Journal Cover Diabetologia
  [SJR: 3.528]   [H-I: 182]   [265 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1432-0428 - ISSN (Online) 0012-186X
   Published by Springer-Verlag Homepage  [2355 journals]
  • Up front
    • Pages: 507 - 508
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-018-4556-8
      Issue No: Vol. 61, No. 3 (2018)
       
  • Hope vs hype: where are we in type 1 diabetes'
    • Authors: Jay S. Skyler
      Pages: 509 - 516
      Abstract: Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4530-x
      Issue No: Vol. 61, No. 3 (2018)
       
  • Blood pressure targets in type 2 diabetes. Evidence against or in favour
           of an aggressive approach
    • Authors: Giuseppe Mancia; Guido Grassi
      Pages: 517 - 525
      Abstract: When associated with high blood pressure, type 2 diabetes mellitus is characterised by a high risk of adverse cardiovascular (CV) and renal outcomes. However, both can be effectively reduced by antihypertensive treatment. Current guidelines on the treatment of hypertension emphasize the need to effectively treat high blood pressure in diabetic individuals, but their recommendations differ in terms of the optimal target blood pressure value to aim for in order to maximise CV and renal protection. In some guidelines the recommended target blood pressure values are <140/90 mmHg (systolic/diastolic), whereas in others, blood pressure values close or even less than 130/80 mmHg are recommended. This paper will discuss the evidence for and against a conservative or more aggressive blood pressure target for treated diabetic hypertensive individuals based on the evidence provided by randomised trials, trial meta-analyses and large observational studies. Based on the available evidence, it appears that blood pressure targets will probably have to be lower than <140/90 mmHg, and that values approaching 130/80 mmHg should be recommended. However, evidence in favour of even lower systolic values, i.e. <130 mmHg, is limited and is definitively against a reduction to <120 mmHg.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4537-3
      Issue No: Vol. 61, No. 3 (2018)
       
  • Considerations and guidelines for mouse metabolic phenotyping in diabetes
           research
    • Authors: Thierry Alquier; Vincent Poitout
      Pages: 526 - 538
      Abstract: Mice are the most commonly used species in preclinical research on the pathophysiology of metabolic diseases. Although they are extremely useful for identifying pathways, mechanisms and genes regulating glucose and energy homeostasis, the specificities of the various mouse models and methodologies used to investigate a metabolic phenotype can have a profound impact on experimental results and their interpretation. This review aims to: (1) describe the most commonly used experimental tests to assess glucose and energy homeostasis in mice; (2) provide some guidelines regarding the design, analysis and interpretation of these tests, as well as for studies using genetic models; and (3) identify important caveats and confounding factors that must be taken into account in the interpretation of findings.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4495-9
      Issue No: Vol. 61, No. 3 (2018)
       
