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  • Heterozygous deletion of Seipin in islet beta cells of male mice has an impact on insulin synthesis and secretion through reduced PPARγ expression.
    Diabetologia (IF 7.113) Pub Date : null
    Jianwei Xiong,Peng Sun,Ya Wang,Xu Hua,Wenyu Song,Yan Wang,Jie Wu,Wenfeng Yu,George Liu,Ling Chen

    AIMS/HYPOTHESIS Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. METHODS We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin-/-) and heterozygous (Seipin+/-) mice. RESULTS Male and female Seipin-/- mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin+/- mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin-/- and Seipin+/- mice but not in female Seipin-/- or Seipin+/- mice. Treatment of male Seipin+/- mice with rosiglitazone corrected the glucose intolerance. Male Seipin+/- mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin-/- mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin+/- mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. CONCLUSIONS/INTERPRETATION Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.

  • GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study
    Diabetologia (IF 7.113) Pub Date : 2019-12-03
    Helga Ellingsgaard, Eleonora Seelig, Katharina Timper, Michael Coslovsky, Line Soederlund, Mark P. Lyngbaek, Nicolai J. Wewer Albrechtsen, Arno Schmidt-Trucksäss, Henner Hanssen, Walter O. Frey, Kristian Karstoft, Bente K. Pedersen, Marianne Böni-Schnetzler, Marc Y. Donath

    IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans.

  • Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes.
    Diabetologia (IF 7.113) Pub Date : null
    Baoyan Fan,Chao Li,Alexandra Szalad,Lei Wang,Wanlong Pan,Ruilan Zhang,Michael Chopp,Zheng Gang Zhang,Xian Shuang Liu

    AIMS/HYPOTHESIS Diabetic peripheral neuropathy (DPN) is one of the major complications of diabetes, which contributes greatly to morbidity and mortality. There is currently no effective treatment for this disease. Exosomes are cell-derived nanovesicles and play an important role in intercellular communications. The present study investigated whether mesenchymal stromal cell (MSC)-derived exosomes improve neurological outcomes of DPN. METHODS Exosomes were isolated from the medium of cultured mouse MSCs by ultracentrifugation. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at the age of 20 weeks were used as DPN models. Heterozygous mice (db/m) of the same age were used as the control. MSC-exosomes were administered weekly via the tail vein for 8 weeks. Neurological function was evaluated by testing motor and sensory nerve conduction velocities, and thermal and mechanical sensitivity. Morphometric analysis was performed by myelin sheath staining and immunohistochemistry. Macrophage markers and circulating cytokines were measured by western blot and ELISA. MicroRNA (miRNA) array and bioinformatics analyses were performed to examine the exosomal miRNA profile and miRNA putative target genes involved in DPN. RESULTS Treatment of DPN with MSC-exosomes markedly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity in diabetic mice. Histopathological analysis showed that MSC-exosomes markedly augmented the density of FITC-dextran perfused blood vessels and increased the number of intraepidermal nerve fibres (IENFs), myelin thickness and axonal diameters of sciatic nerves. Western blot analysis revealed that MSC-exosome treatment decreased and increased M1 and M2 macrophage phenotype markers, respectively. Moreover, MSC-exosomes substantially suppressed proinflammatory cytokines. Bioinformatics analysis revealed that MSC-exosomes contained abundant miRNAs that target the Toll-like receptor (TLR)4/NF-κB signalling pathway. CONCLUSIONS/INTERPRETATION MSC-derived exosomes alleviate neurovascular dysfunction and improve functional recovery in mice with DPN by suppression of proinflammatory genes.

  • Diabetes digital app technology: benefits, challenges, and recommendations. A consensus report by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) Diabetes Technology Working Group
    Diabetologia (IF 7.113) Pub Date : 2019-12-05
    G. Alexander Fleming, John R. Petrie, Richard M. Bergenstal, Reinhard W. Holl, Anne L. Peters, Lutz Heinemann

    Abstract Digital health technology, especially digital and health applications (‘apps’), have been developing rapidly to help people manage their diabetes. Numerous health-related apps provided on smartphones and other wireless devices are available to support people with diabetes who need to adopt either lifestyle interventions or medication adjustments in response to glucose-monitoring data. However, regulations and guidelines have not caught up with the burgeoning field to standardise how mobile health apps are reviewed and monitored for patient safety and clinical validity. The available evidence on the safety and effectiveness of mobile health apps, especially for diabetes, remains limited. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have therefore conducted a joint review of the current landscape of available diabetes digital health technology (only stand-alone diabetes apps, as opposed to those that are integral to a regulated medical device, such as insulin pumps, continuous glucose monitoring systems, and automated insulin delivery systems) and practices of regulatory authorities and organisations. We found that, across the USA and Europe, mobile apps intended to manage health and wellness are largely unregulated unless they meet the definition of medical devices for therapeutic and/or diagnostic purposes. International organisations, including the International Medical Device Regulators Forum and WHO, have made strides in classifying different types of digital health technology and integrating digital health technology into the field of medical devices. As the diabetes digital health field continues to develop and become more fully integrated into everyday life, we wish to ensure that it is based on the best evidence for safety and efficacy. As a result, we bring to light several issues that the diabetes community, including regulatory authorities, policymakers, professional organisations, researchers, people with diabetes and healthcare professionals, needs to address to ensure that diabetes health technology can meet its full potential. These issues range from inadequate evidence on app accuracy and clinical validity to lack of training provision, poor interoperability and standardisation, and insufficient data security. We conclude with a series of recommended actions to resolve some of these shortcomings.

  • Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity
    Diabetologia (IF 7.113) Pub Date : 2019-12-03
    Masaya Oshima, Séverine Pechberty, Lara Bellini, Sven O. Göpel, Mélanie Campana, Claude Rouch, Julien Dairou, Cristina Cosentino, Federica Fantuzzi, Sanna Toivonen, Piero Marchetti, Christophe Magnan, Miriam Cnop, Hervé Le Stunff, Raphaël Scharfmann

    During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment.

  • Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes.
    Diabetologia (IF 7.113) Pub Date : null
    Laura A Claessens,Joris Wesselius,Menno van Lummel,Sandra Laban,Flip Mulder,Dick Mul,Tanja Nikolic,Henk-Jan Aanstoot,Bobby P C Koeleman,Bart O Roep

    AIMS/HYPOTHESIS Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study. METHODS Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively. RESULTS Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading. CONCLUSIONS/INTERPRETATION Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.

  • Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice.
    Diabetologia (IF 7.113) Pub Date : null
    Lisa M Nicholas,Mototsugu Nagao,Laura C Kusinski,Denise S Fernandez-Twinn,Lena Eliasson,Susan E Ozanne

    AIMS/HYPOTHESIS Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. METHODS Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. RESULTS Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05). CONCLUSIONS/INTERPRETATION Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.

  • Persistent poor glycaemic control in individuals with type 2 diabetes in developing countries: 12 years of real-world evidence of the International Diabetes Management Practices Study (IDMPS)
    Diabetologia (IF 7.113) Pub Date : 2020-01-04
    Pablo Aschner, Juan J. Gagliardino, Hasan Ilkova, Fernando Lavalle, Ambady Ramachandran, Jean Claude Mbanya, Marina Shestakova, Jean-Marc Chantelot, Juliana C. N. Chan

    Abstract Aims/hypothesis We evaluated the secular trend of glycaemic control in individuals with type 2 diabetes in developing countries, where data are limited. Methods The International Diabetes Management Practices Study provides real-world evidence of patient profiles and diabetes care practices in developing countries in seven cross-sectional waves (2005–2017). At each wave, each physician collected data from ten consecutive participants with type 2 diabetes during a 2 week period. The primary objective of this analysis was to evaluate trends of glycaemic control over time. Results A total of 66,088 individuals with type 2 diabetes were recruited by 6099 physicians from 49 countries. The proportion of participants with HbA1c <53 mmol/mol (<7%) decreased from 36% in wave 1 (2005) to 30.1% in wave 7 (2017) (p < 0.0001). Compared with wave 1, the adjusted ORs of attaining HbA1c ≤64 mmol/mol (≤8%) decreased significantly in waves 2, 5, 6 and 7 (p < 0.05). Over 80% of participants received oral glucose-lowering drugs, with declining use of sulfonylureas. Insulin use increased from 32.8% (wave 1) to 41.2% (wave 7) (p < 0.0001). The corresponding time to insulin initiation (mean ± SD) changed from 8.4 ± 6.9 in wave 1 to 8.3 ± 6.6 years in wave 7, while daily insulin dosage ranged from 0.39 ± 0.21 U/kg (wave 1) to 0.33 ± 0.19 U/kg (wave 7) for basal regimen and 0.70 ± 0.34 U/kg (wave 1) to 0.77 ± 0.33 (wave 7) U/kg for basal–bolus regimen. An increasing proportion of participants had ≥2 HbA1c measurements within 12 months of enrolment (from 61.8% to 92.9%), and the proportion of participants receiving diabetes education (mainly delivered by physicians) also increased from 59.0% to 78.3%. Conclusions In developing countries, glycaemic control in individuals with type 2 diabetes remained suboptimal over a 12 year period, indicating a need for system changes and better organisation of care to improve self-management and attainment of treatment goals.

  • Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway
    Diabetologia (IF 7.113) Pub Date : 2020-01-03
    Jun Shirakawa, Kazuki Tajima, Tomoko Okuyama, Mayu Kyohara, Yu Togashi, Dario F. De Jesus, Giorgio Basile, Tatsuya Kin, A. M. James Shapiro, Rohit N. Kulkarni, Yasuo Terauchi

    Sodium–glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice.

  • Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial
    Diabetologia (IF 7.113) Pub Date : 2020-01-02
    Rory J. McCrimmon, Andrei-Mircea Catarig, Juan P. Frias, Nanna L. Lausvig, Carel W. le Roux, Desirée Thielke, Ildiko Lingvay

    Abstract Aims/hypothesis Intra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning. Methods Adults (age ≥18 years) with type 2 diabetes, HbA1c 53–91 mmol/mol (7.0–10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min−1 [1.73 m]−2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint. Results A subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: –0.79 [95% CI −2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: −0.78 [−1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [−0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups. Conclusions/interpretation In individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage. Trial registration ClinicalTrials.gov NCT03136484. Funding This trial was supported by Novo Nordisk A/S, Denmark.

  • The changing face of paediatric diabetes
    Diabetologia (IF 7.113) Pub Date : 2020-01-02
    Amy S. Shah, Kristen J. Nadeau

    Abstract The purpose of this review is to provide an update on the changing face of paediatric type 1 diabetes and type 2 diabetes. Paediatric diabetes is on the rise, with extensive research dedicated to understanding its pathophysiology, comorbidities and complications. As obesity continues to increase among all youth, differentiating between type 1 diabetes and type 2 diabetes has become increasingly difficult but remains important for optimising treatment, anticipating complications and predicting disease risk. Novel treatments are emerging, with the ultimate goal being to achieve glycaemic control, limit weight gain, improve quality of life and reduce comorbidities. In this review, we focus on updates regarding the epidemiology, clinical presentation, comorbidities and complications of paediatric type 1 diabetes and type 2 diabetes and conclude with current and emerging treatments.

