]> https://www.researchpad.co/article/5c40f7a2d5eed0c4843864e8

Background

PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.

Objectives

To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.

Method

Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test.

Results

Among n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36–0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20–0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14–5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers.

Conclusion

Rare missense PPP1R3B variants may predispose to T2D.

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