DIRECT - Innovative Medicines Initiative:
DIabetes REsearCh on patient straTification


Zhou K*, Bellenguez C*, [46 authors], Palmer CNA*, Donnelly P*, Pearson ER*. Common variants near ATM are associated with glycaemic response to metformin in type 2 diabetes. Nature Genetics epub December 26, 2010.

Loss of function CYP2C9 variants improve therapeutic response to sulfonylureas – A Go-DARTS study. Zhou K, Donnelly L, Burch L, Doney ASF, Leese G, Hattersley AT, McCarthy MI, Morris AD, Lang CC, Palmer CNA, Pearson ER. Clin Pharmacol Ther. 2010 Jan;87(1):52-6. Epub 2009 Sep 30.

Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT; Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New England Journal of Medicine 2006; 355(5):467-77.

Total Soluble and Endogenous Secretory Receptor for Advanced Glycation Endproducts as Predictive Biomarkers of Coronary Heart Disease Risk in Patients with Type 2 Diabetes: An Analysis from the CARDS Trial. Colhoun, H; Betteridge J, Durrington P, Hitman G, Neil A, Livingstone S, Charlton-Menys V, Bao W, DeMicco D, Preston G, Deshmukh H, Tan K, Fuller J. Diabetes 2011 In press.

Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Charlton-Menys V, DeMicco DA, Fuller JH; CARDS Investigators. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009 Nov;54(5):810-9.

Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004 Aug 21-27;364(9435):685-96.

Mari A, Ferrannini E: Beta-cell function assessment from modelling of oral tests: an effective approach. Diabetes Obes Metab 10 Suppl 4:77-87, 2008.

Mari A, Tura A, Natali A, Laville M, Laakso M , Gabriel R, Beck-Nielsen H, Ferrannini E: Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance. Diabetologia 53:749-756, 2010.

Ferrannini E, Natali A, Muscelli E, Nilsson PM, Golay A, Laakso M, Beck-Nielsen H, Mari A: Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study. Diabetologia 54:1507-1516, 2011.

Pers TH, Hansen NT, Lage K, Koefoed P, Dworzynski P, Miller ML, Flint TJ, Mellerup E, Dam H, Andreassen O, Djurovic S, Melle I, Børglum A, Werge T, Purcell S, Ferreira M, Kouskoumvekaki I, Workman CT, Hansen T, Mors O, Brunak S Meta-analysis of heterogeneous data sources for genome-scale identification of risk genes in complex phenotypes, Genet Epidemiol. 2011; doi: 10.1002/gepi.20580.

Lage K, Hansen NT, Karlberg EO, et al. A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes, PNAS 2008; 105:20870-20875.

Lage K, Karlberg EO, Størling ZM, Olason PI, Pedersen AG, Rigina O, Hinsby AM, Tumer Z, Pociot F, Tommerup N, Moreau Y, Brunak S. A human phenomeinteractome network of protein complexes implicated in genetic disorders. Nat Biotechnol 2007; 25:309-16.

Herzberg-Schäfer SA, Staiger H, Heni M, Ketterer C, Guthoff M, Kantartzis K, Machicao F, Stefan N, Häring HU, Fritsche A. Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function. PLoS One. 2010; 5:e14194.

Heni M, Ketterer C, Hart LM, Ranta F, van Haeften TW, Eekhoff EM, Dekker JM, Boomsma DI, Nijpels G, Kramer MH, Diamant M, Simonis-Bik AM, Heine RJ, de Geus EJ, Schäfer SA, Machicao F, Ullrich S, Thamer C, Stefan N, Staiger H, Häring HU, Fritsche A. The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia. J Clin Endocrinol Metab. 2010;95:E479-84.

Heni M, Ketterer C, Thamer C, Herzberg-Schäfer SA, Guthoff M, Stefan N, Machicao F, Staiger H, Fritsche A, Häring HU. Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion. Diabetes. 2010;59:3247-52.

Illig T, et al. (2010) Nat Genet 42(2): 137-1412.

Suhre K, et al. (2010) PLoS One. 11;5(11):e139533.

Thorand B et al. (2005) Diabetes. Oct;54(10):2932-8.

Gaulton KJ , Nammo T , Pasquali L , Simon J , Giresi PG , Fogarty MP , Panhuis TM , Mieczkowski P , Secchi A ,Bosco D , Berney T , Montanya E , Mohlke KL , Lieb JD , Ferrer J. A map of open chromatin in human pancreatic islets - Nat Genet. 2010 Mar;42(3):255-9.

van Arensbergen, Javier García-Hurtado, Ignasi Moran, Miguel Angel Maestro, Xiaobo Xu, Mark Van de Casteele, Anouchka L. Skoudy, Matteo Palassini, Harry Heimberg, Jorge Ferrer Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing β-cells to adopt a neural gene activity program. Genome Res. 2010 Jun;20(6):722-32.

