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Journal Cover Diabetologia
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1432-0428 - ISSN (Online) 0012-186X
   Published by Springer-Verlag Homepage  [2352 journals]
  • Up front
    • Pages: 2127 - 2128
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4444-7
      Issue No: Vol. 60, No. 11 (2017)
  • Vascular complications in diabetes: old messages, new thoughts
    • Authors: Josephine M. Forbes; Amelia K. Fotheringham
      Pages: 2129 - 2138
      Abstract: Abstract In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4360-x
      Issue No: Vol. 60, No. 11 (2017)
  • Understanding and preventing type 1 diabetes through the unique working
           model of TrialNet
    • Authors: Manuela Battaglia; Mark S. Anderson; Jane H. Buckner; Susan M. Geyer; Peter A. Gottlieb; Thomas W. H. Kay; Åke Lernmark; Sarah Muller; Alberto Pugliese; Bart O. Roep; Carla J. Greenbaum; Mark Peakman
      Pages: 2139 - 2147
      Abstract: Abstract Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4384-2
      Issue No: Vol. 60, No. 11 (2017)
  • Should we screen for type 2 diabetes among asymptomatic individuals'
    • Authors: David Simmons; Janice C. Zgibor
      Pages: 2148 - 2152
      Abstract: RCTs of whether screening asymptomatic individuals for undiagnosed diabetes results in reduced mortality or has other benefits have been suggestive, but inconclusive. In this issue of Diabetologia, two additional controlled studies (
      DOI s: 10.1007/s00125-017-4323-2 and 10.1007/s00125-017-4299-y) that investigated whether screening for type 2 diabetes in asymptomatic individuals is associated with a reduction in mortality are presented. Treating diabetes early, and identifying and treating impaired glucose tolerance, are of benefit, and economic modelling indicates such screening is cost-effective. Now that such screening is already underway in many countries, new data, along with the existing evidence, suggests opportunistic screening is the best way forward. More research is needed, however, on how best to screen and how to improve risk-factor control once dysglycaemia is detected.
      PubDate: 2017-11-01
      Issue No: Vol. 60, No. 11 (2017)
  • Does the evidence support population-wide screening for type 2
           diabetes' No
    • Authors: Jonathan E. Shaw
      Pages: 2153 - 2156
      Abstract: Large-scale, centrally-coordinated screening for undiagnosed type 2 diabetes is an attractive option to reduce the mortality and morbidity resulting from inadequately controlled diabetes. However, there is limited research examining the direct consequences of such screening programmes on outcomes such as cardiovascular disease and death. Two papers published in this edition of Diabetologia (
      DOI s: 10.1007/s00125-017-4323-2 and 10.1007/s00125-017-4299-y) examine data from one of the very few trials conducted in this area. Overall, there was little benefit that could be directly related to the screening programme. In part, this was due to the high levels of opportunistic screening in the control group. Thus, when there are high levels of opportunistic screening for type 2 diabetes, there remains no clear evidence of benefit of centrally-coordinated screening programmes that approach individuals outside usual healthcare settings.
      PubDate: 2017-11-01
      Issue No: Vol. 60, No. 11 (2017)
  • Closed-loop glucose control in young people with type 1 diabetes during
           and after unannounced physical activity: a randomised controlled crossover
    • Authors: Klemen Dovc; Maddalena Macedoni; Natasa Bratina; Dusanka Lepej; Revital Nimri; Eran Atlas; Ido Muller; Olga Kordonouri; Torben Biester; Thomas Danne; Moshe Phillip; Tadej Battelino
      Pages: 2157 - 2167
      Abstract: Aims/hypothesis Hypoglycaemia during and after exercise remains a challenge. The present study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes. Methods A randomised, two-arm, open-label, in-hospital, crossover clinical trial was performed at a single site in Slovenia. The order was randomly determined using an automated web-based programme with randomly permuted blocks of four. Allocation assignment was not masked. Children and adolescents with type 1 diabetes who were experienced insulin pump users were eligible for the trial. During four separate in-hospital visits, the participants performed two unannounced exercise protocols: moderate intensity (55% of \( \overset{\cdot }{V}{\mathrm{O}}_{2\max } \) ) and moderate intensity with integrated high-intensity sprints (55/80% of \( \overset{\cdot }{V}{\mathrm{O}}_{2\max } \) ), using the same study device either for closed-loop or open-loop insulin delivery. We investigated glycaemic control during the exercise period and the following night. The closed-loop insulin delivery was applied from 15:00 h on the day of the exercise to 13:00 h on the following day. Results Between 20 January and 16 June 2016, 20 eligible participants (9 female, mean age 14.2 ± 2.0 years, HbA1c 7.7 ± 0.6% [60.0 ± 6.6 mmol/mol]) were included in the trial and performed all trial-mandated activities. The median proportion of time spent in hypoglycaemia below 3.3 mmol/l was 0.00% for both treatment modalities (p = 0.7910). Use of the closed-loop insulin delivery system increased the proportion of time spent within the target glucose range of 3.9–10 mmol/l when compared with open-loop delivery: 84.1% (interquartile range 70.0–85.5) vs 68.7% (59.0–77.7), respectively (p = 0.0057), over the entire study period. This was achieved with significantly less insulin delivered via the closed-loop (p = 0.0123). Conclusions/interpretation Closed-loop insulin delivery was safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia. Trial registration NCT02657083 Funding University Medical Centre Ljubljana, Slovenian National Research Agency, and ISPAD Research Fellowship
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4395-z
      Issue No: Vol. 60, No. 11 (2017)
  • Screening for neonatal diabetes at day 5 of life using dried blood spot
           glucose measurement
    • Authors: Timothy J. McDonald; Rachel E. Besser; Mandy Perry; Tarig Babiker; Bridget A. Knight; Maggie H. Shepherd; Sian Ellard; Sarah E. Flanagan; Andrew T. Hattersley
      Pages: 2168 - 2173
      Abstract: Aims/hypothesis The majority of infants with neonatal diabetes mellitus present with severe ketoacidosis at a median of 6 weeks. The treatment is very challenging and can result in severe neurological sequelae or death. The genetic defects that cause neonatal diabetes are present from birth. We aimed to assess if neonatal diabetes could be diagnosed earlier by measuring glucose in a dried blood spot collected on day 5 of life. Methods In this retrospective case–control study we retrieved blood spot cards from 11 infants with genetically confirmed neonatal diabetes (median age of diagnosis 6 [range 2–112] days). For each case we also obtained one (n = 5) or two (n = 6) control blood spot cards collected on the same day. Glucose was measured on case and control blood spot cards. We established a normal range for random glucose at day 5 of life in 687 non-diabetic neonates. Results All 11 neonates with diabetes had hyperglycaemia present on day 5 of life, with blood glucose levels ranging from 10.2 mmol/l to >30 mmol/l (normal range 3.2–6.0 mmol/l). In six of these neonates the diagnosis of diabetes was made after screening at day 5, with the latest diagnosis made at 16 weeks. Conclusions/interpretation Neonatal diabetes can be detected on day 5 of life, preceding conventional diagnosis in most cases. Earlier diagnosis by systematic screening could lead to prompt genetic diagnosis and targeted treatment, thereby avoiding the most severe sequelae of hyperglycaemia in neonates.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4383-3
      Issue No: Vol. 60, No. 11 (2017)
  • Individualised variable-interval risk-based screening for
           sight-threatening diabetic retinopathy: the Liverpool Risk Calculation
    • Authors: Antonio Eleuteri; for the Individualised Screening for Diabetic Retinopathy (ISDR) Study Group; Anthony C. Fisher; Deborah M. Broadbent; Marta García-Fiñana; Christopher P. Cheyne; Amu Wang; Irene M. Stratton; Mark Gabbay; Daniel Seddon; Simon P. Harding
      Pages: 2174 - 2182
      Abstract: Aims/hypothesis Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice. Methods Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users. Results Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA1c, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%. Conclusions/interpretation The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4386-0
      Issue No: Vol. 60, No. 11 (2017)
  • Effect of population screening for type 2 diabetes and cardiovascular risk
           factors on mortality rate and cardiovascular events: a controlled trial
           among 1,912,392 Danish adults
    • Authors: Rebecca K. Simmons; Simon J. Griffin; Daniel R. Witte; Knut Borch-Johnsen; Torsten Lauritzen; Annelli Sandbæk
      Pages: 2183 - 2191
      Abstract: Aims/hypothesis Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events. Methods This register-based, non-randomised, controlled trial included men and women aged 40–69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle. Results Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49). Conclusions/interpretation A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4323-2
      Issue No: Vol. 60, No. 11 (2017)
  • Effect of screening for type 2 diabetes on risk of cardiovascular disease
           and mortality: a controlled trial among 139,075 individuals diagnosed with
           diabetes in Denmark between 2001 and 2009
    • Authors: Rebecca K. Simmons; Simon J. Griffin; Torsten Lauritzen; Annelli Sandbæk
      Pages: 2192 - 2199