  • Impact of flash glucose monitoring on hypoglycaemia in adults with type 1
           diabetes managed with multiple daily injection therapy: a pre-specified
           subgroup analysis of the IMPACT randomised controlled trial
    • Authors: Per Oskarsson; Ramiro Antuna; Petronella Geelhoed-Duijvestijn; Jens Krӧger; Raimund Weitgasser; Jan Bolinder
      Pages: 539 - 550
      Abstract: Aims/hypothesis Evidence for the effectiveness of interstitial glucose monitoring in individuals with type 1 diabetes using multiple daily injection (MDI) therapy is limited. In this pre-specified subgroup analysis of the Novel Glucose-Sensing Technology and Hypoglycemia in Type 1 Diabetes: a Multicentre, Non-masked, Randomised Controlled Trial’ (IMPACT), we assessed the impact of flash glucose technology on hypoglycaemia compared with capillary glucose monitoring. Methods This multicentre, prospective, non-masked, RCT enrolled adults from 23 European diabetes centres. Individuals were eligible to participate if they had well-controlled type 1 diabetes (diagnosed for ≥5 years), HbA1c ≤ 58 mmol/mol [7.5%], were using MDI therapy and on their current insulin regimen for ≥3 months, reported self-monitoring of blood glucose on a regular basis (equivalent to ≥3 times/day) for ≥2 months and were deemed technically capable of using flash glucose technology. Individuals were excluded if they were diagnosed with hypoglycaemia unawareness, had diabetic ketoacidosis or myocardial infarction in the preceding 6 months, had a known allergy to medical-grade adhesives, used continuous glucose monitoring (CGM) within the previous 4 months or were currently using CGM or sensor-augmented pump therapy, were pregnant or planning pregnancy or were receiving steroid therapy for any disorders. Following 2 weeks of blinded (to participants and investigator) sensor wear by all participants, participants with sensor data for more than 50% of the blinded wear period (or ≥650 individual sensor results) were randomly assigned, in a 1:1 ratio by a central interactive web response system (IWRS) using the biased-coin minimisation method, to flash sensor-based glucose monitoring (intervention group) or self-monitoring of capillary blood glucose (control group). The control group had two further 14 day blinded sensor-wear periods at the 3 and 6 month time points. Participants, investigators and staff were not masked to group allocation. The primary outcome was the change in time in hypoglycaemia (<3.9 mmol/l) between baseline and 6 months in the full analysis set. Results Between 4 September 2014 and 12 February 2015, 167 participants using MDI were enrolled. After screening and the baseline phase, participants were randomised to intervention (n = 82) and control groups (n = 81). One woman from each group was excluded owing to pregnancy; the full analysis set included 161 randomised participants. At 6 months, mean time in hypoglycaemia was reduced by 46.0%, from 3.44 h/day to 1.86 h/day in the intervention group (baseline adjusted mean change, −1.65 h/day), and from 3.73 h/day to 3.66 h/day in the control group (baseline adjusted mean change, 0.00 h/day), with a between-group difference of −1.65 (95% CI −2.21, −1.09; p < 0.0001). For participants in the intervention group, the mean ± SD daily sensor scanning frequency was 14.7 ± 10.7 (median 12.3) and the mean number of self-monitored blood glucose tests performed per day reduced from 5.5 ± 2.0 (median 5.4) at baseline to 0.5 ± 1.0 (median 0.1). The baseline frequency of self-monitored blood glucose tests by control participants was maintained (from 5.6 ± 1.9 [median 5.2] to 5.5 ± 2.6 [median 5.1] per day). Treatment satisfaction and perception of hypo/hyperglycaemia were improved compared with control. No device-related hypoglycaemia or safety-related issues were reported. Nine serious adverse events were reported for eight participants (four in each group), none related to the device. Eight adverse events for six of the participants in the intervention group were also reported, which were related to sensor insertion/wear; four of these participants withdrew because of the adverse event. Conclusions/interpretation Use of flash glucose technology in type 1 diabetes controlled with MDI therapy significantly reduced time in hypoglycaemia without deterioration of HbA1c, and improved treatment satisfaction. Trial registration: ClinicalTrials.gov NCT02232698 Funding: Abbott Diabetes Care, Witney, UK
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4527-5
      Issue No: Vol. 61, No. 3 (2018)
       
  • Effects of hypoglycaemia on working memory and regional cerebral blood
           flow in type 1 diabetes: a randomised, crossover trial
    • Authors: Michael Gejl; Albert Gjedde; Birgitte Brock; Arne Møller; Eelco van Duinkerken; Hanne L. Haahr; Charlotte T. Hansen; Pei-Ling Chu; Kirstine L. Stender-Petersen; Jørgen Rungby
      Pages: 551 - 561
      Abstract: Aims/hypothesis The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. Methods In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H2 15O-positron emission tomographies (PET) per session. Results Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] −0.63 [95% CI −1.13, −0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST − cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). Conclusions/interpretation During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. Trial registration NCT01789593, clinicaltrials.gov Funding This study was funded by Novo Nordisk.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4502-1
      Issue No: Vol. 61, No. 3 (2018)
       
