638 research outputs found
Precision diabetes: learning from monogenic diabetes.
The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6Â months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).
Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.
Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.
Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Unionâs Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. RWK was funded by a STAR Award Novo Nordisk co-financed PhD fellowship. The work undertaken by PWF was supported in part by programme grants from the ERC-2015-CoG_NASCENT_681742 and the Swedish Research Council; strategic funding for Lund University Diabetes Centre, where some of the work described herein was performed, was provided by the Swedish Research Council, Strategic Research Area Exodiab, (Dnr 2009-1039), the Swedish Foundation for Strategic Research (IRC15-0067), the Swedish Research Council, Linnaeus grant (Dnr 349-2006-237). EP holds a Wellcome Trust Investigator award (grant reference 102820/Z/13/Z). Contributions to this work by SBru. were co-financed by the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001).published version, accepted version (12 month embargo), submitted versio
Parental diabetes and birthweight in 236 030 individuals in the UK biobank study
This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.BACKGROUND: The UK Biobank study provides a unique opportunity to study the causes and consequences of disease. We aimed to use the UK Biobank data to study the well-established, but poorly understood, association between low birthweight and type 2 diabetes. METHODS: We used logistic regression to calculate the odds ratio for participants' risk of type 2 diabetes given a one standard deviation increase in birthweight. To test for an association between parental diabetes and birthweight, we performed linear regression of self-reported parental diabetes status against birthweight. We performed path and mediation analyses to test the hypothesis that birthweight partly mediates the association between parental diabetes and participant type 2 diabetes status. RESULTS: Of the UK Biobank participants, 277 261 reported their birthweight. Of 257 715 individuals of White ethnicity and singleton pregnancies, 6576 had type 2 diabetes, 19 478 reported maternal diabetes (but not paternal), 20 057 reported paternal diabetes (but not maternal) and 2754 participants reported both parents as having diabetes. Lower birthweight was associated with type 2 diabetes in the UK Biobank participants. A one kilogram increase in birthweight was associated with a lower risk of type 2 diabetes (odds ratio: 0.74; 95% CI: 0.71, 0.76; P = 2 Ă 10(-57)). Paternal diabetes was associated with lower birthweight (45 g lower; 95% CI: 36, 54; P = 2 Ă 10(-23)) relative to individuals with no parental diabetes. Maternal diabetes was associated with higher birthweight (59 g increase; 95% CI: 50, 68; P = 3 Ă 10(-37)). Participants' lower birthweight was a mediator of the association between reported paternal diabetes and participants' type 2 diabetes status, explaining 1.1% of the association, and participants' higher birthweight was a mediator of the association between reported maternal diabetes and participants' type 2 diabetes status, explaining 1.2% of the association. CONCLUSIONS: Data from the UK Biobank provides the strongest evidence by far that paternal diabetes is associated with lower birthweight, whereas maternal diabetes is associated with increased birthweight. Our findings with paternal diabetes are consistent with a role for the same genetic factors influencing foetal growth and type 2 diabetes.ERDF (European Regional Development Fund)ESF (European Social Fund) Convergence Programme for Cornwall and the Isles of ScillyWellcome TrustThe European Research CouncilDiabetes U
Le secteur des télécommunications surfe-t-il de bulle en bulle ?
Le secteur des tĂ©lĂ©communications a connu un dĂ©veloppement rapide qui sâest accĂ©lĂ©rĂ© Ă partir de la deuxiĂšme moitiĂ© des annĂ©es 1990, avec lâapparition du GSM et de lâInternet. Mais la croissance rĂ©elle du secteur sâest rapidement transformĂ©e en une gigantesque bulle financiĂšre qui a Ă©tĂ© Ă lâorigine de lâune des pires crises sectorielles quâaient connu les Ă©conomies modernes. Dans cet article, nous essayons dâidentifier les facteurs qui ont conduit Ă une telle valorisation financiĂšre des entreprises de tĂ©lĂ©communications ainsi que ceux qui ont conduit au retournement des marchĂ©s financiers. Enfin, Ă la veille de la mise en place de lâUMTS, certains Ă©lĂ©ments nous amĂšnent Ă penser quâune nouvelle bulle pourrait se former dans les annĂ©es Ă venir. En annexes, nous simulons la rentabilitĂ© financiĂšre de lâUMTS et Ă©valuons lâimpact macroĂ©conomique de ce projet sur les composantes de la croissance française.The telecommunication sector has recently undergone a fast development which accelerated from the second half of the 1990s, with the rise of the GSM and the Internet. But the actual growth of the sector turned into a gigantic financial bubble which was at the origin of one of the worst sector-based crises that the modern economies had seen. In this article, we try to identify the factors driving such a financial valuation of the telecommunications companies as well as those leading to the reversal of financial markets. Finally, on the verge of the implementation of the UMTS in France, some elements let us think that a new bubble might appear in the coming years. In the appendices, we simulate the financial profitability of the UMTS and estimate the macroeconomic impact of this project on the constituents of French economic growth
A genetic syndrome of chronic renal failure with multiple renal cysts and early onset diabetes
Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia
This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control.European
Communityâs Seventh Framework ProgrammeNIHR Exeter Clinical Research FacilityWellcome Trus
Costs and Treatment Pathways for Type 2 Diabetes in the UK:A Mastermind Cohort Study
