Midkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H2O2. Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk−/−) than in wild-type (Mdk+/+) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk−/− than in Mdk+/+ mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk−/− mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.

RESEARCH DESIGN AND METHODS -Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) Ն40 m/s, and HbA 1c Յ9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms.RESULTS -Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P Ͻ 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies.CONCLUSIONS -Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.

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A 52-week multicenter placebo-controlled double-blind parallel group study OBJECTIVE -The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.RESEARCH DESIGN AND METHODS -A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.RESULTS -Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.CONCLUSIONS -The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. Diabetes Care 24:1776 -1782, 2001D iabetic neuropathy is a degenerative disorder triggered by persistent hyperglycemia. The degenerative changes, consisting of axonal atrophy, demyelination, nerve fiber loss, and disordered nerve fiber repair, develop and progress even in the early stage of diabetes. Axonal atrophy, demyelination, and disordered repair can be clinically assessed as a decline in nerve conduction velocity. During hyperglycemia, nerve maturation secondary to nerve fiber loss is also disturbed. Abnormal excitement of these immaturely regenerated nerve fibers causes spontaneous pain, numbness, and paresthesia (1-3). In the majority of patients, these changes, characteristic of diabetic neuropathy, considerably deteriorate the quality of life.After the onset of subjective symptoms, only palliative treatments are currently available. Accordingly, early diagnosis and treatment before the onset of subjective symptoms is considered essential. Diabetic neuropathy is a long-term complication of diabetes that should not be underestimated, bec...

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It is well recognized that the prevalence of dementia is higher in diabetic patients than non-diabetic subjects. The incidence of diabetes has been increasing because of dramatic changes in lifestyles, and combined with longer lifespans as a result of advances in medical technology, this has brought about an increase in the number of elderly diabetic patients. Together, aging and diabetes have contributed to dementia becoming a serious problem. Progression to dementia reduces quality of life, and imposes a burden on both patients themselves and the families supporting them. Therefore, preventing the complication of dementia will become more and more important in the future. Although many mechanisms have been considered for an association between diabetes and cognitive dysfunction, glucose metabolism abnormalities such as hyperglycemia and hypoglycemia, and insulin action abnormalities such as insulin deficiency and insulin resistance can be causes of cognitive impairment. Recent large-scale longitudinal studies have found an association between glycemic control and cognitive decline, although it is still unclear how cognitive decline might be prevented by good glycemic control. However, at an early stage, it is necessary to detect moderate cognitive dysfunction and try to reduce the risk factors for it, which should result in prevention of dementia, as well as vascular events. In the present review, in addition to outlining an association between diabetes and cognitive function, we discuss how glycemic control and cognitive decline are related. (J Diabetes Invest,