  • Angiopoietin-like protein 8 in early pregnancy improves the prediction of
           gestational diabetes
    • Authors: Yun Huang; Xin Chen; Xiaohong Chen; Yu Feng; Heming Guo; Sicheng Li; Ting Dai; Rong Jiang; Xiaoyan Zhang; Chen Fang; Ji Hu
      Pages: 574 - 580
      Abstract: Aims/hypothesis Screening high-risk individuals for gestational diabetes mellitus (GDM) in early pregnancy conventionally relies on established maternal risk factors; however, the sensitivity and specificity of these factors are not satisfactory. The present study aimed to determine whether the concentration of angiopoietin-like protein 8 (ANGPTL8), either alone or combined with other risk factors in early pregnancy, could be used to predict subsequent GDM. Methods From August 2015 to January 2016, 474 women receiving prenatal care at around 12–16 weeks of gestation were recruited into the study. ANGPTL8 levels were measured at the first prenatal visit. All the participants received a 75 g OGTT during weeks 24–28 of gestation. Results ANGPTL8 levels in early pregnancy were considerably higher in women who developed GDM than those who maintained normal glucose tolerance (2822 ± 938 vs 2120 ± 1118 pg/ml, respectively; p < 0.0001). Multivariable logistic regression revealed that ANGPTL8 levels were significantly associated with risk of GDM independent of conventional risk factors. In addition, women in the highest quartile of ANGPTL8 concentration had an 8.75-fold higher risk of developing GDM compared with women in the lowest quartile (OR8.75, 95%CI 2.43, 31.58). More importantly, incorporating ANGPTL8 into the conventional prediction model significantly increased the AUC for prediction of GDM (0.772vs 0.725; p = 0.019). Conclusions Our study suggests that ANGPTL8 levels in early pregnancy are significantly and independently associated with risk of GDM at 24–28 weeks of gestation. Combining ANGPTL8 levels with conventional risk factors could thus improve the prediction of GDM.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4505-y
      Issue No: Vol. 61, No. 3 (2018)
       
  • Three-question set from Michigan Neuropathy Screening Instrument adds
           independent prognostic information on cardiovascular outcomes: analysis of
           ALTITUDE trial
    • Authors: Jelena P. Seferovic; Marc A. Pfeffer; Brian Claggett; Akshay S. Desai; Dick de Zeeuw; Steven M. Haffner; John J. V. McMurray; Hans-Henrik Parving; Scott D. Solomon; Nish Chaturvedi
      Pages: 581 - 588
      Abstract: Aims/hypothesis The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes. Methods In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set. Results In the training set, three questions (‘Are your legs numb'’, ‘Have you ever had an open sore on your foot'’ and ‘Do your legs hurt when you walk'’) were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell’s C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007). Conclusions/interpretation We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4485-y
      Issue No: Vol. 61, No. 3 (2018)
       
