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Journal Cover Diabetologia
  Journal Prestige (SJR): 3.528
  Citation Impact (citeScore): 182
  Number of Followers: 268  
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1432-0428 - ISSN (Online) 0012-186X
   Published by Springer-Verlag Homepage  [2350 journals]
  • Up front
    • Pages: 1493 - 1494
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4650-y
      Issue No: Vol. 61, No. 7 (2018)
       
  • Endocrine-disrupting chemicals and risk of diabetes: an evidence-based
           review
    • Authors: P. Monica Lind; Lars Lind
      Pages: 1495 - 1502
      Abstract: The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p′-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p′-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p′-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4621-3
      Issue No: Vol. 61, No. 7 (2018)
       
  • Diabetes in the older patient: heterogeneity requires individualisation of
           therapeutic strategies
    • Authors: Guntram Schernthaner; Marie Helene Schernthaner-Reiter
      Pages: 1503 - 1516
      Abstract: Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4547-9
      Issue No: Vol. 61, No. 7 (2018)
       
  • Spouses, social networks and other upstream determinants of type 2
           diabetes mellitus
    • Authors: Joreintje D. Mackenbach; Nicole R. den Braver; Joline W. J. Beulens
      Pages: 1517 - 1521
      Abstract: Diabetes risk factors outside the individual are receiving increasing attention. In this issue of Diabetologia, Nielsen et al (
      DOI : https://doi.org/10.1007/s00125-018-4587-1) demonstrate that an individual’s obesity level is associated with incident type 2 diabetes in their spouse. This is in line with studies providing evidence for spousal and peer similarities in lifestyle behaviours and obesity. Non-random mating and convergence over time are two explanations for this phenomenon, but shared exposure to more upstream drivers of diabetes may also play a role. From a systems-science perspective, these mechanisms are likely to occur simultaneously and interactively as part of a complex system. In this commentary, we provide an overview of the wider system-level factors that contribute to type 2 diabetes.
      PubDate: 2018-07-01
      Issue No: Vol. 61, No. 7 (2018)
       
  • Empagliflozin in women with type 2 diabetes and cardiovascular disease –
           an analysis of EMPA-REG OUTCOME®
    • Authors: Bernard Zinman; on behalf of the EMPA-REG OUTCOME® investigators; Silvio E. Inzucchi; Christoph Wanner; Uwe Hehnke; Jyothis T. George; Odd Erik Johansen; David Fitchett
      Pages: 1522 - 1527
      Abstract: Aims/hypothesis The global epidemic of type 2 diabetes affects women and men equally; however, the relative impact on the cardiovascular (CV) system appears greater for women than men when compared with peers without diabetes. Furthermore, women are often under-represented in CV outcome trials, resulting in less certainty about the impact of CV prevention therapies across the sexes. The EMPA-REG OUTCOME® trial, which included 28.5% women, found that empagliflozin, given in addition to standard of care, reduced the risk of CV death by 38%, heart failure (HF) hospitalisation by 35% and a composite endpoint for incident or worsening nephropathy by 39%. Here we report a secondary analysis of the trial to determine the relative effects of empagliflozin in women vs men. Methods The population studied were individuals with type 2 diabetes (HbA1c 53–86 mmol/mol [7–10%] and eGFR >30 ml min−1 [1.73 m]−2), with established atherosclerotic CV disease. Individuals were randomised to receive empagliflozin 10 mg or 25 mg, or placebo once daily in addition to standard of care, and followed. The trial continued until ≥691 individuals had experienced an adjudicated event included in the primary outcome. All CV outcome events, including HF hospitalisations and deaths were prospectively adjudicated by blinded clinical events committees. Results At baseline, the demographic profile of the 2004 women (age ± standard deviation 63.6 ± 8.8 years) compared with the 5016 men (age 63.0 ± 8.6 years) in the trial was largely similar, with the exception that LDL-cholesterol was numerically higher in women (2.5 ± 1.0 vs 2.1 ± 0.9 mmol/l), consistent with lower rates of lipid-lowering therapies (75.4% vs 83.2%). Women were also less likely to have smoked (31.5% vs 69.9%). The annualised incidence rate for women in the placebo group was numerically lower than in men for CV death (1.58% vs 2.19%), numerically higher for HF hospitalisation (1.75% vs 1.33%) and similar for renal events (7.22% vs 7.75%). We did not detect any effect modification by sex within the statistical power restrictions of the analysis for CV death, HF hospitalisation and incident or worsening nephropathy (interaction p values 0.32, 0.20 and 0.85, respectively). Compared with placebo, empagliflozin increased the rates of genital infections in both women (2.5% vs 10.0%) and men (1.5% vs 2.6%). Conclusions/interpretation CV death, HF hospitalisation and incident or worsening nephropathy rate reductions induced by empagliflozin were not different between women and men.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4630-2
      Issue No: Vol. 61, No. 7 (2018)
       