  • A nanobody-based nuclear imaging tracer targeting dipeptidyl peptidase 6 to determine the mass of human beta cell grafts in mice
    Diabetologia (IF 7.113) Pub Date : 2019-12-23
    Stéphane Demine, Rita Garcia Ribeiro, Julien Thevenet, Lorella Marselli, Piero Marchetti, François Pattou, Julie Kerr-Conte, Nick Devoogdt, Decio L. Eizirik

    Type 1 diabetes is characterised by a progressive decline in beta cell mass. This is also observed following implantation of pancreatic islet allografts, but there is no reliable information regarding the time course of beta cell loss. This is due to the limited availability of non-invasive pancreatic islet imaging techniques. We have previously described that dipeptidyl peptidase 6 (DPP6) is an alpha and beta cell-specific biomarker, and developed a camelid antibody (nanobody ‘4hD29’) against it. We demonstrated the possibility to detect DPP6-expressing cells by single-photon emission computed tomography (SPECT)/ computed tomography (CT), but the correlation between the number of cells grafted and the SPECT signal was not assessed. Here, we investigate whether the 4hD29 nanobody allows us to detect different amounts of human pancreatic islets implanted into immune-deficient mice. In addition, we also describe the adaptation of the probe for use with positron emission tomography (PET).

  • Incidence and relative risk of renal replacement therapy in people with and without diabetes between 2002 and 2016 in a German region
    Diabetologia (IF 7.113) Pub Date : 2019-12-21
    Maria Narres, Heiner Claessen, Tatjana Kvitkina, Michael Koch, Lars Christian Rump, Thomas Weinreich, Andrea Icks

    Data on trends of end-stage renal disease among people with diabetes are lacking. We analysed the incidence of end-stage renal disease, defined as renal replacement therapy, among people with and without diabetes, and the corresponding relative risk. Moreover, we investigated time trends for the period 2002–2016.

  • Age of obesity onset, cumulative obesity exposure over early adulthood and risk of type 2 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-12-20
    Juhua Luo, Allison Hodge, Michael Hendryx, Julie E. Byles

    Abstract Aims/hypothesis Obesity is a risk factor for type 2 diabetes, yet little is known about how timing and cumulative exposure of obesity are related to disease risk. The aim of this study was to examine the associations between BMI trajectories, age of onset of obesity and obese-years (a product of degree and duration of obesity) over early adulthood and subsequent risk of type 2 diabetes. Methods Women aged 18–23 years at baseline (n = 11,192) enrolled in the Australian Longitudinal Study on Women’s Health (ALSWH) in 1996 were followed up about every 3 years via surveys for up to 19 years. Self-reported weights were collected up to seven times. Incident type 2 diabetes was self-reported. A growth mixture model was used to identify distinct BMI trajectories over the early adult life course. Cox proportional hazards regression models were used to examine the associations between trajectories and risk of diabetes. Results One hundred and sixty-two (1.5%) women were newly diagnosed with type 2 diabetes during a mean of 16 years of follow-up. Six distinct BMI trajectories were identified, varying by different initial BMI and different slopes of increase. Initial BMI was positively associated with risk of diabetes. We also observed that age at onset of obesity was negatively associated with risk of diabetes (HR 0.87 [95% CI 0.79, 0.96] per 1 year increment), and number of obese-years was positively associated with diabetes (p for trend <0.0001). Conclusions/interpretation Our data revealed the importance of timing of obesity, and cumulative exposure to obesity in the development of type 2 diabetes in young women, suggesting that preventing or delaying the onset of obesity and reducing cumulative exposure to obesity may substantially lower the risk of developing diabetes.

  • 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
    Diabetologia (IF 7.113) Pub Date : 2019-12-19
    John B. Buse, Deborah J. Wexler, Apostolos Tsapas, Peter Rossing, Geltrude Mingrone, Chantal Mathieu, David A. D’Alessio, Melanie J. Davies

    The American Diabetes Association and the European Association for the Study of Diabetes have briefly updated their 2018 recommendations on management of hyperglycaemia, based on important research findings from large cardiovascular outcomes trials published in 2019. Important changes include: (1) the decision to treat high-risk individuals with a glucagon-like-peptide 1 (GLP-1) receptor agonist or sodium–glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse cardiovascular events (MACE), hospitalisation for heart failure (hHF), cardiovascular death or chronic kidney disease (CKD) progression should be considered independently of baseline HbA1c or individualised HbA1c target; (2) GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established cardiovascular disease (CVD) but with the presence of specific indicators of high risk; and (3) SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE and CVD death, as well as in patients with type 2 diabetes with CKD (eGFR 30 to ≤60 ml min−1 [1.73 m]−2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE and cardiovascular death.

  • Geospatial mapping and data linkage uncovers variability in outcomes of foot disease according to multiple deprivation: a population cohort study of people with diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-12-17
    Joanne E. Hurst, Ruth Barn, Lesley Gibson, Hamish Innes, Sicco A. Bus, Brian Kennon, David Wylie, James Woodburn

    Our aim was to investigate the geospatial distribution of diabetic foot ulceration (DFU), lower extremity amputation (LEA) and mortality rates in people with diabetes in small geographical areas with varying levels of multiple deprivation.