  • Clinical and metabolic features of the randomised controlled Diabetes
           Remission Clinical Trial (DiRECT) cohort
    • Authors: Roy Taylor; Wilma S. Leslie; Alison C Barnes; Naomi Brosnahan; George Thom; Louise McCombie; Naveed Sattar; Paul Welsh; Carl Peters; Sviatlana Zhyzhneuskaya; Kieren G. Hollingsworth; Ahmad Al-Mrabeh; Angela M. Rodrigues; Lucia Rehackova; Ashley J. Adamson; Falko F. Sniehotta; John C. Mathers; Hazel M. Ross; Yvonne McIlvenna; Sharon Kean; Ian Ford; Alex McConnachie; Michael E. J. Lean
      Pages: 589 - 598
      Abstract: Aims/hypothesis Substantial weight loss in type 2 diabetes can achieve a return to non-diabetic biochemical status, without the need for medication. The Diabetes Remission Clinical Trial (DiRECT), a cluster-randomised controlled trial, is testing a structured intervention designed to achieve and sustain this over 2 years in a primary care setting to determine practicability for routine clinical practice. This paper reports the characteristics of the baseline cohort. Methods People with type 2 diabetes for <6 years with a BMI of 27–45 kg/m2 were recruited in 49 UK primary care practices, randomised to either best-practice diabetes care alone or with an additional evidence-based weight management programme (Counterweight-Plus). The co-primary outcomes, at 12 months, are weight loss ≥15 kg and diabetes remission (HbA1c <48 mmol/mol [6.5%]) without glucose-lowering therapy for at least 2 months. Outcome assessors are blinded to group assignment. Results Of 1510 people invited, 423 (28%) accepted; of whom, 306 (72%) were eligible at screening and gave informed consent. Seven participants were later found to have been randomised in error and one withdrew consent, leaving 298 (176 men, 122 women) who will form the intention to treat (ITT) population for analysis. Mean (SD) age was 54.4 (7.6) years, duration of diabetes 3.0 (1.7) years, BMI 34.6 (4.4) kg/m2 for all participants (34.2 (4.2) kg/m2 in men and 35.3 (4.6) kg/m2 in women) and baseline HbA1c (on treatment) 59.3 (12.7) mmol/mol (7.6% [1.2%]). The recruitment rate in the intervention and control groups, and comparisons between the subgroups recruited in Scotland and England, showed few differences. Conclusions/interpretation DiRECT has recruited a cohort of people with type 2 diabetes with characteristics similar to those seen in routine practice, indicating potential widespread applicability. Over 25% of the eligible population wished to participate in the study, including a high proportion of men, in line with the prevalence distribution of type 2 diabetes. Trial registration www.controlled-trials.com/ISRCTN03267836; date of registration 20 December 2013
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4503-0
      Issue No: Vol. 61, No. 3 (2018)
       
  • Short-term progression of cardiometabolic risk factors in relation to age
           at type 2 diabetes diagnosis: a longitudinal observational study of
           100,606 individuals from the Swedish National Diabetes Register
    • Authors: Andri O. Steinarsson; Araz Rawshani; Soffia Gudbjörnsdottir; Stefan Franzén; Ann-Marie Svensson; Naveed Sattar
      Pages: 599 - 606
      Abstract: Aims/hypothesis The reasons underlying a greater association of premature mortality with early-onset type 2 diabetes relative to late-onset disease are unclear. We evaluated the clinical characteristics at type 2 diabetes diagnosis and the broad trajectories in cardiometabolic risk factors over the initial years following diagnosis in relation to age at diagnosis. Methods Our cohort consisted of 100,606 individuals with newly diagnosed type 2 diabetes enrolled in the Swedish National Diabetes Register from 2002 to 2012. The average follow-up time was 2.8 years. Analyses were performed using a linear mixed-effects model for continuous risk factors and a mixed generalised linear model with a logistic link function for dichotomous risk factors. Results The individuals diagnosed at the youngest age (18–44 years) were more often male and had the highest BMI (mean of 33.4 kg/m2) at diagnosis and during follow-up compared with all other groups (those diagnosed at 45–59 years, 60–74 years and ≥75 years; p < 0.05), being ~5 kg/m2 higher than the oldest group. Although HbA1c patterns were similar between all age groups, there was a difference of about 5 mmol/mol (0.45%) between the two groups at 8 years post-diagnosis (p < 0.05). Additionally, individuals diagnosed younger had ~0.7 mmol/l higher triacylglycerol, and ~0.2 mmol/l lower HDL-cholesterol levels at diagnosis relative to the oldest group. Such differences continued for several years post diagnosis. Yet, although more of these younger individuals were receiving oral glucose-lowering agents, other cardioprotective therapies were prescribed less often in this group. Differences in BMI, blood glucose and lipid levels remained with adjustment for potential confounders, including marital status, education and country of birth, and, where relevant, differential treatments by age, and in those with at least 5 years of follow-up. Conclusions/interpretation Individuals who develop type 2 diabetes at a younger age are more frequently obese, display a more adverse lipid profile, have higher HbA1c and a faster deterioration in glycaemic control compared with individuals who develop diabetes later in life. These differences largely remain for several years after diagnosis and support the notion that early-onset type 2 diabetes may be a more pathogenic condition than late-onset disease.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4532-8
      Issue No: Vol. 61, No. 3 (2018)
       
