Presence of diabetic complications in type 1 diabetic patients correlates with low expression of mononuclear cell AGE-receptor-1 and elevated serum AGE.

BACKGROUND: Receptors for advanced glycation endproducts (AGE-R) mediate AGE turnover, but can also trigger inflammatory genes that promote diabetic tissue injury and diabetic complications (DC). High AGE levels and reduced AGE-R sites in kidneys of NOD mice prone to type 1 diabetes (T1D) and to renal disease (RD) suggested that impaired AGE-R function may contribute to RD in these mice. MATERIALS AND METHODS: In this study, after confirming reduced AGE-R1 expression in NOD mouse peritoneal macrophages, we tested for differences in AGE-R1, -R2, and -R3 gene expression in 54 human subjects by RT-PCR and Western analysis. Fresh peripheral blood mononuclear cells (PBMN) were isolated from 36 persons: 18 T1D patients with severe RD (DC); 11 age-and DM-duration matched patients without DC (n-DC); and 7 normal volunteers (NL). EBV-transformed lymphoblasts were obtained from an additional 18 subjects (12 T1D patients, 6 with and 6 without DC, and 6 nondiabetics). RESULTS: AGE-R1 mRNA and protein of PBMN from n-DC patients were enhanced (p < .05 versus NL) in proportion to serum AGE levels (sAGE) (p < .005 versus NL). In contrast, PBMN from DC patients exhibited no up-regulation of AGE-R1 mRNA or protein, despite higher sAGE levels (p < .005 versus NL). A similar unresponsiveness in AGE-R1 gene expression was observed in EBV-transformed lymphoblasts from DC patients versus NL (p < .01), but not in n-DC (p = NS). AGE-R2 and -R3 mRNA and protein levels were enhanced in both T1D groups (DC > n-DC) (n-DC AGE-R3, p < .05, DC AGE-R3, p < .05) compared to NL. AGE-R2 mRNA levels correlated with sAGE levels (r = .61, p < .05), and with creatinine clearance (r = -.63, p < .05). No differences were noted in AGE-R2 and -R3 mRNA expression in cultured cells. CONCLUSIONS: The consistent pattern of elevated serum AGE and low expression of AGE-R1 gene in macrophages from T1D mice (NOD), fresh PBMN and EBV-transformed cells from T1D patients with advanced DC suggests ineffective regulation of R1-mediated AGE turnover, possibly of genetic basis.

Vascular growth factors and the development of macrovascular disease in diabetes mellitus.

The pathogenesis of macrovascular disease in diabetes mellitus is still incompletely understood. Within the various pathomechanisms abnormal growth of vascular cells is well established as an intrinsic part of the angiopathic process. In this regard, there are different groups of vascular growth factors that are of potential relevance for the development of macrovascular disease in diabetes : hormones, locally released growth factors of platelet and of arterial wall cell origin. The following hormones whose blood levels could increase under various conditions in diabetes have to be considered : growth hormone, insulin-like growth factor I and II and insulin. Human platelets contain at least eight growth peptides or proteins that all stimulate in vitro growth of arterial wall cells : platelet-derived-, epidermal-, fibroblast-, diabetic serum-, endothelial- and transforming growth factor, vascular endothelial cell proliferation factor and platelet-derived endothelial cell mitogen. In serum and plasma from type II diabetics only the diabetic serum growth factor has been shown to be increased. Platelets from type I and II diabetic patients contain increased growth stimulating activity. This increased growth activity returned to normal levels in both types of diabetes after strict metabolic control. Arterial endothelial and smooth muscle cells, fibroblasts and monocyte/macrophages of different species release at least in culture a variety of growth factors that could participate in an autocrine or paracrine manner in the growth regulation of the arterial wall. Diabetes may affect the release of these factors, but direct evidence to which degree this would contribute to the development of macrovascular disease is lacking.(ABSTRACT TRUNCATED AT 250 WORDS)