  • Community-based pre-pregnancy care programme improves pregnancy
           preparation in women with pregestational diabetes
    • Authors: Jennifer M. Yamamoto; Deborah J. F. Hughes; Mark L. Evans; Vithian Karunakaran; John D. A. Clark; Nicholas J. Morrish; Gerry A. Rayman; Peter H. Winocour; Clare Hambling; Amanda W. Harries; Michael J. Sampson; Helen R. Murphy
      Pages: 1528 - 1537
      Abstract: Aims/hypothesis Women with diabetes remain at increased risk of adverse pregnancy outcomes associated with poor pregnancy preparation. However, women with type 2 diabetes are less aware of and less likely to access pre-pregnancy care (PPC) compared with women with type 1 diabetes. We developed and evaluated a community-based PPC programme with the aim of improving pregnancy preparation in all women with pregestational diabetes. Methods This was a prospective cohort study comparing pregnancy preparation measures before and during/after the PPC intervention in women with pre-existing diabetes from 1 June 2013 to 28 February 2017. The setting was 422 primary care practices and ten National Health Service specialist antenatal diabetes clinics. A multifaceted approach was taken to engage women with diabetes and community healthcare teams. This included identifying and sending PPC information leaflets to all eligible women, electronic preconception care templates, online education modules and resources, and regional meetings and educational events. Key outcomes were preconception folic acid supplementation, maternal HbA1c level, use of potentially harmful medications at conception and gestational age at first presentation, before and during/after the PPC programme. Results A total of 306 (73%) primary care practices actively participated in the PPC programme. Primary care databases were used to identify 5075 women with diabetes aged 18–45 years. PPC leaflets were provided to 4558 (89.8%) eligible women. There were 842 consecutive pregnancies in women with diabetes: 502 before and 340 during/after the PPC intervention. During/after the PPC intervention, pregnant women with type 2 diabetes were more likely to achieve target HbA1c levels ≤48 mmol/mol (6.5%) (44.4% of women before vs 58.5% of women during/after PPC intervention; p = 0.016) and to take 5 mg folic acid daily (23.5% and 41.8%; p = 0.001). There was an almost threefold improvement in ‘optimal’ pregnancy preparation in women with type 2 diabetes (5.8% and 15.1%; p = 0.021). Women with type 1 diabetes presented for earlier antenatal care during/after PPC (54.0% vs 67.3% before 8 weeks’ gestation; p = 0.003) with no other changes. Conclusions/interpretation A pragmatic community-based PPC programme was associated with clinically relevant improvements in pregnancy preparation in women with type 2 diabetes. To our knowledge, this is the first community-based PPC intervention to improve pregnancy preparation for women with type 2 diabetes. Data availability Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from https://digital.nhs.uk/data-and-information/clinical-audits-and-registries/our-clinical-audits-and-registries/national-pregnancy-in-diabetes-audit.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4613-3
      Issue No: Vol. 61, No. 7 (2018)
       
  • Persistence of abnormalities in white matter in children with type 1
           diabetes
    • Authors: Larry A. Fox; for the Diabetes Research in Children Network (DirecNet); Tamara Hershey; Nelly Mauras; Ana Maria Arbeláez; William V. Tamborlane; Bruce Buckingham; Eva Tsalikian; Kim Englert; Mira Raman; Booil Jo; Hanyang Shen; Allan Reiss; Paul Mazaika
      Pages: 1538 - 1547
      Abstract: Aims/hypothesis Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes. Methods One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3 months. Results Axial diffusivity was lower in children with diabetes at baseline (p = 0.022) and at 18 months (p = 0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p = 0.037). Fractional anisotropy was positively correlated with performance (p < 0.002) and full-scale IQ (p < 0.02). Conclusions/interpretation These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4610-6
      Issue No: Vol. 61, No. 7 (2018)
       