  • Rates of glycaemic deterioration in a real-world population with type 2
           diabetes
    • Authors: Louise A. Donnelly; Kaixin Zhou; Alex S. F. Doney; Chris Jennison; Paul W. Franks; Ewan R. Pearson
      Pages: 607 - 615
      Abstract: Aims/hypothesis There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration. Methods An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution. Results The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year. Conclusions/interpretation We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4519-5
      Issue No: Vol. 61, No. 3 (2018)
       
  • Risk of lower limb amputation in a national prevalent cohort of patients
           with diabetes
    • Authors: Jason K. Gurney; James Stanley; Steve York; Dieter Rosenbaum; Diana Sarfati
      Pages: 626 - 635
      Abstract: Aims/hypothesis Lower limb amputation is a serious complication of diabetes mellitus. Understanding how amputation risk differs by population subgroups is crucial in terms of directing preventive strategies. In this study, we describe those factors that impact amputation risk in the entire prevalent diabetic population of New Zealand. Methods A national prevalent cohort of 217,207 individuals with diabetes in 2010 were followed up until the end of 2013 for lower limb amputations, and 2014 for mortality. Inpatient hospitalisation data were used to define lower limb amputation using ICD-10 codes. Cox proportional hazards models were used to describe relative hazard of amputation over the follow-up period. Results A total of 784 individuals (3.6 cases/1000 individuals) underwent a major (above-ankle) lower limb amputation during follow-up, while 1217 (5.6/1000) underwent a minor (below ankle) amputation. The risk of major and minor amputation was 39% and 77% greater for men than women, respectively (adjusted HR: major amputation 1.39, 95% CI 1.20, 1.61; minor amputation 1.77, 95% CI 1.56, 2.00). Indigenous Māori were at 65% greater risk of above-knee amputation compared with the European/Other diabetic population (HR 1.65, 95% CI 1.37, 1.97). Amputation risk increased with increasing comorbidity burden, and peripheral vascular disease conferred the greatest independent risk of all comorbid conditions. Prior minor amputation increased the risk of subsequent major amputation by tenfold (HR 10.04, 95% CI 7.83, 12.87), and increased the risk of another minor amputation by 20-fold (HR 21.39, 95% CI 17.89, 25.57). Death was common among the total cohort, but particularly among those who underwent amputation, with more than half of those who underwent a major amputation dying within 3 years of their procedure (57%). Conclusions/interpretation Using a large, well-defined, national prevalent cohort of people with diabetes, we found that being male, indigenous Māori, living in deprivation, having a high comorbidity burden and/or having a previous amputation were strongly associated with subsequent risk of lower limb amputation. The use of this prevalent cohort strengthens the value of our estimates in terms of applicability to the general population, and highlights the subgroups at greatest risk of lower limb amputation.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4488-8
      Issue No: Vol. 61, No. 3 (2018)
       
  • IFN-α induces a preferential long-lasting expression of MHC class I in
           human pancreatic beta cells
    • Authors: Alexandra Coomans de Brachène; Reinaldo S. Dos Santos; Laura Marroqui; Maikel L. Colli; Lorella Marselli; Raghavendra G. Mirmira; Piero Marchetti; Decio L. Eizirik
      Pages: 636 - 640
      Abstract: Aims/hypothesis IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition. Methods IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot. Results IFN-α-induced expression of inflammatory and ER stress markers returned to baseline after 24–48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-α, prevented MHC class I overexpression, but when added 24 h after IFN-α exposure these inhibitors failed to accelerate MHC class I return to baseline. Conclusions/interpretation IFN-α mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-α-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-α inhibitors might need to be used at very early stages of the disease to be effective.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4536-4
      Issue No: Vol. 61, No. 3 (2018)
       
