In most Western societies, the overall prevalence of Type 2 diabetes mellitus has reached 4-6% and 10-12% among the 60-70 year old individuals. Annual health costs caused by diabetes are around 6-12% of the over-all health expenditures. The major costs of diabetes relate to the long-term complications, the micro- and macrovascular complications. Since Type 2 diabetes accounts for around 90% of all diabetes and since the complications of diabetes develop with comparable frequency in patients with insulin-dependent (Type 1) diabetes and Type 2 diabetes, it follows that the major health and economic burdens of diabetes are due to Type 2 diabetes. Furthermore, macrovascular disease is the major problem in Type 2 diabetes including coronary heart disease, stroke and peripheral atherosclerotic disease. The etiology of Type 2 diabetes is still unclear. It is generally agreed that:
1) the disease has both strong genetic and environmental (acquired) components
2) its inheritance is polygenic, i.e., several genetic abnormalities are necessary for disease manifestation,
3) impairment of insulin sensitivity (insulin resistance) and insulin secretion, each of which is regulated by both genetic and environmental factors, are important elements in its pathogenesis,
4) most patients are obese and obesity, particularly intra-abdominal obesity, causes insulin resistance and is under both genetic and environmental regulation.
Non-obese, healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibit both insulin resistance and impaired insulin secretion as compared to a carefully matched control group lacking a known genetic predisposition for Type 2 diabetes. Type 2 diabetes is clearly a heterogeneous disease. The central pathogenetic factors are insulin resistance and secretion abnormalities, but the underlying genetic defects (with the exception of the rare forms like MODY diabetes) remain to be identified.
We propose to perform extensive and unique in-depth phenotypic characterizations
of healthy glucose-tolerant first degree relatives (FDR) of patients with Type
2 diabetes in order to define subgroups as the basis for specific genetic and
molecular studies on tissue samples (fat and muscle), cell cultures (myoblasts/myotubes,
preadipocytes/adipocytes), RNA expression levels and genomic DNA. This study
can be carried out since large populations of Type 2 diabetic subjects and their
relatives are available in our center.