The DIAbetes COhoRtE (DIACORE) study is a large cohort of prevalent DM2 patients in Germany that started recruitment in February 2010 for long term prospective observation with follow-up examinations every 2 years. DIACORE aims to elucidate novel mechanisms involved in the development of DM2 complications with a focus on diabetes-associated kidney disease. To achieve this, standardized phenotyping is being performed every 2 years, with biobanking of serum, plasma, DNA, mRNA and urine for future scientific analyses. All procedures are standardized for collaborative projects with population-based [30
] and disease-based cohorts [35
]. Due to its size and prospective design, DIACORE is an important extension to the current worldwide repertoire of DM2 cohorts of Caucasian descent investigating diabetes complications [15
] and the first of comparable size in Germany.
DIACORE aims to recruit a representative sample of outpatient, ambulating DM2 patients in Germany. We have adopted a strategy of addressing eligible patients via several channels to achieve this aim: 1) a wide range of public communication media including local press and patient organisations, 2) major health insurance companies, 3) all general practitioners and 4) all diabetes specialists in a defined geographic region. Once the cohort is recruited, comparisons with the DM2 subsets of large population-based cohorts [4
] and with data from German diabetes disease management data bases will serve to assess potential bias.
We have purposefully avoided using the term “diabetic nephropathy” to describe renal outcomes in DIACORE since a clinical diagnosis of diabetic nephropathy based only on proteinuria, eGFR and history is subject to misclassification if a kidney biopsy is not performed [54
]: in biopsy studies, nondiabetic glomerulopathies could be detected in about 23-33% of DM2 patients with macroalbuminuria. Further, it has been shown in DM1 and DM2 patients that a substantial proportion of DM patients develop decreased eGFR without concurrent or prior elevation of albuminuria [58
], suggesting an underlying non-diabetic kidney disease such as hypertension-associated nephrosclerosis. In addition, genetic studies have demonstrated disparate genetic underpinnings for albuminuria and eGFR in both the general population and in diabetes patients [21
]. Taken together, these data support the concept of separate analyses of these traits.
DM2 incidence and prevalence is increasing in industrialized countries. In addition to the disease itself, its complications are a major public health and financial challenge. Thus, the investigation of factors involved in the development and progression of diabetic complications, including CKD, is essential to develop novel strategies for prevention and therapy.
An innovative approach for uncovering mechanisms underlying common diseases includes unbiased high-throughput screening of biomaterials using methods such as genome-wide association studies (GWAS) [29
], and complementary analyses of the metabolome, transcriptome and proteome [64
]. This approach has the advantage of a systematic analysis without prior biological hypothesis, thus bearing the potential of uncovering unexpected and completely novel mechanisms of disease. In this sense, GWAS have been successful for the majority of common diseases [66
] including DM2 and chronic kidney disease (CKD). For example, UMOD
, the gene encoding Uromodulin or Tamm-Horsfall-Protein, is among the loci associated with CKD [24
]. This protein has long been known to be the quantitatively most important protein in human urine, but its function is unknown. Research is now focusing on the mechanisms involved in affecting this established association with risk for CKD in the general population [69
In contrast, genetic variants associated with DM2-associated kidney disease have not consistently been replicated [28
], possibly owing to lack of sufficient power either due to low sample size or to the small effects of genetic variants in common disease. Though DIACORE will be one of the largest DM2 cohorts of European descent, power may not be sufficient for detecting genetic variants with small effects sizes. However, since DIACORE’s study protocol is standardized for collaborative projects with other cohorts, joint meta-analysis is an excellent option for increasing power. Pooling data from several studies in international collaborations such as the CKDGen consortium has been successful in the past in analyzing the genetic underpinning of kidney phenotypes in the general population [24
The strengths of the DIACORE study include its large size, prospective design, rigorous protocol standardization, centralized data management and excellent pre-analytics in biosample archiving. There are limitations that warrant discussion. As management of diabetes and its complications has improved significantly since publication of the study that our power calculation is based on [47
], event rates in DIACORE may be lower than expected. However, the projected sample size makes DIACORE one of the largest DM2 cohorts world wide. Furthermore, bias may arise due to our recruitment strategy, but DM2 patients are addressed repeatedly along multiple channels in the same geographic regions thus providing broad feed back among the targeted population of ambulating DM2 patients. In addition, the questionnaire is designed to help quantify any recruitment bias. We cannot exclude or quantify a potential, small effect on outcomes caused by reporting the laboratory and physical examination results to patients. However, this reporting is an imperative medical duty to volunteering patients. Finally, urinary albumin excretion is estimated from one spot urine sample as it is logistically unfeasible to collect the recommended three urine samples. To compensate this drawback, dipstick testing on fresh urine is performed to exclude urinary tract infection, and the time at which urine is donated is recorded.
In summary, DIAbetes COhoRtE (DIACORE) is a cohort study with a biosample repository aiming to recruit 6000 prevalent diabetes mellitus type 2 patients of Caucasian descent in Germany for long term prospective observation with follow-up examinations every 2 years. Main aims are to discover novel mechanisms involved in developing kidney disease and cardiovascular morbidity among diabetes patients, using systematic genetic and biomarker analyses. In the long-term, DIACORE aims to provide impetus for the development of novel strategies in the prevention and treatment of DM2 complications.