Diabetic neuropathy - a continuing enigma

Sugimoto, Kazuhiro; Murakawa, Yûichi; Sima, Anders A. F.

doi:10.1002/1520-7560(200011/12)16:6<408::aid-dmrr158>3.0.co;2-r

Cited by 161 publications

(92 citation statements)

References 403 publications

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“…Inhibition of PKCβ prevents the hyperglycemia-induced decrease in Na,K-ATPase activity in retina [15]. However, neither strict glycemic control nor restoration of normal glycemia and PKC activity [17], [34] can completely restore Na,K-ATPase activity.…”

Section: Discussionmentioning

confidence: 98%

“…Activation of the Na-pump is of particular clinical interest, as it is reported to be deficient in type 1 diabetes in a number of tissues [2], [13], [14]. Given the central role of Na,K-ATPase in the regulation of intracellular ion concentrations, a reduction in Na,K-ATPase activity may contribute to decreased nerve conduction velocity, retinal cell dysfunction, impaired endothelial function and decreased microvascular blood flow, kidney disorders and development of hyperkalemia [15], [16], [17]. The decreased Na,K-ATPase activity found in association with diabetes mellitus and its complications can be restored to normal by administration of C-peptide [2], [3], [18], although the mechanism of this stimulation is not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells

et al. 2011

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BackgroundReplacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC) in control and hyperglycemic conditions.Methodology/Principal FindingsHRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium (86Rb+) uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM). DNA binding activity was determined by electrical mobility shift assay (EMSA). Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α1-subunit protein expression, accompanied with increase in 86Rb+ uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α1-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6), concomitant with Na,K-ATPase α1-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α1-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing.Conclusions/SignificanceDespite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C-peptide-mediated signaling. Importantly, only physiological concentrations of C-peptide elicit this effect.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells

et al. 2011

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“…In particular, the present study is the first to present evidence of relationships among insulin deficiency, p44/42 MAPK activation, and peripheral nerve dysfunction in a rat model of type 1 diabetes. Since insulin has been shown to function both in the central and peripheral nervous systems [33], [34] and to improve peripheral nerve function in non-diabetic [35] and diabetic subjects [36], [37], independent of glycemic levels, insulin receptor signaling in peripheral nerves may deserve much greater attention when considering the unmet need to better understand and establish more effective therapeutic strategies for human diabetic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Low-Dose Insulin on Peripheral Nerve Insulin Receptor Signaling in Streptozotocin-Induced Diabetic Rats

et al. 2013

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BackgroundThe precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause.Methodology and Principal FindingsDiabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001).Conclusions and SignificanceLow-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy.

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“…However, others have painful diabetic neuropathy that manifests as positive symptoms of hyperalgesia, tactile allodynia, paresthesias, abnormal sensitivity to temperature, and unremitting pain [23, 25]. Data on the prevalence of painful diabetic has varied widely with some reporting a prevalence rate of 7-20% [26] and others reporting 40-50% of those with diabetic neuropathy having neuropathic complications.…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy

Jack¹,

Wright²

2012

Translational Research

120

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Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with over half of all patients developing altered sensation as a result of damage to peripheral sensory neurons. Hyperglycemia results in altered nerve conduction velocities, loss of epidermal innervation, and the development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine if a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One of the mechanisms that has been recognized to have a role in the pathogenesis of sensory neuron damage is the process of reactive dicarbonyls forming advanced glycation endproducts (AGEs) as a direct result of hyperglycemia. The glyoxalase system, composed of the enzymes glyoxalase I (GLO1) and glyoxalase II, is the main detoxification pathway involved in breaking down toxic reactive dicarbonyls before producing carbonyl stress and forming AGEs on proteins, lipids, or nucleic acids. This review discusses AGEs, GLO1, their role in diabetic neuropathy, and potential therapeutic targets of the AGE pathway.

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Diabetic neuropathy - a continuing enigma

Cited by 161 publications

References 403 publications

C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells

C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells

The Impact of Low-Dose Insulin on Peripheral Nerve Insulin Receptor Signaling in Streptozotocin-Induced Diabetic Rats

Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy

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