Alsaleh A, etal RISCK Study Group. Single nucleotide polymorphisms at the ADIPOQ gene locus interact with age and dietary intake of fat to determine serum adiponectin in subjects at risk of the metabolic syndrome. Am J Clin Nutr. 2011 May 11.

Bodinham CL, etal. Short-term effects of whole-grain wheat on appetite and food intake in healthy adults: a pilot study. Br J Nutr. 2011 Apr 18:1-4.

Walker CG, etal RISCK Study Group. Variation in the FFAR1 Gene Modifies BMI, Body Composition and Beta-Cell Function in Overweight Subjects: An Exploratory Analysis. PLoS One. 2011 Apr 28;6(4):e19146.

Thomas EL, etal. The Missing Risk: MRI and MRS Phenotyping of Abdominal Adiposity and Ectopic Fat. Obesity (Silver Spring). 2011 Jun 9. doi: 10.1038/oby.2011.142.

Modi N, etal. The influence of maternal Body Mass Index on infant adiposity and hepatic lipid content. Pediatr Res. 2011 May 27.

Hankir MK, etal. Peptide YY 3-36 and pancreatic polypeptide differentially regulate hypothalamic neuronal activity in mice in vivo as measured by manganese-enhanced magnetic resonance imaging. J Neuroendocrinol. 2011 Apr;23(4):371-80.

Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernérus H, Björling L, Ponten F. (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 2010 28(12):1248-50.

Rockberg J, Löfblom J, Hjelm B, Ståhl S, Uhlen M. (2010) Epitope mapping using gram-positive surface display. Curr Protoc Immunol. 9:Unit 9.9.

Lundberg E, Uhlen M. (2010) Creation of an antibody-based subcellular protein atlas. Proteomics, 10(22):3984-96.

Jonasson K, Berglund L, Uhlen M. (2010) The 6th HUPO Antibody Initiative (HAI) workshop: sharing data about affinity reagents and other recent developments. September 2009, Toronto, Canada. Proteomics. 10(11):2066-8.

Fagerberg L, Jonasson K, von Heijne G, Uhlen M, Berglund L. (2010) Prediction of the human membrane proteome. Proteomics 10(6):1141-9.

Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfelt O, Spruck C, Leibold EA, Wohlschlegel JA. (2009) Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science. 326(5953):718-21.

Rockberg J, Uhlen M. (2009) Prediction of antibody response using recombinant human protein fragments as antigen. Protein Science 18(11):2346-55.

Bouatia-Naji N, Bonnefond A et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009 Jan;41(1):89-94.

Walters RG, Jacquemont S, Valsesia A, et al A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010 Feb 4;463(7281):671-5.

Bouatia-Naji N, Rocheleau G, et al A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science. 2008 May 23;320(5879):1085-8.

Sladek R, Rocheleau G, Rung J, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007 Feb 22;445(7130):881-5.

Babenko AP et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006 Aug 3;355(5):456-66.

't Hart,LM, Simonis-Bik,AM, Nijpels,G et al.: A Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First Phase Glucose Stimulated Insulin Secretion During Hyperglycemic Clamps. Diabetes 59:287-293, 2010.

Simonis-Bik,AM, Nijpels,G, Van Haeften,TW et al., 't Hart,LM: Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A and MTNR1B affect different aspects of pancreatic beta cell function. Diabetes 59:293-301, 2010.

Reiling,E, Jafar-Mohammadi,B, van 't Riet,E, et al. Mccarthy,MI, 't Hart,LM: Genetic association analysis of LARS2 with type 2 diabetes. Diabetologia 53:103-110, 2010.

Reiling,E, van 't Riet,E, Groenewoud,MJ, Welschen,LM, et al. 't Hart,LM: Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk. Diabetologia 52:1866-1870, 2009.

Maassen,Ja, 't Hart,LM, Ouwens,DM: Lessons that can be learned from patients with iabetogenic mutations in mitochondrial DNA: Implications for common type 2 diabetes. Current Opinion in Clinical Nutrition and Metabolic Care 10:693-697, 2007.

Manimozhiyan A et al.: Enterotypes of the human gut microbiome. Nature 473: 174–180, 2011.

