Recent Advancement of Understanding Pathogenesis of Type 1 Diabetes and Potential Relevance to Diabetic Nephropathy

Abstract

Type 1 diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta cells by genetic and environmental factors which leads to an absolute dependence of insulin for survival and maintenance of health. Although the majority of mechanisms of beta cell destruction remain unclear, many molecules, including proinflammatory cytokines and chemokines such as tumor necrosis factor alpha and monocyte chemoattractant protein-1, are implicated in the development of beta cell damage. Furthermore, beta cell destruction is enhanced by the Th1 and Th17 subsets of CD4+ T cells. In contrast, there are mechanisms involved in the maintenance of peripheral tolerance by regulatory T cells, the function of which depends on the pleiotropic cytokine transforming growth factor beta. Development and progression of renal injuries in patients with diabetic nephropathy are also associated with several growth factors and proinflammatory cytokines, including tumor necrosis factor alpha, insulin-like growth factor-1, monocyte chemoattractant protein-1, vascular endothelial growth factor, and transforming growth factor beta. Although the pathogenic mechanisms underlying type 1 diabetes and diabetic nephropathy are principally different, i.e., autoimmunity and inflammation, some common factors, including susceptibility genes and proinflammatory cytokines, are involved in both mechanisms, including infiltrating cell recruitment, upregulation of other cytokines and chemokines, or apoptosis.

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

“…Microalbuminuria and proteinuria are classic and important biomarkers of this disease (Ichinose et al. 2007; Dronavalli et al. 2008).…”

“…Participation of the proximal tubule in diabetes proteinuria has become a focus of interest in recent years and has been shown to be more than a simple downstream factor induced by glomerular injury (Gilbert and Cooper 1999; Ichinose et al. 2007; Dronavalli et al. 2008; Tang et al.…”

Role of Nitric Oxide Donor and Phosphodiesterase-Ii Inhibitor in a Streptozotocin Induced Diabetic Nephropathy in Rats

“…Diabetes mellitus (DM) is a complex metabolic syndrome characterized by absolute insulin deficiency or development of insulin resistance that leads to hyperglycemia and an altered glucose, fat and protein metabolism 20 . DN is a microvascular complication and leading cause of morbidity and mortality 21 .…”

Microinflammation as a Candidate for Diabetic Nephropathy

“…Increased infiltration of immune cells including monocytes/macrophages, Tcells, B cells and masT-cells into the kidney, as well as augmented expressions of inflammatory cytokines, chemokines, adhesion molecules, receptors and transcription factors which modulate the local inflammatory response in the kidneys, have been reported in patients with DN [1,[31][32][33][34][35].…”