The protein kinase C-beta inhibitor, ruboxistaurin, for the treatment of diabetic microvascular complications.
The potential for addressing the underlying biological abnormalities in diabetes has eluded most investigators because of the complex mechanisms underlying the effects of diabetes on the pathogenesis of the complications. Although macrovascular complications, such as myocardial infarction, stroke and gangrene, are only partially attributable to hyperglycaemia and its attendant effects, the microvascular complications including retinopathy, nephropathy and neuropathy are directly related to the degree of hyperglycaemia. In controlled trials, a 22-34% reduction in one of these side effects was achieved for every 1% reduction in glycosylated haemoglobin. Theoretically, it should be feasible to eliminate these complications in a perfect world. However, achieving euglycaemia is nearly impossible and there is increasing data to suggest that it may be an elusive target with ever lower levels being implicated in the pathogenesis of microvascular disease and there is a price to be paid of hypoglycaemia if further intensification is pursued. A logical argument would be to block pathways that are activated by hyperglycaemia. A major pathway implicated is the activation of protein kinase C-beta in all of the targeted tissues, and there is animal data to support the notion that blocking this pathway can reverse or abrogate the untoward effects of diabetes. The possible role of the protein kinase C-beta inhibitor, ruboxistaurin, in animal studies and the recently reported clinical studies to place in perspective a possible addition to the therapeutic armamentarium of the imperfect world of diabetes control will be reviewed.
Vinik
Aaron
A
The Strelitz Diabetes Institute, Eastern Virginia Medical School, Norfolk, VA 23510, USA. vinikai@evms.edu
D000818:Animals; D048909:Diabetes Complications / Q000188:drug therapy / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D008833:Microcirculation / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta
D007004:Hypoglycemic Agents; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta