Effects of combined insulin and sorbinil treatment on diabetes-induced vascular dysfunction in rats.
These experiments were undertaken to assess the effects of combined treatment with insulin (designed to partially restore metabolic control) and sorbinil (an aldose reductase inhibitor [ARI]) versus the effects of sorbinil alone or of two insulin regimens providing different degrees of glycemic control on diabetes-induced metabolic derangements and vascular function. Streptozocin-diabetic rats were divided into the following five groups: (1) untreated (D); (2) treated with approximately 1 U NPH insulin/100 g body weight/d administered in one subcutaneous (SC) injection (DI-1); (3) treated with the same total daily dose of insulin administered in two SC injections (DI-2); (4) treated with approximately 0.2 mmol sorbinil in the diet/kg body weight/d (DS); and (5) treated with once-daily insulin plus sorbinil (DSI-1). Two groups of nondiabetic rats, untreated (C) and sorbinil-treated (CS), served as controls. Metabolic parameters were unaffected by sorbinil treatment in controls and diabetics, whereas insulin administration in the diabetics virtually normalized body growth, food consumption, urine volume, and plasma glucose levels, and markedly decreased hemoglobin A1 (HbA1) levels. Two daily injections were more effective than one in improving metabolic control as measured by HbA1 levels. Regional vascular 131I-albumin permeation was increased about twofold to threefold by diabetes in ocular tissues, sciatic nerve, aorta, diaphragm, and new granulation tissue; it was decreased (but not normalized) by insulin treatment in accordance with improved metabolic control, and was completely normalized by sorbinil. 131I-albumin kidney clearance, as well as urinary albumin and IgG excretion, were markedly increased in diabetic rats and were significantly decreased but not completely normalized by sorbinil and by twice-daily insulin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Pugliese
G
G
Department of Pathology, Washington University School of Medicine, St Louis, MO 63100.
Tilton
R G
RG
Speedy
A
A
Oates
P J
PJ
Williamson
J R
JR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D007328:Insulin / Q000627:therapeutic use*; D007668:Kidney / Q000503:physiopathology; D008297:Male; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism
D007093:Imidazoles; D048289:Imidazolidines; D007328:Insulin; D012710:Serum Albumin, Bovine; D000449:Aldehyde Reductase; C026411:sorbinil