      Abstract: Aims/hypothesis There is continuing debate about the net benefits of population screening for type 2 diabetes. We compared the risk of cardiovascular disease (CVD) and mortality among incident cases of type 2 diabetes in a screened group with those in an unscreened group. Methods In this register-based non-randomised controlled trial, eligible individuals were all men and women aged 40–69 years without known diabetes, registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes-risk-score questionnaire. Individuals at moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075), and compared risk of CVD and mortality in these groups between 2001 and 2012. Results In the screening group, 27,177/153,107 (18%) individuals attended for screening, of whom 1533 were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Between 2001 and 2012, the risks of CVD and mortality were lower among individuals with diabetes in the screening group compared with individuals with diabetes in the no-screening (control) group (CVD HR 0.84, 95% CI 0.80, 0.89; mortality HR 0.79, 95% CI 0.74, 0.84). Conclusions/interpretation A single round of diabetes screening and cardiovascular risk assessment in middle-aged Danish adults in general practice was associated with a significant reduction in risk of all-cause mortality and CVD events in those diagnosed with diabetes.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4299-y
      Issue No: Vol. 60, No. 11 (2017)
  • Perceived racism and incident diabetes in the Black Women’s Health
    • Authors: Kathryn L. Bacon; Sherri O. Stuver; Yvette C. Cozier; Julie R. Palmer; Lynn Rosenberg; Edward A. Ruiz-Narváez
      Pages: 2221 - 2225
      Abstract: Aims/hypothesis Our aim was to assess the association of perceived racism with type 2 diabetes, and the possible mediating influence of diet and BMI. Methods The Black Women’s Health Study, a follow-up of 59,000 African-American women, began in 1995. Over 16 years 5344 incident cases of diabetes occurred during 576,577 person-years. Cox proportional hazards models were used to estimated HRs and 95% CIs for categories of ‘everyday racism’ (interpersonal racism in daily life) and ‘lifetime racism’ (reporting ever treated unfairly due to race with respect to police, housing or work) and incident type 2 diabetes. Models were adjusted for age, questionnaire cycle, marital status, socioeconomic status, education, family history of diabetes, physical activity, alcohol use and smoking status, with and without inclusion of terms for dietary patterns and adult BMI. Results Compared with women in the lowest quartile of exposure, women in the highest quartile of exposure to everyday racism had a 31% increased risk of diabetes (HR 1.31; 95% CI 1.20, 1.42) and women with the highest exposure to lifetime racism had a 16% increased risk (HR 1.16; 95% CI 1.05, 1.27). Mediation analysis estimated that BMI accounted for half of the association between either the everyday or lifetime racism measure and incident diabetes. Conclusions/interpretation Perceived everyday and lifetime racism were associated with increased risk of type 2 diabetes in this cohort of African-American women and appear to be at least partly mediated by BMI.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4400-6
      Issue No: Vol. 60, No. 11 (2017)
  • Immigration to Israel during childhood is associated with diabetes at
           adolescence: a study of 2.7 million adolescents
    • Authors: Alon Peled; Barak Gordon; Gilad Twig; Joseph Mendlovic; Estela Derazne; Michal Lisnyansky; Itamar Raz; Arnon Afek
      Pages: 2226 - 2230
      Abstract: Aims/hypothesis Immigration studies can shed light on diabetes pathogenesis and risk factors. To this end, we investigated the association between age at immigration and diabetes occurrence at adolescence among immigrants to Israel. Methods We analysed cross-sectional data on 2,721,767 Jewish adolescents assessed for mandatory military service at approximately 17 years of age between 1967 and 2014. The study population comprised 430,176 immigrants with origins in Ethiopia, former USSR, Middle East and North Africa (ME/NA) and western countries. ORs for diabetes were calculated for men and women, grouped according to age at immigration, with Israel-born participants as controls. Unadjusted and fully adjusted models were made to account for possible confounders. Additionally, the study population was stratified by origin and each immigrant group was referenced to Israel-born participants of the same origin. Results There was a graded decrease in OR for diabetes across the study groups in the fully adjusted model. Immigrants arriving at age 0–5 years had comparable OR for diabetes to the Israeli-born reference group; those arriving at age 6–11 years had an OR of 0.82 (95% CI 0.70, 0.97; p = 0.017) and recent immigrants, arriving at age 12–19 years, had the lowest OR of 0.65 (95% CI 0.54, 0.77; p < 0.0001). When age at immigration was treated as a continuous variable, there was an adjusted risk for occurrence of diabetes of 0.97 (95% CI 0.96, 0.99; p = 0.001) for every year increment. The lower risk for diabetes among recent immigrants persisted in the unadjusted model and persisted when the study sample was stratified by sex and origin, except for immigrants arriving from ME/NA. Notably, Ethiopians born in Israel had a sixfold higher diabetes crude prevalence than Ethiopian immigrants arriving after the age of 5 years. Conclusions/interpretation Immigrants of different ethnic groups arriving earlier in childhood lose their protection against diabetes at adolescence, relative to children born in Israel. This is perhaps due to environmental and lifestyle changes, especially those beginning at an early age.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4399-8
