Towards Newer Molecular Targets for Chronic Diabetic Complications

Abstract

Prior to the discovery of insulin, the major cause of death in the diabetic population was ketoacidosis. Although insulin and improved glycemic control have improved the longevity of diabetic patients, they still suffer from significant morbidity and mortality due to chronic secondary complications. Long standing diabetes leads to structural and functional alterations in both the micro- and macrovasculature. These complications, involving the retina, kidney, and peripheral nerves, as well as cardiovascular system, severely compromise the quality and expectancy of life. Large scale clinical trials have identified hyperglycemia as the key determinant for the development of such complications. Therapeutic modalities have been developed to target glucose-induced alterations, such as protein kinase C activation, augmented polyol pathway activity, non-enzymatic glycation and oxidative stress to ameliorate chronic complications. However, clinical trials targeting these biochemical alterations have failed to show significant beneficial effects. The plethora of biochemical anomalies that govern the development of chronic diabetic complications may therefore be subject to cross-interaction and complex interplays. Studies in both animal and human diabetes have, however, showed alteration of several vasoactive effector molecules such as endothelins. These molecules may be instrumental in mediating diabetes-induced structural and functional deficits at both the early and late stages of the disease. This review will discuss the current mechanistic understanding of chronic diabetic complications and will explore the potential novel therapeutic interventions.

Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

“…7,8 Vascular endothelial cells lining blood vessel walls are the first to encounter high levels of circulating glucose. [7][8][9] Sustained uptake of glucose by vessel endothelial cells results in impaired cellular function, resulting in microvascular and macrovascular changes. 8,9 One of the earliest defects apparent in target organs of diabetic complications is a diminished capacity for vasodilation due to the unbalanced production of vasodilators and vasoconstrictors.…”

“…[7][8][9] Sustained uptake of glucose by vessel endothelial cells results in impaired cellular function, resulting in microvascular and macrovascular changes. 8,9 One of the earliest defects apparent in target organs of diabetic complications is a diminished capacity for vasodilation due to the unbalanced production of vasodilators and vasoconstrictors. [7][8][9] Decreased levels of the vasodilator nitric oxide, coupled increased production of the powerful vasoconstrictor endothelin-1, results in impaired vasoregulation.…”

“…8,9 One of the earliest defects apparent in target organs of diabetic complications is a diminished capacity for vasodilation due to the unbalanced production of vasodilators and vasoconstrictors. [7][8][9] Decreased levels of the vasodilator nitric oxide, coupled increased production of the powerful vasoconstrictor endothelin-1, results in impaired vasoregulation. This functional alteration is accompanied by sustained structural remodelling of the vessels in target organs manifesting as retinopathy, nephropathy, neuropathy, cardiomyopathy, and accelerated atherosclerosis.…”

“…This functional alteration is accompanied by sustained structural remodelling of the vessels in target organs manifesting as retinopathy, nephropathy, neuropathy, cardiomyopathy, and accelerated atherosclerosis. [7][8][9] Initiation as well as the progression of these complications also entails an impaired repair/regenerative mechanism. 10,11 Vascular repair is largely dependent on the proliferation, mobilization and differentiation of bone marrow-derived progenitor cells.…”

Cell Therapy for Diabetic Retinopathy—A Work in Progress

“…11,[34][35][36] The therapeutic challenge is quite straightforward in theory-neutralization of ischemia and preservation of vision. Our approach to ischemic DR is the destruction of these ischemic/hypoxic areas of retina with laser, thus removing the hypoxic stimulus and the pro-angiogenic tide that this promotes.…”