  • Systems biology of the IMIDIA biobank from organ donors and
           pancreatectomised patients defines a novel transcriptomic signature of
           islets from individuals with type 2 diabetes
    • Authors: Michele Solimena; Anke M. Schulte; Lorella Marselli; Florian Ehehalt; Daniela Richter; Manuela Kleeberg; Hassan Mziaut; Klaus-Peter Knoch; Julia Parnis; Marco Bugliani; Afshan Siddiq; Anne Jörns; Frédéric Burdet; Robin Liechti; Mara Suleiman; Daniel Margerie; Farooq Syed; Marius Distler; Robert Grützmann; Enrico Petretto; Aida Moreno-Moral; Carolin Wegbrod; Anke Sönmez; Katja Pfriem; Anne Friedrich; Jörn Meinel; Claes B. Wollheim; Gustavo B. Baretton; Raphael Scharfmann; Everson Nogoceke; Ezio Bonifacio; Dorothée Sturm; Birgit Meyer-Puttlitz; Ugo Boggi; Hans-Detlev Saeger; Franco Filipponi; Mathias Lesche; Paolo Meda; Andreas Dahl; Leonore Wigger; Ioannis Xenarios; Mario Falchi; Bernard Thorens; Jürgen Weitz; Krister Bokvist; Sigurd Lenzen; Guy A. Rutter; Philippe Froguel; Manon von Bülow; Mark Ibberson; Piero Marchetti
      Pages: 641 - 657
      Abstract: Aims/hypothesis Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). Methods Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. Results Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes. Conclusions/interpretation These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4500-3
      Issue No: Vol. 61, No. 3 (2018)
       
  • Combinatorial detection of autoreactive CD8 + T cells with HLA-A2
           multimers: a multi-centre study by the Immunology of Diabetes Society T
           Cell Workshop
    • Authors: Eddie A. James; on behalf of the Immunology of Diabetes Society T Cell Workshop Committee; Joana R. F. Abreu; John W. McGinty; Jared M. Odegard; Yvonne E. Fillié; Claire N. Hocter; Slobodan Culina; Kristin Ladell; David A. Price; Aimon Alkanani; Marynette Rihanek; Lisa Fitzgerald-Miller; Ania Skowera; Cate Speake; Peter Gottlieb; Howard W. Davidson; F. Susan Wong; Bart Roep; Roberto Mallone
      Pages: 658 - 670
      Abstract: Aims/hypothesis Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8+ T cell populations. Here, we set out to evaluate the performance of a combinatorial HLA-A2 multimer assay in a multi-centre setting. Methods The combinatorial HLA-A2 multimer assay was applied in five participating centres using centralised reagents and blinded replicate samples. In preliminary experiments, samples from healthy donors were analysed using recall antigen multimers. In subsequent experiments, samples from healthy donors and individuals with type 1 diabetes were analysed using beta cell antigen and recall antigen multimers. Results The combinatorial assay was successfully implemented in each participating centre, with CVs between replicate samples that indicated good reproducibility for viral epitopes (mean %CV = 33.8). For beta cell epitopes, the assay was very effective in a single-centre setting (mean %CV = 18.4), but showed sixfold greater variability across multi-centre replicates (mean %CV = 119). In general, beta cell antigen-specific CD8+ T cells were detected more commonly in individuals with type 1 diabetes than in healthy donors. Furthermore, CD8+ T cells recognising HLA-A2-restricted insulin and glutamate decarboxylase epitopes were found to occur at higher frequencies in individuals with type 1 diabetes than in healthy donors. Conclusions/interpretation Our results suggest that, although combinatorial multimer assays are challenging, they can be implemented in multiple laboratories, providing relevant T cell frequency measurements. Assay reproducibility was notably higher in the single-centre setting, suggesting that biomarker analysis of clinical trial samples would be most successful when assays are performed in a single laboratory. Technical improvements, including further standardisation of cytometry platforms, will likely be necessary to reduce assay variability in the multi-centre setting.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4508-8
      Issue No: Vol. 61, No. 3 (2018)
       
  • Adapting to insulin resistance in obesity: role of insulin secretion and
           clearance
    • Authors: Sang-Hee Jung; Chan-Hee Jung; Gerald M. Reaven; Sun H. Kim
      Pages: 681 - 687
      Abstract: Aims/hypothesis The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes. Methods Obese (BMI ≥30 kg/m2) individuals without diabetes (n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant). Results There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8–36.3] mmol/l × h) and insulin responses (1711 [1476–2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8–32.9] mmol/l × h, p = 0.04, and 851 [600–1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41–0.59]; SSPG-2, 0.43 [0.39–0.50]; SSPG-3, 0.34 [0.31–0.40]). Conclusions/interpretation While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4511-0
      Issue No: Vol. 61, No. 3 (2018)
       