      Issue No: Vol. 60, No. 11 (2017)
  • Evidence-based prioritisation and enrichment of genes interacting with
           metformin in type 2 diabetes
    • Authors: Adem Y. Dawed; Ashfaq Ali; Kaixin Zhou; Ewan R. Pearson; Paul W. Franks
      Pages: 2231 - 2239
      Abstract: Aims/hypothesis There is an extensive body of literature suggesting the involvement of multiple loci in regulating the action of metformin; most findings lack replication, without which distinguishing true-positive from false-positive findings is difficult. To address this, we undertook evidence-based, multiple data integration to determine the validity of published evidence. Methods We (1) built a database of published data on gene–metformin interactions using an automated text-mining approach (n = 5963 publications), (2) generated evidence scores for each reported locus, (3) from which a rank-ordered gene set was generated, and (4) determined the extent to which this gene set was enriched for glycaemic response through replication analyses in a well-powered independent genome-wide association study (GWAS) dataset from the Genetics of Diabetes and Audit Research Tayside Study (GoDARTS). Results From the literature search, seven genes were identified that are related to the clinical outcomes of metformin. Fifteen genes were linked with either metformin pharmacokinetics or pharmacodynamics, and the expression profiles of a further 51 genes were found to be responsive to metformin. Gene-set enrichment analysis consisting of the three sets and two more composite sets derived from the above three showed no significant enrichment in four of the gene sets. However, we detected significant enrichment of genes in the least prioritised category (a gene set in which their expression is affected by metformin) with glycaemic response to metformin (p = 0.03). This gene set includes novel candidate genes such as SLC2A4 (p = 3.24 × 10−04) and G6PC (p = 4.77 × 10−04). Conclusions/interpretation We have described a semi-automated text-mining and evidence-scoring algorithm that facilitates the organisation and extraction of useful information about gene–drug interactions. We further validated the output of this algorithm in a drug-response GWAS dataset, providing novel candidate loci for gene–metformin interactions.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4404-2
      Issue No: Vol. 60, No. 11 (2017)
  • Metabolic crosstalk between fatty pancreas and fatty liver: effects on
           local inflammation and insulin secretion
    • Authors: Felicia Gerst; Robert Wagner; Gabriele Kaiser; Madhura Panse; Martin Heni; Jürgen Machann; Malte N. Bongers; Tina Sartorius; Bence Sipos; Falko Fend; Christian Thiel; Silvio Nadalin; Alfred Königsrainer; Norbert Stefan; Andreas Fritsche; Hans-Ulrich Häring; Susanne Ullrich; Dorothea Siegel-Axel
      Pages: 2240 - 2251
      Abstract: Aims/hypothesis Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. Methods Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. Results In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic pre-adipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca2+-dependent, manner. Conclusions/interpretation These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4385-1
      Issue No: Vol. 60, No. 11 (2017)
  • Relapsing/remitting type 1 diabetes
    • Authors: Kayleigh M. van Megen; Matthew P. Spindler; Fleur M. Keij; Ineke Bosch; Fleur Sprangers; Annet van Royen-Kerkhof; Tatjana Nikolic; Bart O. Roep
      Pages: 2252 - 2255
      Abstract: Aims/hypothesis Type 1 diabetes is believed to be an autoimmune disease associated with irreversible loss of insulin secretory function that follows a chronic progressive course. However, it has been speculated that relapsing/remitting disease progression may occur in type 1 diabetes. Methods We report the case of an 18-year-old girl with Graves’ disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple islet autoantibodies, presenting with relapsing/remitting hyperglycaemia. Peripheral blood mononuclear cells were analysed for islet autoimmunity. Results There were two instances of hyperglycaemia relapse during CIDP flare-ups that required insulin therapy and remitted after i.v. immunoglobulin (IVIG) therapy improving neurological symptoms. A diagnosis of type 1 diabetes was assigned on the basis of insulin need, HbA1c and