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There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high‐threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)‐induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death. Using electrophysiologic and pharmacologic techniques, the present study provides evidence that significant impairment of G‐protein‐coupled modulation of calcium channel function may underlie the enhanced calcium entry in diabetes. N‐ and P‐type voltage‐activated, high‐threshold calcium channels in DRGs are coupled to mu opiate receptors via inhibitory G(o)‐type G proteins. The responsiveness of this receptor coupled model was tested in dorsal root ganglion (DRG) neurons from spontaneously‐diabetic BB/W rats, and streptozotocin‐induced (STZ) diabetic rats. Intracellular dialysis with GTPgammaS decreased calcium current amplitude in diabetic BB/W DRG neurons compared with those of age‐matched, nondiabetic controls, suggesting that inhibitory G‐protein activity was diminished in diabetes, resulting in larger calcium currents. Facilitation of calcium current density (I(DCa)) by large‐amplitude depolarizing prepulses (proposed to transiently inactivate G proteins), was significantly less effective in neurons from BB/W and STZ‐induced diabetic DRGs. Facilitation was enhanced by intracellular dialysis with GTPgammaS, decreased by pertussis toxin, and abolished by GDPbetaS within 5 min. Direct measurement of GTPase activity using opiate‐mediated GTPgamma[(35)S] binding, confirmed that G‐protein activity was significantly diminished in STZ‐induced diabetic neurons compared with age‐matched nondiabetic controls. Diabetes did not alter the level of expression of mu opiate receptors and G‐protein alpha subunits. These studies indicate that impaired regulation of calcium channels by G proteins is an important mechanism contributing to enhanced calcium influx in diabetes.

In order to explore the neuroprotective and crossspecies activities of.C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant Cpeptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 μg of hrC-peptide/kg body weight/ day from onset of diabetes. After 2 months of hrC-peptide administration, 100 μg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neural Na+/K+-ATPase activity in diabetic rats with 500 μg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide

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In this article we will review the clinical signs and symptoms of diabetic somatic polyneuropathy (DPN), its prevalence and clinical management. Staging and classi®cation of DPN will be exempli®ed by various staging paradigms of varied sophistication. The results of therapeutic clinical trials will be summarized. The pathogenesis of diabetic neuropathy reviews an extremely complex issue that is still not fully understood. Various recent advances in the understanding of the disease will be discussed, particularly with respect to the differences between neuropathy in the two major types of diabetes. The neuropathology and natural history of diabetic neuropathy will be discussed pointing out the heterogeneities of the disease. Finally, the various prospective therapeutic avenues will be dealt with and discussed.