Glomerular Effects Of Sulf In Insulindeficient Diabetes Mellitus

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SULF have been extensively used in the treatment of type 2 diabetes. However, the renal effects of SULF in diabetes have not been determined. A study of complications in patients with type 2 diabetes investigated the effects of intensive glycemic control with insulin or SULF (UK Prospective Diabetes Study) (55). These results revealed a reduction in proteinuria and renal failure, in association with improved glycemic control. However, owing to either the relatively few number of patients who developed renal disease or the confounding effects of combinations of sequential therapies in individual patients, no conclusive differences were detected between insulin- and SULF-treated groups. Since this trial, other studies have proven inconclusive (56,57). Therefore, the current status of clinical knowledge does not render definitive conclusions regarding any beneficial or deleterious renal effects by exogenous SULF or an endogenous SULF-like ligand.

In an attempt to extend prior observations of altered matrix metabolism and increased cellular contractility in MCs after SULF exposure, the effect of chronic administration of various SULF on the progression of diabetic nephropathy was evaluated in animal models of types 1 and 2 diabetes mellitus. Our observations revealed an attenuation of proteinuria

Fig. 1. Mesangial KATP are formed as tetradimers of Kir6.1 and SUR2B. KATP mediate changes in extracellular matrix (ECM) metabolism following binding of either sulfonylurea (SULF) or a-endosulfine. Low-concentration SULF inhibits a-endosulfine action at the KATP site and limits ECM formation. However, high concentrations of SULF increase ECM accumulation as a consequence of the increased expression of GLUT1 and enhanced GLUT1-mediated intracellular glucose transport with the consequent upregulation of TGF-Pr This growth factor, in turn upregulates membrane-associated GLUT1 expression. Heightened mesangial contractility represents a Ca2+-mediated event in response to exposure to SULF and possibly to a-endosulfine.

Fig. 1. Mesangial KATP are formed as tetradimers of Kir6.1 and SUR2B. KATP mediate changes in extracellular matrix (ECM) metabolism following binding of either sulfonylurea (SULF) or a-endosulfine. Low-concentration SULF inhibits a-endosulfine action at the KATP site and limits ECM formation. However, high concentrations of SULF increase ECM accumulation as a consequence of the increased expression of GLUT1 and enhanced GLUT1-mediated intracellular glucose transport with the consequent upregulation of TGF-Pr This growth factor, in turn upregulates membrane-associated GLUT1 expression. Heightened mesangial contractility represents a Ca2+-mediated event in response to exposure to SULF and possibly to a-endosulfine.

and morphological glomerular alterations after glibenclamide or tolazamide administration to streptozotocin-treated rats (58). Notably, these salutary effects proceeded in the absence of changes in glycemia or (as studied in the case of glibenclamide) in glomerular filtration rate or renal hypertrophy. In separate experiments with insulin-resistant db/db mice, SULF treatment did not impact the course of glomerulosclerosis in functional or morphological assays. In toto, these observations imply that the direct glomerular effects of SULF at low concentrations (and by extrapolation, of their endogenous counterpart, a-endosulfine) may suppress or retard the TGF-P1-mediated accrual of glomerular extracellular matrix (ECM), the hallmark of diabetic glomerulosclerosis and may significantly alter the course of insulin-deficient diabetic kidney disease.

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