Alteration in the Signal Transduction Pathway

This last theory may once again provide a conceptual framework to link the various clinical manifestations of the complications. While AGEs and oxidants can play a role, the diacylglycerol, protein kinase C (DAG-PKC) activation pathway has been best studied. The presence of hyperglycemia increases DAG and PKC actions that through multiple intermediary substances can result in many cellular abnormalities. These include such changes as basement membrane thickening, increased permeability, coagulation and contractibility abnormalities as well as increased angiogenesis and cardiomyopathy. These changes are all found clinically in diabetic patients so it is reasonable to try to block the PKC by inhibitors to see if this would reduce or reverse the abnormalities. The use of a specific PKC beta isoform inhibitor, LY333531, has been studied and a delay in the hemodynamic changes seen in diabetic retinopathy, nephropathy, and cardiovascular disease has been observed. The drug is now being studied clinically in patients with macular edema and neovascularization to see if visual loss can be prevented (10).

A recent study noted that the oral administration of ruboxistaurin (RBX) mesylate, a selective PKC beta inhibitor, in a dose of 16 mg twice daily, the diabetes induced increase in retinal circulation time was ameliorated. No serious safety problems were identified in the 28-day trial. This is the first direct human evidence of the effects of an oral PKC beta inhibitor and more long-term data is awaited (44).

In another study RBX was used to treat patients with diabetes and diabetic peripheral neuropathy. This was a randomized, PHASE 11, double-blind placebo-controlled parallel-group trial of 205 patients and used 32 or 64 mg of RBX for 1 year. Overall there were no significant changes in vibration detection threshold or neuropathy total symptom score between the groups. However a subgroup with less severe neuropathy did benefit with relief of sensory symptoms and improved nerve function (45).

From the many theories that have been advanced to play a role in the pathogenesis of the microvascular complications of diabetes, it is evident that the one common abnormality in all theories is the presence of an elevated blood glucose level. Therefore it is very important to try and correct this abnormality optimally using all currently available therapies and then to add other therapies that will be of additional benefit as they become available.

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