  • A comparison of obesity indices in relation to mortality in type 2 diabetes: the Fremantle Diabetes Study
    Diabetologia (IF 7.113) Pub Date : 2019-12-14
    Joel Tate, Matthew Knuiman, Wendy A. Davis, Timothy M. E. Davis, David G. Bruce

    This prospective association study aimed to compare the relationship between each of four obesity indices and mortality risk in people with type 2 diabetes.

  • Pregnant women with gestational diabetes and with well controlled glucose levels have decreased concentrations of individual fatty acids in maternal and cord serum
    Diabetologia (IF 7.113) Pub Date : 2019-12-12
    Henar Ortega-Senovilla, Ute Schaefer-Graf, Emilio Herrera

    Both arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA,22:6 n-3), long-chain polyunsaturated fatty acids (LCPUFA), are involved in fetal development and, based on their percentage compositions, appear to be specifically accumulated in fetal circulation in a proposed phenomenon known as biomagnification. Discrepancies exist in the literature concerning the effect of gestational diabetes mellitus (GDM) on circulating fatty acids. Our objective was to analyse individual fatty acid concentrations in a large cohort of maternal and cord paired serum samples from pregnant women with and without GDM.

  • Type 2 diabetes does not account for ethnic differences in exercise capacity or skeletal muscle function in older adults
    Diabetologia (IF 7.113) Pub Date : 2019-12-09
    Siana Jones, Therese Tillin, Suzanne Williams, Sophie V. Eastwood, Alun D. Hughes, Nishi Chaturvedi

    The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes.

  • Longitudinal changes in glucose metabolism in women with gestational diabetes, from late pregnancy to the postpartum period
    Diabetologia (IF 7.113) Pub Date : 2019-12-09
    Thaddeus P. Waters, Shin Y. Kim, Andrea J. Sharma, Pamela Schnellinger, Janet K. Bobo, Robert T. Woodruff, Lisa A. Cubbins, Mary Haghiac, Judi Minium, Larraine Presley, Honor Wolfe, Sylvie Hauguel-de Mouzon, William Adams, Patrick M. Catalano

    This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), insulin response and disposition index (DI) from late pregnancy (34–37 weeks gestation, T1), to early postpartum (1–5 days, T2) and late postpartum (6–12 weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in ISOGTT, insulin response and DI.

  • Allostasis and the origins of adult-onset diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-12-07
    R. David Leslie, Tanwi Vartak

    Physiological plasticity enables homeostasis to be maintained in biological systems, but when such allostasis fails, then disease can develop. In a new population-based study by Rolandsson et al ( https://doi.org/10.1007/s00125-019-05016-3), autoimmunity, defined by an immunogenotype, predicted adult-onset non-insulin requiring diabetes. Type 1 diabetes is no longer viewed as a disease confined to children, with a significant proportion, maybe the majority, presenting in adulthood. Such cases masquerade as type 2 diabetes and their identification has clinical utility. Nevertheless, in this study, autoimmunity had a limited effect on the overall risk of adults developing diabetes.

  • Predicting renal disease progression in a large contemporary cohort with type 1 diabetes mellitus
    Diabetologia (IF 7.113) Pub Date : 2019-12-05
    Marco Colombo, Stuart J. McGurnaghan, Samira Bell, Finlay MacKenzie, Alan W. Patrick, John R. Petrie, John A. McKnight, Sandra MacRury, Jamie Traynor, Wendy Metcalfe, Paul M. McKeigue, Helen M. Colhoun, on behalf of the Scottish Diabetes Research Network (SDRN) Type 1 Bioresource Investigators and the Scottish Renal Registry

    The aim of this study was to provide data from a contemporary population-representative cohort on rates and predictors of renal decline in type 1 diabetes.

  • Metabolomic profiles associated with subtypes of prediabetes among Mexican Americans in Starr County, Texas, USA
    Diabetologia (IF 7.113) Pub Date : 2019-12-04
    Goo Jun, David Aguilar, Charles Evans, Charles F. Burant, Craig L. Hanis

    To understand the complex metabolic changes that occur long before the diagnosis of type 2 diabetes, we investigated differences in metabolomic profiles in plasma between prediabetic and normoglycaemic individuals for subtypes of prediabetes defined by fasting glucose, 2 h glucose and HbA1c measures.

  • Lipid-associated metabolic signalling networks in pancreatic beta cell function
    Diabetologia (IF 7.113) Pub Date : 2019-08-19
    Marc Prentki, Barbara E. Corkey, S. R. Murthy Madiraju

    Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (KATP)-dependent Ca2+ signalling and KATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning ‘switch’, the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle.

  • Breast, cervical and colorectal cancer screening in adults with diabetes: a systematic review and meta-analysis
    Diabetologia (IF 7.113) Pub Date : 2019-10-24
    Dominika Bhatia, Iliana C. Lega, Wei Wu, Lorraine L. Lipscombe

    Individuals with diabetes are at increased risk of developing and dying from cancer. Evidence-based guidelines recommend universal screening for breast, cervical and colorectal cancer; however, evidence on the uptake of these tests in individuals with diabetes is mixed. We conducted a meta-analysis to quantify the association between diabetes and participation in breast, cervical and colorectal cancer screening.

  • Trends in cancer mortality among people with vs without diabetes in the USA, 1988–2015
    Diabetologia (IF 7.113) Pub Date : 2019-09-12
    Jessica L. Harding, Linda J. Andes, Edward W. Gregg, Yiling J. Cheng, Hannah K. Weir, Kai M. Bullard, Nilka Ríos Burrows, Giuseppina Imperatore

    Cancer-related death is higher among people with vs without diabetes. However, it is not known if this excess risk has changed over time or what types of cancer may be driving these changes.

