Aims/hypothesisThe DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.MethodsPrediabetic participants (target sample size 2,200–2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires.Conclusions/interpretationDIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3216-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:

Aims-Small, short studies suggest metformin influences the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM). In the Carotid Atherosclerosis: Metformin for insulin ResistAnce (CAMERA) trial (NCT00723307) we investigated whether this effect is sustained and related to changes in glycaemia or weight. In the cross-sectional DIabetes Contributors: DP had the idea for and designed the analysis, analysed and interpreted data, wrote the first draft and revised later drafts of the article. AD analysed the DIRECT data and contributed to the manuscript. ERP, PWF, AJ and MW participated in the design and sample collection of the DIRECT diabetes progression study, interpreted the data and revised the manuscript. PW coordinated the laboratory work for GLP-1 and leptin measurements, interpreted data and revised the article. CS analysed leptin, analysed and interpreted the data and revised the article. RRH interpreted the data and revised the article. NS had the idea for and designed the analysis, interpreted data, revised the article, and supervised the analysis. DIRECT collaborators are listed in Supplementary Table 3.Conflicts of interest: DP, PW, CS, AJ, THH, JD, and RK report no conflicts of interest. RRH has received research support from Amylin, Bayer, Merck, and Novartis; participated in advisory boards for Amylin, Lilly, Merck, Novartis, and Novo Nordisk; and received compensation for lectures from Bayer, Lilly, Merck, and Merck Serono. ERP has received lecture fees from Eli Lilly, Novo Nordisk, Astra Zeneca and Sanofi. NS has consulted for Eli Lilly, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Sanofi, and Boehringer Ingelheim; and received research support from Merck. PWF has received consulting honoraria from Sanofi Aventis and Eli Lilly Inc, and research support from Novo Nordisk. REsearCh on patient straTification (DIRECT) study, we investigated basal and post-meal GLP-1 levels in diabetic patients. Europe PMC Funders GroupMaterials and Methods-CAMERA was a double-blinded randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using six-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures and ANCOVA analyses. In DIRECT, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 patients recently diagnosed with T2DM treated with metformin or diet, using Student's T-tests and linear regression. but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and HbA1c. Results-InConclusions-In non-diabetic individuals, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated diabetic patients also have higher fasted GLP-1 independent of weight and glycaemia.

Highlights d Soft clustering based on 32 phenotypes identified 4 quantitative archetypes d These reflect different patterns of dysfunction across T2D etiological processes d The four archetypes are different in disease progression, GRSs, and omics signals d Some patients are dominated by one archetype, but many have etiological combinations

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/m 2 ; 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/m 2 ; 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. Electronic supplementary mater...

Genome-Wide Association Study (GWAS) Higher Blood pressure Arthritides Neuropsychiatric conditions Malignancies Lower Anaemias Lipidaemias Ischaemic heart disease Genetically higher central obesity Highlights Variants in HFE and TMPRSS6 are associated with higher liver iron. There is genetic evidence that higher central obesity causes higher liver iron. Liver iron variants are not organ specific and associate with multiple diseases.

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

It is now widely acknowledged that autologous leucocytes are inappropriately activated during cardiopulmonary bypass (CPB). Removal of these activated leucocytes has been proposed as a clinical intervention. Several papers have recently reported benefits of systemic leucocyte depletion during CPB. There is also evidence that leucocyte-depleted blood cardioplegia is advantageous in the globally ischaemic human heart transplant setting. Recently, a new leucocyte-depleting filter for blood cardioplegia has been developed (Pall, BC1). In this paper, we report on the safety and efficiency of this device in the clinical situation. Fourteen patients undergoing routine cardiac surgery were recruited into this study. The BC1 blood cardioplegia filter was found to be an efficient leucocyte-depleting device, removing in excess of 70% (p = 0.001) of white blood cells, on average, from up to 5.3 litres of blood cardioplegia. The filter removed a small proportion of platelets (typically 11.3%), however, this was not statistically significant and no bleeding problems were encountered. Red cell removal was negligible and was not statistically significant, and no evidence of haemolysis was noted. The filter offered a very low resistance to flow with a mean pressure drop (deltaP) of 10.8 mmHg at a mean flow rate of 315 ml/min. We conclude that the Pall BC1 filter is a safe and efficient device for use with blood cardioplegia.