Scientific Concept of the National Cohort (status ... - Nationale Kohorte

A.2 Scientific background and rationale for study elements
Increased formation and accumulation of advanced glycation end-products is one of the
pathogenetic mechanisms underlying accelerated atherosclerosis in type 2 diabetes 168 and
plays a role in inflammation and immune responses 169 . Both crosslinking of proteins by advanced
glycation end-products and receptor-mediated cellular activation contribute to loss
of vascular elasticity and to propagation and maintenance of inflammation, contributing to
the development of microvascular and macrovascular disease. Moreover, cross-linking by
advanced glycation end-products results in vascular and myocardial stiffening, which are
hallmarks in the pathogenesis of heart failure 823 . Several studies have shown an association
of skin autoflourescence (AF) with levels of C-reactive protein, suggesting that skin AF
may represent both inflammatory and hyperglycemic episodes 170 . Levels of advanced glycation
end-products in skin tissue (measured in skin biopsies) statistically significantly predict
long-term diabetic microvascular complications, even after adjustment for hemoglobin A1c
(HbA1c) 171-174 . Skin AF was better able to predict fatal and nonfatal CVD events and all-cause
mortality than was HbA1c 175 . The superiority of risk prediction by advanced glycation endproducts
in skin has been explained by the concept of “metabolic memory”, i.e., the idea
that stable advanced glycation end-products bound to long-lived protein such as skin collagen
provide long-term memory of episodes of hyperglycemia and oxidative stress, whereas
HbA1c only ”remembers” this for several weeks. Further diseases for which an association
with advanced glycation end-products or the soluble advanced glycation end-products’ receptor
has been reported are mild cognitive impairment and Alzheimer’s disease 176, 177 .
Retinopathy (e.g., microaneurysms, retinal hemorrhages, and exudates) is the most specific
microvascular complication of diabetes. It eventually affects up to 40% of patients with type
2 diabetes 178 , but is also seen in 2–15% of the nondiabetic general population 179 . So far, no
population-based data are available for Germany. The threshold for defining diabetes by
fasting plasma glucose levels of ≥7.0 mmol/l is based on the assumption that it separates
persons at high and low risk of developing diabetic microvascular complications. However,
there seems to be a linear relationship, rather than a threshold level, between fasting glucose
levels and the occurrence of retinopathy 180 . The association of hyperglycemia and elevated
blood pressure with the occurrence of retinopathy indicates that different etiological pathways
contribute to the development of microvascular changes in the retinal vessels 178, 181 and most
likely also in the vascular beds of other organs. Consequently, retinal vascular characteristics
have been described as risk indicators for a number of chronic diseases (including diabetes,
hypertension, stroke, and ischemic heart disease) and all-cause mortality 182-184 . In addition,
retinopathy is also associated with lower cognitive test scores, thus also providing a link to
neurocognitive functions 182, 184 . Computer-assisted grading systems can be used to rapidly
assess qualitative and quantitative signs and extent of retinopathy based on retinal photographs
178 . The combination of diverse functional measurements of the cardiovascular system,
measures of metabolic impairments (e.g., impaired glucose tolerance), and neurologic
and psychiatric functional assessment offers the unique opportunity to better understand the
mechanisms underlying early pathological changes that ultimately progress to clinical stages
of the major diseases in the focus of the National Cohort, and to identify their determinants.
Assessment of diabetes-related functions and intermediate (preclinical) phenotypes:
Examinations (at baseline and during reassessment)
Level 2: OGTT
Advanced glycation end products (AGE) reader / skin AF
Retinal photography
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A.2