Is autoimmunity or insulin resistance the primary driver of type 1 diabetes?

The final publication is available at Springer via http://dx.doi.org/10.1007/s11892-013-0407-7Diabetes is usually classified as autoimmune or metabolic but, as difficulties have arisen with the taxonomy of diabetes, it may help to forego the conventional classification for a more inclusive model. Thus, all diabetes can be ascribed to beta cell insufficiency-hyperglycemia occurs only when the insulin supply fails to meet demand. Humans enter the world with a reserve of beta cells, which is eroded variably by apoptosis over the course of a lifetime. For most, the loss is slow and inconsequential but, for others fast enough to be critical within a lifetime. The challenge now is to define the factors that vary the tempo of beta cell loss, because tempo, not type, seems likely to determine whether diabetes occurs at all, in adulthood or in childhood. Insulin resistance is generally believed to underpin T2D, but has been a feature of insulin-dependent diabetes as well for nearly 80 years, though largely ignored until immunotherapy trials to test the autoimmunity hypothesis persistently failed to bring patient benefit. It seems possible that insulin resistance accelerates beta cell loss generally, its impact modulated by an immune response (autoimmunity) to the beta-cell stress whose intensity varies with immunogenotype. If so, the target for prevention of T1D might more logically lie with insulin sensitivity than with immunoregulation

THE ACCELERATOR HYPOTHESIS – AN EVOLVING CONCEPT

Clinical trials designed to prevent type 1 diabetes (T1D) based on the autoimmunity paradigm have proved disappointing, and have not so far translated into patient benefit. Meanwhile, the incidence of T1D continues to rise. The accelerator hypothesis explores the role of weight gain in childhood diabetes, as both islet cell immunity and T1D are associated with BMI. Insulin resistance, which results largely from weight gain, increases insulin demand, and demand puts stress on beta cells, which accelerates their apoptotic loss. An immune response to the stress in those who are genetically predisposed (‘autoimmunity’) hastens the loss further, and may explain by default why autoimmunity is a feature of diabetes in the young. The accelerator hypothesis was proposed in 2001 and, like most hypothesis, has evolved over the years.Key words: Accelerator hypothesis, type 1 diabetes, clinical trial, insulin resistance,classification of diabetes, tempo in diabetes, hybrid diabete

Effectiveness of intervention on physical activity of children: systematic review and meta-analysis of controlled trials with objectively measured outcomes (EarlyBird 54).

addresses: Department of Endocrinology and Metabolism, Peninsula College of Medicine and Dentistry, Plymouth University Campus, Plymouth, UK. [email protected]: Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't; ReviewCopyright © 2012 by the BMJ Publishing Group Ltd. This articles was first published in: BMJ, 2012, Vol. 345, pp. e5888 -To determine whether, and to what extent, physical activity interventions affect the overall activity levels of children

Childhood obesity: Evidence for distinct early and late environmental determinants a 12-year longitudinal cohort study (EarlyBird 62)

Background/objective:The prevalence of childhood obesity continues to rise in most countries, but the exposures responsible remain unclear. The shape of the body mass index (BMI) distribution curve defines how a population responds, and can be described by its three parameters-skew (L), median (M) and variance (S). We used LMS analysis to explore differences in the BMI trajectories of contemporary UK children with those of 25 years ago, and to draw inferences on the exposures responsible.Subjects/methods:We applied Cole's LMS method to compare the BMI trajectories of 307 UK children (EarlyBird cohort) measured annually from 5-16 years (2000-2012) with those of the BMI data set used to construct the UK 1990 growth centiles, and used group-based trajectory modelling (GBTM) to establish whether categorical trajectories emerged.Results:Gender-specific birth weights were normally distributed and similar between both data sets. The skew and variance established by 5 years in the 1990 children remained stable during the remainder of their childhood, but the pattern was different for children 25 years on. The skew at 5 years among the EarlyBird children was greatly exaggerated, and involved selectively the offspring of obese parents, but returned to 1990 levels by puberty. As the skew diminished, so the variance in BMI rose sharply. The median BMI of the EarlyBird children differed little from that of 1990 before puberty, but diverged from it as the variance rose. GBTM uncovered four groups with distinct trajectories, which were related to parental obesity.Conclusions:There appear to be two distinct environmental interactions with body mass among contemporary children, the one operating selectively according to parental BMI during early childhood, the second more generally in puberty.Bright Future TrustBUPA FoundationPeninsula FoundationKirby Laing TrustEarlyBird Diabetes Trus

Exploring the Adolescent Fall in Physical Activity: A 10-yr Cohort Study (EarlyBird 41)

This is a non-final version of an article published in final form in Medicine & Science in Sports & Exercise Vol. 47 (10), pp. 2084–2092 (2015)INTRODUCTION: Contemporary adolescents are deemed inactive, especially girls, but whether for biological reasons associated with their maturation, changes in their behavior or because of environmental constraints, is uncertain. We examined the trends in physical activity (PA) in relation to both biological and environmental factors in an attempt to establish what drives activity patterns from childhood through adolescence. METHODS: Physical activity (7-d Actigraph accelerometry) was measured annually from 5 to 15 yr in a single cohort of some 300 UK children. Total PA (TPA; in-school and out-of-school separately and combined as whole day) and intensity-specific PA (sedentary, light, and moderate-and-vigorous [MVPA]) were analyzed. Biological age (years before/after measured peak height velocity) and pubertal stage (self-reported pubic hair development-Tanner staging) were also measured as was socioeconomic status (postcode-derived index of multiple deprivation [IMD]). RESULTS: Total PA was stable from 5 to 8 yr (trend P = 0.10) but fell progressively from 9 to 15 yr (by approximately 30% in girls and approximately 20% in boys, both P < 0.001; sex interaction, P < 0.01). Half of this fall was attributable to light intensity PA and only a quarter to MVPA. The decline in PA was related similarly to chronological and biological age, whereas pubertal stage explained the more rapid PA decline in girls (puberty-adjusted sex interaction, P = 0.51). Total PA fell to the same extent for in-school and out-of-school settings (both P < 0.001), and for lower and higher IMD areas (both P < 0.001). Total PA tracked moderately to strongly from childhood into adolescence (r = 0.58; P < 0.001). CONCLUSIONS: The adolescent decline in PA is consistent across different environmental settings, attributable to falls in light-intensity/habitual activity and influenced by puberty, suggesting that the inactivity of adolescence may, in part, be under biological control.Bright Future TrustKirby Laing FoundationPeninsula FoundationEarlyBird Diabetes TrustNational Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC

Objectively Measured Physical Activity and Its Association With Adiponectin and Other Novel Metabolic Markers: A longitudinal study in children (EarlyBird 38)

OBJECTIVE—Recent evidence suggests that, in children, traditional markers of metabolic disturbance are related only weakly to physical activity. We therefore sought to establish the corresponding relationships with newer metabolic markers

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9-16 years (EarlyBird 66)

The final publication is available at Springer via http://dx.doi.org/10.1007/s00125-015-3714-5There is another ORE record for this publication: http://hdl.handle.net/10871/34546AIMS/HYPOTHESIS: The aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: The peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2)' interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.Bright Future TrustKirby Laing FoundationPeninsula FoundationEarlyBird Diabetes TrustNational Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC

Proinsulin is stable at room temperature for 24 hours in EDTA:A clinical laboratory analysis (adAPT 3)

AIMS:Reference laboratories advise immediate separation and freezing of samples for the assay of proinsulin, which limit its practicability for smaller centres. Following the demonstration that insulin and C-peptide are stable in EDTA at room temperature for at least 24hours, we undertook simple stability studies to establish whether the same might apply to proinsulin. METHODS:Venous blood samples were drawn from six adult women, some fasting, some not, aliquoted and assayed immediately and after storage at either 4°C or ambient temperature for periods from 2h to 24h. RESULTS:There was no significant variation or difference with storage time or storage condition in either individual or group analysis. CONCLUSION:Proinsulin appears to be stable at room temperature in EDTA for at least 24h. Immediate separation and storage on ice of samples for proinsulin assay is not necessary, which will simplify sample transport, particularly for multicentre trials

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research