  • A heterogeneous response of liver and skeletal muscle fat to the
           combination of a Paleolithic diet and exercise in obese individuals with
           type 2 diabetes: a randomised controlled trial
    • Authors: Julia Otten; Andreas Stomby; Maria Waling; Andreas Isaksson; Ingegerd Söderström; Mats Ryberg; Michael Svensson; Jón Hauksson; Tommy Olsson
      Pages: 1548 - 1559
      Abstract: Aims/hypothesis The aim of the study was to investigate ectopic fat deposition and insulin sensitivity, in a parallel single-blinded randomised controlled trial, comparing Paleolithic diet alone with the combination of Paleolithic diet and exercise in individuals with type 2 diabetes. Methods Thirty-two individuals with type 2 diabetes with BMI 25–40 kg/m2 and 30–70 years of age followed a Paleolithic diet ad libitum for 12 weeks. In addition, study participants were randomised by computer program to either supervised combined exercise training (PD-EX group) or standard care exercise recommendations (PD group). Staff performing examinations and assessing outcomes were blinded to group assignment. Thirteen participants were analysed in each group: hepatic and peripheral insulin sensitivity were measured using the hyperinsulinaemic–euglycaemic clamp technique combined with [6,6-2H2]glucose infusion, and liver fat was assessed by proton magnetic resonance spectroscopy; both analyses were secondary endpoints. Intramyocellular lipid (IMCL) content was measured by magnetic resonance spectroscopy as a secondary analysis. All examinations were performed at Umeå University Hospital, Umeå, Sweden. Results Both study groups showed a median body weight loss of 7 kg. Fat mass decreased by 5.7 kg in the PD group and by 6.5 kg in the PD-EX group. Maximum oxygen uptake increased in the PD-EX group only. Liver fat showed a consistent reduction (74% decrease) in the PD group, while the response in the PD-EX group was heterogeneous (p < 0.05 for the difference between groups). IMCL content of the soleus muscle decreased by 40% in the PD group and by 22% in the PD-EX group (p < 0.05 for the difference between groups). Both groups improved their peripheral and adipose tissue insulin sensitivity, but not their hepatic insulin sensitivity. Plasma fetuin-A decreased by 11% in the PD group (p < 0.05) and remained unchanged in the PD-EX group. Liver fat changes during the intervention were correlated with changes in fetuin-A (rS = 0.63, p < 0.01). Participants did not report any important adverse events caused by the intervention. Conclusions/interpretation A Paleolithic diet reduced liver fat and IMCL content, while there was a tissue-specific heterogeneous response to added exercise training. Trial registration ClinicalTrials.gov NCT01513798 Funding Swedish Diabetes Research Foundation, County Council of Västerbotten, Swedish Heart and Lung Foundation, King Gustav V and Queen Victoria’s Foundation
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4618-y
      Issue No: Vol. 61, No. 7 (2018)
       
  • Spousal cardiometabolic risk factors and incidence of type 2 diabetes: a
           prospective analysis from the English Longitudinal Study of Ageing
    • Authors: Jannie Nielsen; Adam Hulman; Daniel R. Witte
      Pages: 1572 - 1580
      Abstract: Aims/hypothesis In the UK, more than one million people have undiagnosed diabetes and an additional five million are at high risk of developing the disease. Given that early identification of these people is key for both primary and secondary prevention, new screening approaches are needed. Since spouses resemble each other in cardiometabolic risk factors related to type 2 diabetes, we aimed to investigate whether diabetes and cardiometabolic risk factors in one spouse can be used as an indicator of incident type 2 diabetes in the other spouse. Methods We analysed data from 3649 men and 3478 women from the English Longitudinal Study of Ageing with information on their own and their spouse’s diabetes status and cardiometabolic risk factors. We modelled incidence rates and incidence rate ratios with Poisson regression, using spousal diabetes status or cardiometabolic risk factors (i.e. BMI, waist circumference, systolic and diastolic BP, HDL- and LDL-cholesterol and triacylglycerols) as exposures and type 2 diabetes incidence in the index individual as the outcome. Models were adjusted for two nested sets of covariates. Results Spousal BMI and waist circumference were associated with incident type 2 diabetes, but with different patterns for men and women. A man’s risk of type 2 diabetes increased more steeply with his wife’s obesity level, and the association remained statistically significant even after adjustment for the man’s own obesity level. Having a wife with a 5 kg/m2 higher BMI (30 kg/m2 vs 25 kg/m2) was associated with a 21% (95% CI 11%, 33%) increased risk of type 2 diabetes. In contrast, the association between incident type 2 diabetes in a woman and her husband’s BMI was attenuated after adjusting for the woman’s own obesity level. Findings for waist circumference were similar to those for BMI. Regarding other risk factors, we found a statistically significant association only between the risk of type 2 diabetes in women and their husbands’ triacylglycerol levels. Conclusions/interpretation The main finding of this study is the sex-specific effect of spousal obesity on the risk of type 2 diabetes. Having an obese spouse increases an individual’s risk of type 2 diabetes over and above the effect of the individual’s own obesity level among men, but not among women. Our results suggest that a couples-focused approach may be beneficial for the early detection of type 2 diabetes and individuals at high risk of developing type 2 diabetes, especially in men, who are less likely than women to attend health checks. Data availability Data were accessed via the UK Data Service under the data-sharing agreement no. 91400 (https://discover.ukdataservice.ac.uk/catalogue/'sn=5050&type=Data%20catalogue).
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4587-1
      Issue No: Vol. 61, No. 7 (2018)
       