  • Bioelectronic modulation of carotid sinus nerve activity in the rat: a
           potential therapeutic approach for type 2 diabetes
    • Authors: Joana F. Sacramento; Daniel J. Chew; Bernardete F. Melo; Matteo Donegá; Wesley Dopson; Maria P. Guarino; Alison Robinson; Jesus Prieto-Lloret; Sonal Patel; Bradley J. Holinski; Nishan Ramnarain; Victor Pikov; Kristoffer Famm; Silvia V. Conde
      Pages: 700 - 710
      Abstract: Aims/hypothesis A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents. Methods Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT. Results KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks. Conclusions/interpretation KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4533-7
      Issue No: Vol. 61, No. 3 (2018)
       
  • Development and characterisation of a novel glucagon like peptide-1
           receptor antibody
    • Authors: Emma K. Biggs; Lihuan Liang; Jacqueline Naylor; Shimona Madalli; Rachel Collier; Matthew P. Coghlan; David J. Baker; David C. Hornigold; Peter Ravn; Frank Reimann; Fiona M. Gribble
      Pages: 711 - 721
      Abstract: Aims/hypothesis Glucagon like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion by binding to GLP-1 receptors (GLP1Rs) on pancreatic beta cells. GLP-1 mimetics are used in the clinic for the treatment of type 2 diabetes, but despite their therapeutic success, several clinical effects of GLP-1 remain unexplained at a mechanistic level, particularly in extrapancreatic tissues. The aim of this study was to generate and characterise a monoclonal antagonistic antibody for the GLP1R for use in vivo. Methods A naive phage display selection strategy was used to isolate single-chain variable fragments (ScFvs) that bound to GLP1R. The ScFv with the highest affinity, Glp1R0017, was converted into a human IgG1 and characterised further. In vitro antagonistic activity was assessed in a number of assays: a cAMP-based homogenous time-resolved fluorescence assay in GLP1R-overexpressing cell lines, a live cell cAMP imaging assay and an insulin secretion assay in INS-1 832/3 cells. Glp1R0017 was further tested in immunostaining of mouse pancreas, and the ability of Glp1R0017 to block GLP1R in vivo was assessed by both IPGTT and OGTT in C57/Bl6 mice. Results Antibodies to GLP1R were selected from naive antibody phage display libraries. The monoclonal antibody Glp1R0017 antagonised mouse, human, rat, cynomolgus monkey and dog GLP1R. This antagonistic activity was specific to GLP1R; no antagonistic activity was found in cells overexpressing the glucose-dependent insulinotropic peptide receptor (GIPR), glucagon like peptide-2 receptor or glucagon receptor. GLP-1-stimulated cAMP and insulin secretion was attenuated in INS-1 832/3 cells by Glp1R0017 incubation. Immunostaining of mouse pancreas tissue with Glp1R0017 showed specific staining in the islets of Langerhans, which was absent in Glp1r knockout tissue. In vivo, Glp1R0017 reversed the glucose-lowering effect of liraglutide during IPGTTs, and reduced glucose tolerance by blocking endogenous GLP-1 action in OGTTs. Conclusions/interpretation Glp1R0017 is a monoclonal antagonistic antibody to the GLP1R that binds to GLP1R on pancreatic beta cells and blocks the actions of GLP-1 in vivo. This antibody holds the potential to be used in investigating the physiological importance of GLP1R signalling in extrapancreatic tissues where cellular targets and signalling pathways activated by GLP-1 are poorly understood.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4491-0
      Issue No: Vol. 61, No. 3 (2018)
       
  • Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts:
           inhibition of Na + /H + exchanger, lowering of cytosolic Na + and
           vasodilation
    • Authors: Laween Uthman; Antonius Baartscheer; Boris Bleijlevens; Cees A. Schumacher; Jan W. T. Fiolet; Anneke Koeman; Milena Jancev; Markus W. Hollmann; Nina C. Weber; Ruben Coronel; Coert J. Zuurbier
      Pages: 722 - 726
      Abstract: Aims/hypothesis Sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na+ ([Na+]c) and cytosolic Ca2+ ([Ca2+]c) concentrations through inhibition of Na+/H+ exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na+]c; (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. Methods Cardiac NHE activity and [Na+]c in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 μmol/l), DAPA (1 μmol/l), CANA (3 μmol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. Results EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH4 + pulse: EMPA 6.69 ± 0.09, DAPA 6.77 ± 0.12 and CANA 6.80 ± 0.18 vs vehicle 7.09 ± 0.09; p < 0.001 for all three comparisons) and reduced [Na+]c (in mmol/l: EMPA 10.0 ± 0.5, DAPA 10.7 ± 0.7 and CANA 11.0 ± 0.9 vs vehicle 12.7 ± 0.7; p < 0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na+-binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. Conclusions/interpretation EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na+]c, possibly by binding with the Na+-binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na+]c-lowering class effect of SGLT2i is a potential approach to combat elevated [Na+]c that is known to occur in heart failure and diabetes.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4509-7
      Issue No: Vol. 61, No. 3 (2018)
       
  • Loss of renal SNX5 results in impaired IDE activity and insulin resistance
           in mice
    • Authors: Fengmin Li; Jian Yang; Van Anthony M. Villar; Laureano D. Asico; Xiaobo Ma; Ines Armando; Hironobu Sanada; Minoru Yoneda; Robin A. Felder; Pedro A. Jose; Xiaoyan Wang
      Pages: 727 - 737
      Abstract: Aims/hypothesis We hypothesised that renal sorting nexin 5 (SNX5) regulates the insulin-degrading enzyme (IDE) and, thus, circulating insulin levels. We therefore studied the dynamic interaction between SNX5 and IDE in human renal proximal tubule cells (hRPTCs), as well as in rat and mouse kidneys. Methods The regulation of IDE by SNX5 expressed in the kidney was studied in vitro and in vivo. Snx5 or mock siRNA was added to immortalised hRPTCs (passage <20) in culture or selectively infused, via osmotic mini-pump, into the remnant kidney of uninephrectomised mice and rats. Results SNX5 co-localised with IDE at the plasma membrane and perinuclear area of hRPTCs and in the brush border membrane of proximal tubules of human, rat, and mouse kidneys. Insulin increased the co-localisation and co-immunoprecipitation of SNX5 and IDE in hRPTCs. Silencing SNX5 in hRPTCs decreased IDE expression and activity. Renal-selective silencing of Snx5 (SNX5 protein: 100 ± 25 vs 29 ± 10, p < 0.05 [% of control]) in C57Bl/6J mice decreased IDE protein (100 ± 13 vs 57 ± 6, p < 0.05 [% of control]) and urinary insulin excretion, impaired the responses to insulin and glucose, and increased blood insulin and glucose levels. Spontaneously hypertensive rats (SHRs) had increased blood insulin and glucose levels and decreased renal SNX5 (100 ± 27 vs 29 ± 6, p < 0.05 [% of control]) and IDE (100 ± 5 vs 75 ± 4, p < 0.05 [% of control]) proteins, compared with normotensive Wistar–Kyoto (WKY) rats. Kidney Snx5-depleted WKY rats also had increased blood insulin and glucose levels. The expression of SNX5 and IDE was decreased in RPTCs from SHRs and hypertensive humans compared with cells from normotensive volunteers, indicating a common cause for hyperinsulinaemia and hypertension. Conclusions/interpretation Renal SNX5 positively regulates IDE expression and function. This study is the first to demonstrate the novel and crucial role of renal SNX5 in insulin and glucose metabolism.
      PubDate: 2018-03-01
      DOI: 10.1007/s00125-017-4482-1
      Issue No: Vol. 61, No. 3 (2018)
       
 
 
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