The role of euglycemia and recurrent insulin induced hypoglycemia on ATP and Angiotensin-II induced hypertension and associated renal damage

Diabetic patients often experience hypoglycemic episodes along with various other complications which include but are not restricted to endothelial dysfunction leading to hypertension and eventual end organ damage. The systemic role of circulating angiotensin II (AngII) in elevating mean arterial pressure (MAP) and heme oxygenase (HO)-I leading to end organ damage was previously demonstrated in our lab. Efficiency of renal function depends on an efficient tubuloglomerular feedback (TGF) mechanism. Adenosine triphosphate (ATP) plays a crucial role in maintaining a balanced TGF mechanism. In the current study, we identified the prominent and synergistic roles of ATP and AngII in renal interstitial fluid using a novel technique, namely chronic renal microdialysis. Recurrent insulin induced hypoglycemia (RIIH) significantly elevated interstitial ATP which in turn elevated interstitial AngII. Both synergistically disrupted TGF and renin angiotensin-aldosterone system (RAS) feedback regulation mechanisms resulting in persistent hypertension. Elevated AngII in turn promoted oxidative stress which enhanced renal damage. However, was the present hypertension produced by insulin injections alone or by the induced hypoglycemia? Hence we adapted a glucose clamp model to identify the importance and role of insulin and/or hypoglycemia in promoting hypertension. Administering recurrent insulin injections with a simultaneous glucose diet to animals, which maintained normotensive conditions; would distinguish if the observed hypertension was produced by insulin or by the induced hypoglycemia. This euglycemic model also maintained normal interstitial ATP and AngII along with reduced oxidative stress without any significant elevation during recurrent insulin treatment. This suggests the role of hypoglycemia in promoting hypertension and renal damage during insulin treatment in diabetic patients. The importance of NO in attenuating coronary endothelial dysfunction, one more complication in the diabetic status was evaluated. Larginine treatment enhanced NO production in septal coronary arteries of obese Zucker rats; thus abolishing the difference between lean and obese groups. Maintaining euglycemic conditions and enhancing NO production proves to be potential novel approaches in achieving successful treatment to renal damage and coronary endothelial dysfunction.