This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.INTRODUCTION: Medication therapy for type 2 diabetes has become increasingly complex, and there are few reliable data on the current state of clinical practice. We report treatment pathways and associated costs of medication therapy for people with type 2 diabetes in the UK, their variability and changes over time. METHODS: Prescription and biomarker data for 7159 people with type 2 diabetes were extracted from the GoDARTS cohort study, covering the period 1989-2013. Average follow-up was 10Â years. Individuals were prescribed on average 2.4 (SD: 1.2) drugs with average annual costs of ÂŁ241. We calculated summary statistics for first- and second-line therapies. Linear regression models were used to estimate associations between therapy characteristics and baseline patient characteristics. RESULTS: Average time from diagnosis to first prescription was 3Â years (SD: 4.0Â years). Almost all first-line therapy (98%) was monotherapy, with average annual cost of ÂŁ83 (SD: ÂŁ204) for 3.8Â (SD: 3.5)Â years. Second-line therapy was initiated in 73% of all individuals, at an average annual cost of ÂŁ219 (SD: ÂŁ305). Therapies involving insulin were markedly more expensive than other common therapies. Baseline HbA1c was unrelated to future therapy costs, but higher average HbA1c levels over time were associated with higher costs. CONCLUSIONS: Medication therapy has undergone substantial changes during the period covered in this study. For example, therapy is initiated earlier and is less expensive than in the past. The data provided in this study will prove useful for future modelling studies, e.g. of stratified treatment approaches.The authors gratefully acknowledge funding by the Medical Research Council (MRC) and the Association of the British Pharma Industry (ABPI) for âMastermindâ (MRC APBI STratification and Extreme Response Mechanism IN DiabetesâMASTERMIND. Grant Ref.: MRIK005707/1). ERP holds Wellcome Trust New Investigator award 102820/Z/13/Z. GoDARTS was funded by the Wellcome Trust as the Wellcome Trust Type 2 diabetes case control study
Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes:A joint modelling approach
This is the author accepted manuscript. The final version is available from Dove Medical Press via the DOI in this record.Data statement:
No additional data are available from the authors although the individual participant data from the ADOPT trial used in this study are available from GlaxoSmithKline on application via www.clinicalstudydatarequest.comObjective: Precision medicine drug therapy seeks to maximise efficacy and minimise harm for individual patients. This will be difficult if drug response and side-effects are positively associated, meaning patients likely to respond best are at increased risk of side-effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and risk of side-effects (survival outcome) for patients initiating type 2 diabetes therapy.
Study Design and Setting: Participants were randomised to metformin, sulfonylurea or thiazolidinedione therapy in the ADOPT drug-efficacy trial (n=4,351). Joint models were parameterised for: 1) current HbA1c response (change from baseline in HbA1c); 2) cumulative HbA1c response (total HbA1c change).
Results: With metformin, greater HbA1c response did not increase risk of gastrointestinal events (Hazard ratio (HR) per 1% absolute greater current response 0.82 (95% confidence interval 0.67,1.01); HR per 1% higher cumulative response 0.90 (0.81,1.00)). With sulfonylureas, greater current response was associated with increased risk of hypoglycaemia (HR 1.41 (1.04,1.91)). With thiazolidinediones, greater response was associated with increased risk of oedema (current HR 1.45 (1.05,2.01); cumulative 1.22 (1.07,1.38)) but not fracture.
Conclusion: Joint modelling provides a useful framework to evaluate the association between response to a drug and risk of developing side-effects. There may be great potential for widespread application of joint modelling to evaluate the risks and benefits of both new and established medications.This work was supported by the Medical Research Council (UK) (Grant MR/N00633X/1). ATH is a NIHR Senior Investigator and a Wellcome Trust Senior Investigator. ERP is a Wellcome Trust New Investigator (102820/Z/13/Z). AGJ is supported by an NIHR Clinician Scientist award. ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. WEH received additional support from IQVIA and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR CLAHRC South West Peninsula)
Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3
ArtĂculo de publicaciĂłn ISIOBJECTIVEâNEUROG3 plays a central role in the development
of both pancreatic islets and enteroendocrine cells. Homozygous
hypomorphic missense mutations in NEUROG3 have been recently
associated with a rare form of congenital malabsorptive diarrhea
secondary to enteroendocrine cell dysgenesis. Interestingly, the
patients did not develop neonatal diabetes but childhood-onset
diabetes. We hypothesized that null mutations in NEUROG3
might be responsible for the disease in a patient with permanent
neonatal diabetes and severe congenital malabsorptive diarrhea.
RESEARCH DESIGN AND METHODSâThe single coding
exon of NEUROG3 was amplified and sequenced from genomic
DNA. The mutant protein isoforms were functionally characterized
by measuring their ability to bind to an E-box element in the
NEUROD1 promoter in vitro and to induce ectopic endocrine cell
formation and cell delamination after in ovo chicken endoderm
electroporation.
RESULTSâTwo different heterozygous point mutations in
NEUROG3 were identified in the proband [c.82G.T (p.E28X)
and c.404T.C (p.L135P)], each being inherited from an unaffected
parent. Both in vitro and in vivo functional studies indicated
that the mutant isoforms are biologically inactive. In
keeping with this, no enteroendocrine cells were detected in intestinal
biopsy samples from the patient.
CONCLUSIONSâSevere deficiency of neurogenin 3 causes
a rare novel subtype of permanent neonatal diabetes. This finding
confirms the essential role of NEUROG3 in islet development and
function in humans
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Gain-of-Function Mutations in the K<sub>ATP</sub> Channel (KCNJ11) Impair Coordinated Hand-Eye Tracking
Background: Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease.Methods: Control participants (nâ=â14), patients with iDEND syndrome (nâ=â6 or 7), and patients with PNDM (nâ=â7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing.Results: No differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (pâ=â0.009) and more velocity errors (p â=â0.009) than controls.Conclusions: These results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms.</p
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