  • Circulating amino acids and the risk of macrovascular, microvascular and
           mortality outcomes in individuals with type 2 diabetes: results from the
           ADVANCE trial
    • Authors: Paul Welsh; Naomi Rankin; Qiang Li; Patrick B. Mark; Peter Würtz; Mika Ala-Korpela; Michel Marre; Neil Poulter; Pavel Hamet; John Chalmers; Mark Woodward; Naveed Sattar
      Pages: 1581 - 1591
      Abstract: Aims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. Results In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012). Conclusions/interpretation We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4619-x
      Issue No: Vol. 61, No. 7 (2018)
       
  • Global burden of hypoglycaemia-related mortality in 109 countries, from
           2000 to 2014: an analysis of death certificates
    • Authors: Francesco Zaccardi; Nafeesa N. Dhalwani; David R. Webb; Melanie J. Davies; Kamlesh Khunti
      Pages: 1592 - 1602
      Abstract: Aims/hypothesis In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality. Methods We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time. Results Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000–2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000–2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA. Conclusions/interpretation Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia. Data availability Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4626-y
      Issue No: Vol. 61, No. 7 (2018)
       
  • Discordant association of the CREBRF rs373863828 A allele with increased
           BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian)
           people living in Aotearoa/New Zealand
    • Authors: Mohanraj Krishnan; Tanya J. Major; Ruth K. Topless; Ofa Dewes; Lennex Yu; John M. D. Thompson; Lesley McCowan; Janak de Zoysa; Lisa K. Stamp; Nicola Dalbeth; Jennie Harré Hindmarsh; Nuku Rapana; Ranjan Deka; Winston W. H. Eng; Daniel E. Weeks; Ryan L. Minster; Stephen T. McGarvey; Satupa’itea Viali; Take Naseri; Muagututi’a Sefuiva Reupena; Phillip Wilcox; David Grattan; Peter R. Shepherd; Andrew N. Shelling; Rinki Murphy; Tony R. Merriman
      Pages: 1603 - 1613
      Abstract: Aims/hypothesis The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand. Methods Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis. Results For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 × 10−6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 × 10−6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (β = 0.012 mmol/l, pcorrected = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59). Conclusions/interpretation Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4623-1
      Issue No: Vol. 61, No. 7 (2018)
       
  • Patterns of differential gene expression in a cellular model of human
           islet development, and relationship to type 2 diabetes predisposition
    • Authors: Marta Perez-Alcantara; Christian Honoré; Agata Wesolowska-Andersen; Anna L. Gloyn; Mark I. McCarthy; Mattias Hansson; Nicola L. Beer; Martijn van de Bunt
      Pages: 1614 - 1622
      Abstract: Aims/hypothesis Most type 2 diabetes-associated genetic variants identified via genome-wide association studies (GWASs) appear to act via the pancreatic islet. Observed defects in insulin secretion could result from an impact of these variants on islet development and/or the function of mature islets. Most functional studies have focused on the latter, given limitations regarding access to human fetal islet tissue. Capitalising upon advances in in vitro differentiation, we characterised the transcriptomes of human induced pluripotent stem cell (iPSC) lines differentiated along the pancreatic endocrine lineage, and explored the contribution of altered islet development to the pathogenesis of type 2 diabetes. Methods We performed whole-transcriptome RNA sequencing of human iPSC lines from three independent donors, at baseline and at seven subsequent stages during in vitro islet differentiation. Differentially expressed genes (q < 0.01, log2 fold change [FC] > 1) were assigned to the stages at which they were most markedly upregulated. We used these data to characterise upstream transcription factors directing different stages of development, and to explore the relationship between RNA expression profiles and genes mapping to type 2 diabetes GWAS signals. Results We identified 9409 differentially expressed genes across all stages, including many known markers of islet development. Integration of differential expression data with information on transcription factor motifs highlighted the potential contribution of REST to islet development. Over 70% of genes mapping within type 2 diabetes-associated credible intervals showed peak differential expression during islet development, and type 2 diabetes GWAS loci of largest effect (including TCF7L2; log2FC = 1.2; q = 8.5 × 10−10) were notably enriched in genes differentially expressed at the posterior foregut stage (q = 0.002), as calculated by gene set enrichment analyses. In a complementary analysis of enrichment, genes differentially expressed in the final, beta-like cell stage of in vitro differentiation were significantly enriched (hypergeometric test, permuted p value <0.05) for genes within the credible intervals of type 2 diabetes GWAS loci. Conclusions/interpretation The present study characterises RNA expression profiles during human islet differentiation, identifies potential transcriptional regulators of the differentiation process, and suggests that the inherited predisposition to type 2 diabetes is partly mediated through modulation of islet development. Data availability Sequence data for this study has been deposited at the European Genome-phenome Archive (EGA), under accession number EGAS00001002721.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4612-4
      Issue No: Vol. 61, No. 7 (2018)
       
  • SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor
           graft function in islet allograft recipients
    • Authors: Else M. Balke; Simke Demeester; DaHae Lee; Pieter Gillard; Robert Hilbrands; Ursule Van de Velde; Bart J. Van der Auwera; Zhidong Ling; Bart O. Roep; Daniël G. Pipeleers; Bart Keymeulen; Frans K. Gorus
      Pages: 1623 - 1632
      Abstract: Aims/hypothesis HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients’ zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome. Methods We retrospectively analysed data of a hospital-based patient cohort followed for 18 months post transplantation. Forty C-peptide-negative type 1 diabetic individuals who received >2 million beta cells (>4000 islet equivalents) per kg body weight in one or two intraportal implantations under similar immunosuppression were genotyped for SLC30A8. Outcome measurements included achievement and maintenance of graft function. Metabolic benefit was defined as <25% CV of fasting glycaemia in the presence of >331 pmol/l C-peptide, in addition to achievement of insulin independence and maintenance of C-peptide positivity. Results In multivariate analysis, HLA-A*24 positivity, presence of SLC30A8 CT or TT genotypes and BMI more than or equal to the group median (23.9 kg/m2) were independently associated with failure to achieve insulin independence (p = 0.015–0.046). The risk increased with the number of factors present (p < 0.001). High BMI interacted with SLC30A8 T allele carriership to independently predict difficulty in achieving graft function with metabolic benefit (p = 0.015). Maintenance of C-peptide positivity was mainly associated with older age at the time of implantation. Only HLA-A*24 carriership independently predicted failure to maintain acceptable graft function once achieved (p = 0.012). Conclusions/interpretation HLA-A*24, the SLC30A8 T allele and high BMI are associated with poor graft outcome and should be considered in the interpretation of future transplantation trials. Trial registration ClinicalTrials.gov NCT00798785 and NCT00623610
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4609-z
      Issue No: Vol. 61, No. 7 (2018)
       
  • A proinflammatory CD4 + T cell phenotype in gestational diabetes mellitus
    • Authors: Angela Sheu; Yixian Chan; Angela Ferguson; Mohammad B. Bakhtyari; Wendy Hawke; Chris White; Yuk Fun Chan; Patrick J. Bertolino; Heng G. Woon; Umaimainthan Palendira; Frederic Sierro; Sue Mei Lau
      Pages: 1633 - 1643
      Abstract: Aims/hypothesis Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4+ (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4+ subsets and severity of GDM. Methods This is a prospective longitudinal case–control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4+ T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose. Results Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62–4.60] vs 1.85% [1.13–2.98], p = 0.012) and Th17.1 (3.06% [1.30–4.33] vs 1.55% [0.65–3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without. Conclusions/interpretation Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4615-1
      Issue No: Vol. 61, No. 7 (2018)
       
  • Autoantibodies to N-terminally truncated GAD improve clinical phenotyping
           of individuals with adult-onset diabetes: Action LADA 12
    • Authors: Peter Achenbach; on behalf of the Action LADA consortium; Mohammed I. Hawa; Stephanie Krause; Vito Lampasona; Samuel T. Jerram; Alistair J. K. Williams; Ezio Bonifacio; Anette G. Ziegler; R. David Leslie
      Pages: 1644 - 1649
      Abstract: Aims/hypothesis Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy. Methods Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96–585) GAD65 autoantibodies (t-GADA). Individuals’ clinical phenotypes were analysed according to antibody binding patterns. Results Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p < 0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p = 0.0005). Conclusions/interpretation In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4605-3
      Issue No: Vol. 61, No. 7 (2018)
       