Li Y, Vinckenbosch N, Tian G et al.: Resequencing of 200 human exomes identifies an excess of low-frequency nonsynonymus coding variations. Nature Genetics 42:969-72, 2010.

Qin J, Li R, Raes J, et al.: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59-65, 2010.

Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. New Engl J Med 362, 485-93, 2010.

Dupuis J., Lyssenko V, Franks PW, Groop L., Barroso. Novel genetic loci implicated in fasting glucose homeostasis and their impact on related metabolic traits. Nat Genet 42, 105-16, 2010.

Rosengren AH, Jobubka R, Tojjar D, Granhall C, Tuncel J, Eliasson L, Groop L, Rorsman P, Salehi A, Lyssenko V, Luthman H and Renström E: Overexpression of alpha-2-adrenergic receptor contributes to type 2 diabetes. Science 327:217-20, 2010.

Saxena R, Lyssenko V (PI:s Altshuler D, Groop L, Hughes T): Genome-Wide Association Analysis identifies loci for Type 2 Diabetes and triglyceride levels. Science 316;1331-1336, 2007.

Ingelsson E, (57 authors), Walker M, Wareham NJ, Meigs JB, McCarthy MI, Groop L, Watanabe RM, Florez JC, MAGIC Investigators. Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans. Diabetes 59: 1266-1275, 2010.

Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, The RISC Consortium, The UK Type 2 Diabetes Genetics Consortium, RISC consortium, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, Frayling TM, Walker M. Common variants of the novel type 2 diabetes genes, CDKAL1 and HHEX/IDE, are associated with decreased pancreatic ß-cell function. Diabetes 56: 3101-3104, 2007.

Walker M, Mari A, Jayapaul MK, Bennett SMA, Ferrannini E. Impaired beta-cell glucose sensitivity and whole body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects. Diabetologia 48: 2470-2476, 2005.

Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Ellard S, Hattersley AT. Urinary Cpeptide to creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1 alpha/hepatocyte nuclear factor 4 alpha Maturity Onset Diabetes of the Young from young duration type 1diabetes. Diabetes Care 2011 in press.

Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet. 2003 Oct 18;362(9392):1275-81.

Pearson ER, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006 Aug 3;355(5):467-77.

Montgomery et al. 2011 PLoS Genetics in press.

Montgomery et al. 2010. Nature 464: 773-777.

Dermitzakis E.T. and A.G. Clark. 2009. Science 326: 239-240.

Dimas A.S., et al. 2009. Science 325: 1246-1250.

Stranger, B.E et al.. 2007. Nature Genetics 39: 1217.

Stranger, B.E., et al. 2007. Science 315: 848-853.

Halban, P.A., German, M.S., Kahn, S.E. and Weir, G.C. Current status of islet cell replacement and regeneration therapy. J. Clin. Endocrinol. Metab. 95:1034-1043 (2010).

Donath, M.Y., Marianne Böni-Schnetzler, M., Ellingsgaard, Halban, P.A. and Ehses, J.A. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol. Metab. 21: 261-267 (2010).

Bouzakri, K., Plomgaard, P., Berney, T., Donath, M.Y., Pedersen, B.K. and Halban P.A. Bimodal effect on pancreatic beta-cells of secretory products from normal or insulin resistant human skeletal muscle. Diabetes In Press.

Frayling TM et al. Science 2007;316:889-894.

Zeggini E et al. Science 2007 316:1336-1341.

The Wellcome Trust Case Control Consortium. Nature 2007;447:661-678.

Zeggini E et al. Nat Gen 2008; 40:638-645.

Loos RJF et al.. Nat Gen 2008;40:768-775.

Prokopenko I et al. Nat Gen 2009;41:77-81.

Willer CJ et al. Nat Gen 2009;41:25-34.

Dupuis J et al. Nat Gen 2010;42:105-116.

Moore et al. JAMA. 2010;303:1282-1287.

Speliotes EK et al. Nat Gen 2010;42:937-948.

Heid IM et al. Nat Gen 2010;42:949-960.

Voight BF et al. Nat Gen 2010;42:579-589.

Kaye J and Spencer D. Developing Interdisciplinary Research on the Ground - Barriers and Opportunities In –Spires 2010 Vol.5, No.1, 40-54.

Kaye J, Boddington P, de Vries J, Hawkins N, Melham K, Ethical Implications of the Use of Whole Genome Methods in Medical Research European Journal of Human Genetics 2010 18:398-403.

Curren L, Boddington P, Gowans H, Hawkins N, Kanellopoulou N, Kaye J, and Melham K (2010) Identifiability, Genomics and U.K. data protection law. Eur J Health Law, 17(4):329-44.

