Diabetes mellitus is a
chronic disease caused by inherited and/or acquired deficiency in production of
insulin by the pancreas, and by resistance to
insulin's effects. Such a deficiency results in increased concentrations of
glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of
diabetes mellitus: Type 1 diabetes (
insulin-dependent diabetes,
IDDM or
juvenile onset diabetes) and
Type 2 diabetes (non-
insulin-dependent diabetes,
NIDDM or adult-onset). Chronic
hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several
hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased
polyol pathway flux, altered cellular redox state, increased formation of
diacylglycerol (DAG) and the subsequent activation of
protein kinase C (PKC)
isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of
diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the
retinal, renal, neural and cardiovascular tissues in
diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis,
cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta
isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-
ATPase, cPLA(2), PI3Kinase and MAP
kinase. Inhibition of PKC, especially the beta1/2
isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that
ruboxistaurin, a PKCbeta
isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several
isoforms is likely to be responsible for some of the pathologies in
diabetic retinopathy, nephropathy and
cardiovascular disease. PKC
isoform selective inhibitors are likely new
therapeutics, which can delay the onset or stop the progression of
diabetic vascular disease with very little side effects.