Diabetes underlies common neurological disorders

The diabetes epidemic is probably the greatest health problem facing developed and developing nations alike. The current global prevalence of diagnosed diabetes is 165 million and is estimated to increase to 250 million by 2010 and to 330 million by 2025. These alarming figures do not include undiagnosed diabetes or prediabetic states. The long-term complications associated with diabetes carries a heavy burden of increased morbidity and mortality as well as the brunt of diabetes health care costs. The most common long-term complication of diabetes affects the peripheral nervous system leading to limb amputations and sudden cardiac death secondary to autonomic polyneuropathy. The central nervous system is affected secondarily by diabetic macrovascular disease with an increased incidence of stroke in the diabetic population. Direct cerebral effects of metabolic aberrations caused by diabetes result in a diabetes duration-related cognitive decline, so-called primary diabetic encephalopathy, and may even predispose patients to Alzheimer’s disease. Despite decades of intensive experimental and clinical research, we still have no effective or specific therapies for somatic and autonomic diabetic polyneuropathies (DPNs). Vigorous hyperglycemic control is the only advice given to patients, which unfortunately is not sufficient to fully prevent or control DPN as demonstrated by the Diabetes Control and Complications Trial. The reason for this is most likely the generally held misconception that hyperglycemia, and hyperglycemia alone, is the culprit underlying long-term complications. This is probably in part founded in the most commonly used diabetic animal model from which data, often from acutely diabetic rats, are too commonly extrapolated to the human disorders. Streptozotocin induction of diabetes in rats causes a partial -cell destruction and hyperglycemia, the latter being the only attribute it has in common with human diabetes. It is neither insulinopenic (type 1 diabetes) nor is it insulin resistant (type 2 diabetes). Hence, much effort has been spent on a suboptimal disease model to which the human diabetic disorders have been molded. By using animal models which closely resemble the pathophysiological bases for the human diabetic disorders, it is becoming increasingly clear that impaired insulin action, be it through insulinopenia in type 1 diabetes or via insulin resistance in type 2 diabetes, plays probably an equally important initiating pathogenetic role in the development of the late complications. Insulin and C-peptide are now recognized as potent neuroprotective and neurotrophic hormones, with gene regulatory, antiapoptotic, and posttranslationally modifying effects on functional and structural proteins. C-peptide is part of proinsulin and is split off from insulin with which it is secreted in equimolar concentrations. It has insulin-like effects on its own and by synergizing insulin signaling activities. Insulin/Cpeptide have direct regulatory functions on neural Na /K -ATPase and endothelial nitric oxide (eNOS) via extracellular signal regulated kinase (ERK) and protein kinase C (PKC)-mediated pathways. Perturbations of Na /K -ATPase and NO are implicated as major contributors to the early metabolic and functionally reversible phase of DPN. A direct cause and effect relationship has repeatedly been established between Na / K -ATPase activity and the acute metabolic nerve conduction defect. Therefore, in addition to the decreased Na /K -ATPase activity caused downstream by the hyperglycemia-induced activation of the polyol pathway, insulin/C-peptide deficiencies contribute substantially to this early defect. This is consistent with the data reported in this issue by Kitano and colleagues, who using the threshold tracking technique in mildly neuropathic diabetic patients showed restoration of reduced transaxolemmal Na gradients and improved nerve conduction velocity after 4 weeks of intensive insulin treatment, thereby also improving glycemic control. This finding was supported by increased strength duration time constant and decreased rheobase. These eloquent human data are consistent with earlier reported nodal clamp analyses in the acutely diabetic BB/Wor-rat, showing decreased axolemmal Na equilibrium potentials and decreased Na permeability and currents, resulting in decreased nerve conduction velocity. The early bioelectrical abnormalities are perpetuated by increased intraaxonal [Na ] resulting from impaired neural Na /K -ATPase activity. These abnormalities were corrected by insulin treatment in acutely diabetic rats, consistent with the data by Kitano and colleagues, but not in rats with long-standing diabetes. The irreversibility in chronically diabetic nerves is associated with degeneration of the paranodal ion channel barrier, so-called axoglial dysjunction, and internodal lateralization of Na channels resulting in decreased initial nodal Na currents as well as increased leak conductances and K permeabilities, all consistent with paranodal pathology. The molecular underpinnings of the breach of the paranodal ionchannel barrier and the dislodging of pore-forming -Na channels from the nodal axolemma were recently described and were interestingly prevented by insulinomimetic C-peptide, suggesting an insulinrelated defect. The expression of the main molecular EDITORIAL