Heeney C, de Vries J, Hawkins N, Boddington P, Kaye J Assessing the Privacy Risks of Data Sharing in Genomics Public Health Genomics (DOI:10.1159/000294150) Published Online: 29/03/2010

Kaye Jane (2010) Building a Foundation for Biobanking: The 2009 OECD Guidelines on Human Biobanks and Genetic Research Databases (HBGRDs) European Journal of Health Law, 17:187- 190.

Alssema M, Vistisen D, Heymans MW, Nijpels G, Glümer C, Zimmet PZ, Shaw JE, Eliasson M, Stehouwer CD, Tabák AG, Colagiuri S, Borch-Johnsen K, Dekker JM; for the DETECT-2 collaboration. The evaluation of screening and early detection strategies for type 2 diabetes and impaired glucose tolerance (DETECT-2) update of the Finnish diabetes risk score for prediction of incident type 2 diabetes. Diabetologia 2011; 54: 1004-1012.

Lamberts EJ, Nijpels G, Welschen LM, Hugtenburg JG, Dekker JM, Souverein PC, Bouvy ML. Long term patterns of use after initiation of oral antidiabetic drug therapy. Pharmacoepidemiol Drug Saf 2011; 20: 351-835.

Rijkelijkhuizen JM, McQuarrie K, Girman CJ, Stein PP, Mari A, Holst JJ, Nijpels G, Dekker JM. Effects of meal size and composition on incretin, alpha-cell and beta-cell responses. Metabolism 2010; 59: 502-511.

Simonis-Bik AM, Boomsma DI, Dekker JM, Diamant M, de Geus EJ, 't Hart LM, Heine RJ, Kramer MH, Maassen JA, Mari A, Tura A, Willemsen G, Eekhoff EM. The heritability of beta cell function parameters in a mixed meal test design. Diabetologia 2011; 54:1043–1051.

Zavrelova H, Hoekstra T, Alssema M, Welschen LM, Nijpels G, Moll AC, de Vet HC, Polak BC, Dekker JM. Progression and regression: distinct developmental patterns of diabetic retinopathy in patients with type 2 diabetes treated in the diabetes care system west-friesland, the Netherlands. Diabetes Care 2011; 34: 867-872.

Brorsson C, Hansen NT, Bergholdt R, Brunak S, Pociot F and T1DGC. The type 1 diabetes – MHC susceptibility interactome – Identification of HLA genotype-specific disease genes for type 1 diabetes. PLoS One. Mar 5;5(3):e9576, 2010.

Bergholdt R, Brorsson C, Lage K, Nielsen JH, Brunak S and Pociot F. Expression profiling of human genetic and protein interaction networks in Type 1 Diabetes. Plos ONE, 4: issue 7, e250, 2009.

Bergholdt R. Understanding type 1 diabetes genetics – approaches for identification of susceptibility genes in multi-factorial diseases. Danish Medical Bulletin. Volume 56(1):1-39, 2009.

Brorsson C, Hansen NT, Lage K, Bergholdt R, Brunak S, Pociot F, Type 1 Diabetes Genetics Consortium. Identification of T1D susceptibility genes within the MHC region by combining protein interaction networks and SNP genotyping data. Diabetes, Obesity and Metabolism. 11 Suppl 1:60-6, 2009.

Bergholdt R, Størling ZM, Lage K, Karlberg EO, Òlason PÌ, Aalund M, Nerup J, Brunak S, Workman CT, Pociot F. Novel human protein networks of genetic interactions in type 1 diabetes. Genome Biology, 8:R253, 2007.

Bergholdt R, Karlsen AE, Hagedorn PH, Aalund M, Nielsen JH, Kruhøffer M, Ørntoft T, Wang H, Wollheim CB, Nerup J, Pociot F. Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets. Genes and Immunity, 8(3): 232-238, 2007.

Mathurin P, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.  Gastroenterology. 2009;137(2):532-4.

Vantyghem MC et al. Primary graft function, metabolic control, and graft survival after islet transplantation. Diabetes Care. 2009;32(8):147.

Caiazzo R et al. Long-term metabolic outcome and quality of life after laparoscopic adjustable gastric banding in obese patients with type 2 diabetes mellitus or impaired fasting glucose. Br J Surg. 2010;97:884-91.

Walters RG et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010 4;463(7281):671-5.

Pattou F et al. GLP1-receptor scanning for imaging of beta cells transplanted in muscle. New Engl J Med. 2010 23 ;363(13):12.