  • Cognitive dysfunction in diabetes: how to implement emerging guidelines
    Diabetologia (IF 7.113) Pub Date : 2019-08-16
    Geert J. Biessels, Rachel A. Whitmer

    Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognised as an important comorbidity and complication of diabetes that affects an individual’s well-being and diabetes management, and is associated with diabetes treatment-related complications. Recent guidelines therefore recommend screening for cognitive impairment in older individuals with diabetes. In addition, these guidelines suggest that glucose-lowering treatment should be tailored in those diagnosed with cognitive impairment, to reduce the risk of hypoglycaemia and improve treatment adherence. This review gives an overview of cognitive dysfunction in people with diabetes, briefly describing the clinical features of different stages of cognitive dysfunction and their epidemiology. In particular, it addresses essential additional steps that need to be taken to fully implement the emerging guidelines on screening and management of cognitive dysfunction in diabetes into daily practice.

  • Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data
    Diabetologia (IF 7.113) Pub Date : 2019-11-27
    Fay Crawford, Donald J. Nicolson, Aparna E. Amanna, Angela Martin, Saket Gupta, Graham P. Leese, Robert Heggie, Francesca M. Chappell, Heather H. McIntosh

    Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data.

  • Functional cytochrome P450 1A enzymes are induced in mouse and human islets following pollutant exposure
    Diabetologia (IF 7.113) Pub Date : 2019-11-27
    Muna Ibrahim, Erin M. MacFarlane, Geronimo Matteo, Myriam P. Hoyeck, Kayleigh R. C. Rick, Salar Farokhi, Catherine M. Copley, Shannon O’Dwyer, Jennifer E. Bruin

    Exposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are involved in metabolising xenobiotics, could serve as a useful biomarker for direct exposure of islets to pollutants. Moreover, functional CYP enzymes in islets could also impact beta cell physiology. The aim of this study was to determine whether CYP1A enzymes are activated in islets following direct or systemic exposure to environmental pollutants.

  • Incidence and prevalence of type 2 diabetes by occupation: results from all Swedish employees
    Diabetologia (IF 7.113) Pub Date : 2019-09-17
    Sofia Carlsson, Tomas Andersson, Mats Talbäck, Maria Feychting

    The workplace is a potentially important arena for prevention of type 2 diabetes and the first step is to identify occupations where the disease is common and/or risk is high. Therefore, our aim was to analyse incidence and prevalence of type 2 diabetes across all occupational groups in Sweden.

  • miR-409-3p is reduced in plasma and islet immune infiltrates of NOD diabetic mice and is differentially expressed in people with type 1 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-10-28
    Giuliana Ventriglia, Francesca Mancarella, Guido Sebastiani, Dana P. Cook, Roberto Mallone, Chantal Mathieu, Conny Gysemans, Francesco Dotta

    MicroRNAs (miRNAs) are a novel class of potential biomarkers emerging in many diseases, including type 1 diabetes. Here, we aim to analyse a panel of circulating miRNAs in non-obese diabetic (NOD) mice and individuals with type 1 diabetes.

  • Association of moderate and vigorous physical activity with incidence of type 2 diabetes and subsequent mortality: 27 year follow-up of the Whitehall II study
    Diabetologia (IF 7.113) Pub Date : 2019-12-02
    Manasa S. Yerramalla, Aurore Fayosse, Aline Dugravot, Adam G. Tabak, Mika Kivimäki, Archana Singh-Manoux, Séverine Sabia

    This work examined the role of physical activity in the course of diabetes using data spanning nearly three decades. Our first aim was to examine the long-term association of moderate and vigorous physical activity with incidence of type 2 diabetes. Our second aim was to investigate the association of moderate-to-vigorous physical activity post-diabetes diagnosis with subsequent risk of all-cause and cardiovascular disease mortality.

  • Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance
    Diabetologia (IF 7.113) Pub Date : 2019-09-11
    Zhenwei Gong, Xinyi Zhang, Kai Su, Ruihua Jiang, Zhe Sun, Wei Chen, Erick Forno, Eric S. Goetzman, Jieru Wang, H. Henry Dong, Partha Dutta, Radhika Muzumdar

    Absent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1β and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis.

  • Induced pluripotent stem cell macrophages present antigen to proinsulin-specific T cell receptors from donor-matched islet-infiltrating T cells in type 1 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-09-12
    Kriti Joshi, Colleen Elso, Ali Motazedian, Tanya Labonne, Jacqueline V. Schiesser, Fergus Cameron, Stuart I. Mannering, Andrew G. Elefanty, Edouard G. Stanley

    Type 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4+ T cells from a deceased organ donor who had type 1 diabetes.

  • Mechanisms of hyperinsulinaemia in apparently healthy non-obese young adults: role of insulin secretion, clearance and action and associations with plasma amino acids
    Diabetologia (IF 7.113) Pub Date : 2019-09-06
    Steven Hamley, Danielle Kloosterman, Tamara Duthie, Chiara Dalla Man, Roberto Visentin, Shaun A. Mason, Teddy Ang, Ahrathy Selathurai, Gunveen Kaur, Maria G. Morales-Scholz, Kirsten F. Howlett, Greg M. Kowalski, Christopher S. Shaw, Clinton R. Bruce

    This study aimed to examine the metabolic health of young apparently healthy non-obese adults to better understand mechanisms of hyperinsulinaemia.

  • Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy
    Diabetologia (IF 7.113) Pub Date : 2019-08-08
    Cong Tao, Yajun Wang, Ying Zhao, Jianfei Pan, Yiping Fan, Xiaojuan Liang, Chunwei Cao, Jianguo Zhao, Michael J. Petris, Kui Li, Yanfang Wang

    ATPase copper transporting α (ATP7A), also known as Menkes disease protein, is a P-type ATPase that transports copper across cell membranes. The critical role of ATP7A-mediated copper homeostasis has been well recognised in various organs, such as the intestine, macrophages and the nervous system. However, the importance of adipocyte ATP7A-mediated copper homeostasis on fat metabolism is not well understood. Here, we sought to reveal the contribution of adipose ATP7A to whole-body fat metabolism in mice.

  • Short-term strength and balance training does not improve quality of life but improves functional status in individuals with diabetic peripheral neuropathy: a randomised controlled trial
    Diabetologia (IF 7.113) Pub Date : 2019-08-29
    Kavita Venkataraman, Bee Choo Tai, Eric Y. H. Khoo, Subramaniam Tavintharan, Kurumbian Chandran, Siew Wai Hwang, Melissa S. L. A. Phua, Hwee Lin Wee, Gerald C. H. Koh, E. Shyong Tai

    The aim of this study was to test the effectiveness of a structured strength and balance training intervention in improving health-related quality of life (HRQoL) and functional status in individuals with diabetic peripheral neuropathy (DPN).

  • Dietary inflammatory index and type 2 diabetes risk in a prospective cohort of 70,991 women followed for 20 years: the mediating role of BMI
    Diabetologia (IF 7.113) Pub Date : 2019-08-09
    Nasser Laouali, Francesca Romana Mancini, Mariem Hajji-Louati, Douae El Fatouhi, Beverley Balkau, Marie-Christine Boutron-Ruault, Fabrice Bonnet, Guy Fagherazzi

    Diet is one of the main lifestyle-related factors that can modulate the inflammatory process. Surprisingly the dietary inflammatory index (DII) has been little investigated in relation to type 2 diabetes, and the role of BMI in this relationship is not well established. We studied this association and the role of BMI in the inflammatory process in a large population-based observational study.

  • Echocardiography improves prediction of major adverse cardiovascular events in a population with type 1 diabetes and without known heart disease: the Thousand & 1 Study
    Diabetologia (IF 7.113) Pub Date : 2019-10-30
    Magnus T. Jensen, Peter Sogaard, Ida Gustafsson, Jan Bech, Thomas F. Hansen, Thomas Almdal, Simone Theilade, Tor Biering-Sørensen, Peter G. Jørgensen, Søren Galatius, Henrik U. Andersen, Peter Rossing

    Cardiovascular disease is the most common comorbidity in type 1 diabetes. However, current guidelines do not include routine assessment of myocardial function. We investigated whether echocardiography provides incremental prognostic information in individuals with type 1 diabetes without known heart disease.

  • Circulating metabolites in progression to islet autoimmunity and type 1 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-08-23
    Santosh Lamichhane, Esko Kemppainen, Kajetan Trošt, Heli Siljander, Heikki Hyöty, Jorma Ilonen, Jorma Toppari, Riitta Veijola, Tuulia Hyötyläinen, Mikael Knip, Matej Orešič

    Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

  • Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice
    Diabetologia (IF 7.113) Pub Date : 2019-08-13
    Laurits J. Holm, Martin Haupt-Jorgensen, Jano D. Giacobini, Jane P. Hasselby, Mesut Bilgin, Karsten Buschard

    Sphingolipid metabolism regulates beta cell biology and inflammation and is abnormal at the onset of type 1 diabetes. Fenofibrate, a regulator of sphingolipid metabolism, is known to prevent diabetes in NOD mice. Here, we aimed to investigate the effects of fenofibrate on the pancreatic lipidome, pancreas morphology, pancreatic sympathetic nerves and blood glucose homeostasis in NOD mice.

  • Associations of short stature and components of height with incidence of type 2 diabetes: mediating effects of cardiometabolic risk factors
    Diabetologia (IF 7.113) Pub Date : 2019-09-09
    Clemens Wittenbecher, Olga Kuxhaus, Heiner Boeing, Norbert Stefan, Matthias B. Schulze

    This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers.

  • Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-11-15
    Sophie R. Sayers, Rebecca L. Beavil, Nicholas H. F. Fine, Guo C. Huang, Pratik Choudhary, Kamila J. Pacholarz, Perdita E. Barran, Sam Butterworth, Charlotte E. Mills, J. Kennedy Cruickshank, Marta P. Silvestre, Sally D. Poppitt, Anne-Thea McGill, Gareth G. Lavery, David J. Hodson, Paul W. Caton

    Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes.

  • Potential impact of diabetes prevention on mortality and future burden of dementia and disability: a modelling study
    Diabetologia (IF 7.113) Pub Date : 2019-11-15
    Piotr Bandosz, Sara Ahmadi-Abhari, Maria Guzman-Castillo, Jonathan Pearson-Stuttard, Brendan Collins, Hannah Whittaker, Martin J. Shipley, Simon Capewell, Eric J. Brunner, Martin O’Flaherty

    Diabetes is associated with an increased risk of dementia. We estimated the potential impact of trends in diabetes prevalence upon mortality and the future burden of dementia and disability in England and Wales.

  • Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: the TEDDY study
    Diabetologia (IF 7.113) Pub Date : 2019-11-14
    Markus Mattila, Iris Erlund, Hye-Seung Lee, Sari Niinistö, Ulla Uusitalo, Carin Andrén Aronsson, Sandra Hummel, Hemang Parikh, Stephen S. Rich, William Hagopian, Jorma Toppari, Åke Lernmark, Anette G. Ziegler, Marian Rewers, Jeffrey P. Krischer, Jill M. Norris, Suvi M. Virtanen, for the TEDDY Study Group

    We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes.

  • A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence
    Diabetologia (IF 7.113) Pub Date : 2019-11-13
    Wei Perng, Brandy M. Ringham, Harry A. Smith, Gregory Michelotti, Katerina M. Kechris, Dana Dabelea

    This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence.

  • Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-11-13
    Hiroshi Nomoto, Lina Pei, Chiara Montemurro, Madeline Rosenberger, Allison Furterer, Giovanni Coppola, Brian Nadel, Matteo Pellegrini, Tatyana Gurlo, Peter C. Butler, Slavica Tudzarova

    The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway.

  • An artificial intelligence-based deep learning algorithm for the diagnosis of diabetic neuropathy using corneal confocal microscopy: a development and validation study
    Diabetologia (IF 7.113) Pub Date : 2019-11-12
    Bryan M. Williams, Davide Borroni, Rongjun Liu, Yitian Zhao, Jiong Zhang, Jonathan Lim, Baikai Ma, Vito Romano, Hong Qi, Maryam Ferdousi, Ioannis N. Petropoulos, Georgios Ponirakis, Stephen Kaye, Rayaz A. Malik, Uazman Alam, Yalin Zheng

    Corneal confocal microscopy is a rapid non-invasive ophthalmic imaging technique that identifies peripheral and central neurodegenerative disease. Quantification of corneal sub-basal nerve plexus morphology, however, requires either time-consuming manual annotation or a less-sensitive automated image analysis approach. We aimed to develop and validate an artificial intelligence-based, deep learning algorithm for the quantification of nerve fibre properties relevant to the diagnosis of diabetic neuropathy and to compare it with a validated automated analysis program, ACCMetrics.

  • Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality
    Diabetologia (IF 7.113) Pub Date : 2019-11-11
    Martijn C. G. J. Brouwers, Nynke Simons, Coen D. A. Stehouwer, Aaron Isaacs

    Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

  • Autoimmunity plays a role in the onset of diabetes after 40 years of age
    Diabetologia (IF 7.113) Pub Date : 2019-11-11
    Olov Rolandsson, Christiane S. Hampe, Stephen J. Sharp, Eva Ardanaz, Heiner Boeing, Guy Fagherazzi, Francesca Romana Mancini, Peter M. Nilsson, Kim Overvad, Maria-Dolores Chirlaque, Miren Dorronsoro, Marc J. Gunter, Rudolf Kaaks, Timothy J. Key, Kay-Tee Khaw, Vittorio Krogh, Tilman Kühn, Domenico Palli, Salvatore Panico, Carlotta Sacerdote, Maria-José Sánchez, Gianluca Severi, Annemieke M. W. Spijkerman, Rosario Tumino, Yvonne T. van der Schouw, Elio Riboli, Nita G. Forouhi, Claudia Langenberg, Nicholas J. Wareham

    Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort.

  • Characterising nitric oxide-mediated metabolic benefits of low-dose ultraviolet radiation in the mouse: a focus on brown adipose tissue
    Diabetologia (IF 7.113) Pub Date : 2019-11-11
    Gursimran K. Dhamrait, Kunjal Panchal, Naomi J. Fleury, Tamara N. Abel, Mathew K. Ancliffe, Rachael C. Crew, Kevin Croft, Bernadette O. Fernandez, Magdalena Minnion, Prue H. Hart, Robyn M. Lucas, Peter J. Mark, Martin Feelisch, Richard B. Weller, Vance Matthews, Shelley Gorman

    Exposure to sunlight has the potential to suppress metabolic dysfunction and obesity. We previously demonstrated that regular exposure to low-doses of ultraviolet radiation (UVR) reduced weight gain and signs of diabetes in male mice fed a high-fat diet, in part via release of nitric oxide from skin. Here, we explore further mechanistic pathways through which low-dose UVR exerts these beneficial effects.

  • Higher circulating omentin is associated with increased risk of primary cardiovascular events in individuals with diabetes
    Diabetologia (IF 7.113) Pub Date : 2019-11-09
    Corinna Niersmann, Maren Carstensen-Kirberg, Haifa Maalmi, Bernd Holleczek, Michael Roden, Hermann Brenner, Christian Herder, Ben Schöttker

    Higher concentrations of the adipokine omentin are associated with lower levels of cardiometabolic risk factors in experimental and cross-sectional studies, but with higher risk of type 2 diabetes and cardiovascular diseases in population-based cohort studies. However, it is unknown whether high omentin concentrations are associated with increased risk of cardiovascular events in people with established diabetes. Therefore, the present study investigated the association between serum omentin concentrations and the risk of cardiovascular events in individuals with diabetes.

  • Recruited fibroblasts reconstitute the peri-islet membrane: a longitudinal imaging study of human islet grafting and revascularisation
    Diabetologia (IF 7.113) Pub Date : 2019-11-07
    Julia Nilsson, Rabiah Fardoos, Lisbeth Hansen, Håkan Lövkvist, Kristian Pietras, Dan Holmberg, Anja Schmidt-Christensen

    Rapid and adequate islet revascularisation and restoration of the islet–extracellular matrix (ECM) interaction are significant factors influencing islet survival and function of the transplanted islets in individuals with type 1 diabetes. Because the ECM encapsulating the islets is degraded during islet isolation, understanding the process of revascularisation and engraftment after transplantation is essential and needs further investigation.