islet autoantibodies. Insulin requirements disappeared following IVIG treatment and peaked during CIDP flare-ups. Pro- and anti-inflammatory cytokine responses were noted against islet autoantigens. Conclusions/interpretation We provide clinical evidence of relapsing/remitting type 1 diabetes associated with IVIG treatment and the regulation of islet autoimmunity. Despite sufficient residual beta cell mass, individuals can experience episodes of impaired glycaemia control. This disconnect between beta cell mass and function highlighted by our case may have implications for the use of beta cell function as the primary endpoint for immune intervention trials aiming to protect beta cell mass rather than function. Immune modulation may restore beta cell function and glycaemic control.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4403-3
      Issue No: Vol. 60, No. 11 (2017)
  • The effect of interleukin-22 treatment on autoimmune diabetes in the NOD
    • Authors: Danielle J. Borg; Ran Wang; Lydia Murray; Hui Tong; Raymond J. Steptoe; Michael A. McGuckin; Sumaira Z. Hasnain
      Pages: 2256 - 2261
      Abstract: Aims/hypothesis The aim of this study was to determine whether therapy with the cytokine IL-22 could be used to prevent the development of, or treat, autoimmune diabetes in the NOD mouse. Methods Six-week-old NOD mice were administered bi-weekly either recombinant mouse IL-22 (200 ng/g) or PBS (vehicle control) intraperitoneally until overt diabetes was diagnosed as two consecutive measurements of non-fasting blood glucose ≥ 11 mmol/l. At this time, NOD mice in the control arm were treated with LinBit insulin pellets and randomised to bi-weekly therapeutic injections of either PBS or IL-22 (200 ng/g) and followed until overt diabetes was diagnosed, as defined above. Results IL-22 therapy did not delay the onset of diabetes in comparison with the vehicle-treated mice. We did not observe an improvement in islet area, glycaemic control, beta cell residual function, endoplasmic reticulum stress, insulitis or macrophage and neutrophil infiltration as determined by non-fasting blood glucose, C-peptide and histological scoring. Therapeutic administration of IL-22 did not reduce circulating lipopolysaccharide, a marker of impaired gut mucosal integrity. Conclusions/interpretation Our study suggests that, at this dosing regimen introduced either prior to overt diabetes or at diagnosis of diabetes, recombinant mouse IL-22 therapy cannot prevent autoimmune diabetes, or prolong the honeymoon period in the NOD mouse.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4392-2
      Issue No: Vol. 60, No. 11 (2017)
  • VLDL and apolipoprotein CIII induce ER stress and inflammation and
           attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal
           muscle cells
    • Authors: Gaia Botteri; Marta Montori; Anna Gumà; Javier Pizarro; Lídia Cedó; Joan Carles Escolà-Gil; Diana Li; Emma Barroso; Xavier Palomer; Alison B. Kohan; Manuel Vázquez-Carrera
      Pages: 2262 - 2273
      Abstract: Aim/hypothesis Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle. Methods Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII. Results C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor. Conclusions/interpretation These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4401-5
      Issue No: Vol. 60, No. 11 (2017)
  • Topical administration of DPP-IV inhibitors prevents retinal
           neurodegeneration in experimental diabetes
    • Authors: Cristina Hernández; Patricia Bogdanov; Cristina Solà-Adell; Joel Sampedro; Marta Valeri; Xavier Genís; Olga Simó-Servat; Marta García-Ramírez; Rafael Simó
      Pages: 2285 - 2298
      Abstract: Aims/hypothesis The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. Methods To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and age-matched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate−aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. Results DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. Conclusions/interpretation The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out.
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4388-y
      Issue No: Vol. 60, No. 11 (2017)
  • Gastrointestinal motility in people with type 1 diabetes and peripheral
    • Authors: Chinmay S. Marathe; Christopher K. Rayner; Karen L. Jones; Michael Horowitz
      Pages: 2312 - 2313
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4391-3
      Issue No: Vol. 60, No. 11 (2017)
  • Gastrointestinal motility in people with type 1 diabetes and peripheral
           neuropathy. Reply to Marathe CS, Rayner CK, Jones KL, et al [letter]
    • Authors: Adam D. Farmer; Anne Grave Pedersen; Birgitte Brock; Poul Erik Jakobsen; Jesper Karmisholt; Sahar D. Mohammed; S. Mark Scott; Asbjørn Mohr Drewes; Christina Brock
      Pages: 2314 - 2315
      PubDate: 2017-11-01
      DOI: 10.1007/s00125-017-4414-0
      Issue No: Vol. 60, No. 11 (2017)
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