  • Abnormal islet sphingolipid metabolism in type 1 diabetes
    • Authors: Laurits J. Holm; Lars Krogvold; Jane P. Hasselby; Simranjeet Kaur; Laura A. Claessens; Mark A. Russell; Clayton E. Mathews; Kristian F. Hanssen; Noel G. Morgan; Bobby P. C. Koeleman; Bart O. Roep; Ivan C. Gerling; Flemming Pociot; Knut Dahl-Jørgensen; Karsten Buschard
      Pages: 1650 - 1661
      Abstract: Aims/hypothesis Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. Methods We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. Results We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. Conclusions/interpretation These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. Data availability The RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx'dl=0. A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx'dl=0.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4614-2
      Issue No: Vol. 61, No. 7 (2018)
       
  • Evaluation of anti-insulin receptor antibodies as potential novel
           therapies for human insulin receptoropathy using cell culture models
    • Authors: Gemma V. Brierley; Kenneth Siddle; Robert K. Semple
      Pages: 1662 - 1675
      Abstract: Aims/hypothesis Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies. Methods Ten naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes. Results All expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A. Conclusions/interpretation Anti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4606-2
      Issue No: Vol. 61, No. 7 (2018)
       
  • The impact of hypoglycaemia awareness status on regional brain responses
           to acute hypoglycaemia in men with type 1 diabetes
    • Authors: Joel T. Dunn; Pratik Choudhary; Ming Ming Teh; Ian Macdonald; Katharine F. Hunt; Paul K. Marsden; Stephanie A. Amiel
      Pages: 1676 - 1687
      Abstract: Aims/hypothesis Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes increases the risk of severe hypoglycaemia sixfold and can be resistant to intervention. We explored the impact of IAH on central responses to hypoglycaemia to investigate the mechanisms underlying barriers to therapeutic intervention. Methods We conducted [15O]water positron emission tomography studies of regional brain perfusion during euglycaemia (target 5 mmol/l), hypoglycaemia (achieved level, 2.4 mmol/l) and recovery (target 5 mmol/l) in 17 men with type 1 diabetes: eight with IAH, and nine with intact hypoglycaemia awareness (HA). Results Hypoglycaemia with HA was associated with increased activation in brain regions including the thalamus, insula, globus pallidus (GP), anterior cingulate cortex (ACC), orbital cortex, dorsolateral frontal (DLF) cortex, angular gyrus and amygdala; deactivation occurred in the temporal and parahippocampal regions. IAH was associated with reduced catecholamine and symptom responses to hypoglycaemia vs HA (incremental AUC: autonomic scores, 26.2 ± 35.5 vs 422.7 ± 237.1; neuroglycopenic scores, 34.8 ± 88.8 vs 478.9 ± 311.1; both p < 0.002). There were subtle differences (p < 0.005, k ≥ 50 voxels) in brain activation at hypoglycaemia, including early differences in the right central operculum, bilateral medial orbital (MO) cortex, and left posterior DLF cortex, with additional differences in the ACC, right GP and post- and pre-central gyri in established hypoglycaemia, and lack of deactivation in temporal regions in established hypoglycaemia. Conclusions/interpretation Differences in activation in the post- and pre-central gyri may be expected in people with reduced subjective responses to hypoglycaemia. Alterations in the activity of regions involved in the drive to eat (operculum), emotional salience (MO cortex), aversion (GP) and recall (temporal) suggest differences in the perceived importance and urgency of responses to hypoglycaemia in IAH compared with HA, which may be key to the persistence of the condition.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4622-2
      Issue No: Vol. 61, No. 7 (2018)
       
  • Correction to: Clinically meaningful and lasting HbA 1c improvement rarely
           occurs after 5 years of type 1 diabetes: an argument for early, targeted
           and aggressive intervention following diagnosis
    • Authors: Krishnarajah Nirantharakumar; Nuredin Mohammed; Konstantinos A. Toulis; G. Neil Thomas; Parth Narendran
      Pages: 1688 - 1689
      Abstract: In Table 1 the data for age group, sex and Townsend index were incorrectly identified as mean ± SD instead of n (%). The table is corrected here.
      PubDate: 2018-07-01
      DOI: 10.1007/s00125-018-4620-4
      Issue No: Vol. 61, No. 7 (2018)
       
 
 
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