  • Positioning time in range in diabetes management
    Diabetologia (IF 7.113) Pub Date : 2019-11-07
    Andrew Advani

    Recent upswings in the use of continuous glucose monitoring (CGM) technologies have given people with diabetes and healthcare professionals unprecedented access to a range of new indicators of glucose control. Some of these metrics are useful research tools and others have been welcomed by patient groups for providing insights into the quality of glucose control not captured by conventional laboratory testing. Among the latter, time in range (TIR) is an intuitive metric that denotes the proportion of time that a person’s glucose level is within a desired target range (usually 3.9–10.0 mmol/l [3.5–7.8 mmol/l in pregnancy]). For individuals choosing to use CGM technology, TIR is now often part of the expected conversation between patient and healthcare professional, and consensus recommendations have recently been produced to facilitate the adoption of standardised TIR targets. At a regulatory level, emerging evidence linking TIR to risk of complications may see TIR being more widely accepted as a valid endpoint in future clinical trials. However, given the skewed distribution of possible glucose values outside of the target range, TIR (on its own) is a poor indicator of the frequency or severity of hypoglycaemia. Here, the state-of-the-art linking TIR with complications risk in diabetes and the inverse association between TIR and HbA1c are reviewed. Moreover, the importance of including the amount and severity of time below range (TBR) in any discussions around TIR and, by inference, time above range (TAR) is discussed. This review also summarises recent guidance in setting ‘time in ranges’ goals for individuals with diabetes who wish to make use of these metrics. For most people with type 1 or type 2 diabetes, a TIR >70%, a TBR <3.9 mmol/l of <4%, and a TBR <3.0 mmol/l of <1% are recommended targets, with less stringent targets for older or high-risk individuals and for those under 25 years of age. As always though, glycaemic targets should be individualised and rarely is that more applicable than in the personal use of CGM and the data it provides.

  • Extracellular vesicles in metabolic disease
    Diabetologia (IF 7.113) Pub Date : 2019-11-05
    Naveed Akbar, Valerio Azzimato, Robin P. Choudhury, Myriam Aouadi

    Extracellular vesicles (EVs) are submicron-sized lipid envelopes that are produced and released from a parent cell and can be taken up by a recipient cell. EVs are capable of mediating cellular signalling by carrying nucleic acids, proteins, lipids and cellular metabolites between cells and organs. Metabolic dysfunction is associated with changes in plasma concentrations of EVs as well as alterations in their EV cargo. Since EVs can act as messengers between parent and recipient cells, they could be involved in cell-to-cell and organ-to-organ communication in metabolic diseases. Recent literature has shown that EVs are produced by cells within metabolic tissues, such as adipose tissue, pancreas, muscle and liver. These vesicles have therefore been proposed as a novel intercellular communication mode in systemic metabolic regulation. In this review, we will describe and discuss the current literature that investigates the role of adipose-derived EVs in the regulation of obesity-associated metabolic disease. We will particularly focus on the EV-dependent communication between adipocytes, the vasculature and immune cells in type 2 diabetes.

  • Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation
    Diabetologia (IF 7.113) Pub Date : 2019-11-05
    Maurice B. Bizino, Ingrid M. Jazet, Paul de Heer, Huub J. van Eyk, Ilona A. Dekkers, Patrick C. N. Rensen, Elisabeth H. M. Paiman, Hildebrandus J. Lamb, Johannes W. Smit

    The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus.

  • Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans
    Diabetologia (IF 7.113) Pub Date : 2019-11-05
    Lingling Ding, Gijs H. Goossens, Yvonne Oligschlaeger, Tom Houben, Ellen E. Blaak, Ronit Shiri-Sverdlov

    Insulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic–euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans.

  • Association of genetic variants related to plasma fatty acids with type 2 diabetes mellitus and glycaemic traits: a Mendelian randomisation study
    Diabetologia (IF 7.113) Pub Date : 2019-11-05
    Shuai Yuan, Susanna C. Larsson

    Epidemiological data on the associations of circulating fatty acid levels with type 2 diabetes are inconsistent. We conducted a two-sample Mendelian randomisation study to explore the causal associations of plasma levels of ten fatty acids with type 2 diabetes and glycaemic traits.

  • Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study
    Diabetologia (IF 7.113) Pub Date : 2019-11-04
    Chia-Ing Li, Hui-Man Cheng, Chiu-Shong Liu, Chih-Hsueh Lin, Wen-Yuan Lin, Mu-Cyun Wang, Shing-Yu Yang, Tsai-Chung Li, Cheng-Chieh Lin

    Elevated glucose level is one of the risk factors for lower extremity amputation (LEA), but whether glycaemic variability confers independent risks of LEA remains to be elucidated. This study aimed to investigate the association between visit-to-visit glycaemic variability and minor and major LEA risks during 8 years of follow-up in type 2 diabetic individuals aged 50 years and older.

  • Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis
    Diabetologia (IF 7.113) Pub Date : 2019-11-01
    Domenico Tricò, Alessandro Mengozzi, Lorenzo Nesti, Mensud Hatunic, Rafael Gabriel Sanchez, Thomas Konrad, Katarina Lalić, Nebojša M. Lalić, Andrea Mari, Andrea Natali, for the EGIR-RISC Study Group

    Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or ‘lipokine’) to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans.

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