Nitrosative Stress, Uric Acid, and Peripheral Nerve Function in Early Type 1 Diabetes

Hoeldtke, Robert D.; Bryner, Kimberly D.; McNeill, Daniel R.; Hobbs, Gerald R.; Riggs, Jack E.; Warehime, Sarah S.; Christie, I.; Ganser, Gary H.; Dyke, Knox Van

doi:10.2337/diabetes.51.9.2817

Cited by 94 publications

(78 citation statements)

References 49 publications

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“…Our results demonstrate that a shortened lag time to ONOO Ϫ production is an independent risk factor for the severity of diabetic PN. This is compatible with the notion that ONOO Ϫ is toxic to the endothelium and perineurium (25). A recent immunohistochemistry study (27) in sural nerve biopsies from patients with different PNs, including that of diabetic origin, showed that N⑀-carboxymethyllysine, a major advanced glycation end product resulting from glycoxidation and lipid peroxidation, was detected in the perineurium as well as epineurial, perineurial, and endoneurial vessels.…”

Section: Discussionsupporting

confidence: 85%

“…Nitrotyrosine, which has been used as an indirect marker of ONOO Ϫ generation, is increased in plasma from type 1 and type 2 diabetic patients (24 -26). In patients with early type 1 diabetes, increased nitrotyrosine levels were associated with a deterioration in composite MNCV in the median, ulnar, and peroneal nerves after 3 years (25). Our results demonstrate that a shortened lag time to ONOO Ϫ production is an independent risk factor for the severity of diabetic PN.…”

Section: Discussionmentioning

confidence: 55%

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Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy

2004

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OBJECTIVE—Oxidative stress resulting from enhanced free-radical formation and/or a defect in antioxidant defenses has been implicated in the pathogenesis of experimental diabetic neuropathy. The objective of this study was to evaluate plasma levels of various biomarkers of oxidative stress in diabetic subjects in relation to the presence or absence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS—Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), superoxide anion (O2·−) generation, lag phase to peroxidation by peroxynitrite (ONOO−), vitamin E-to-lipid ratio, and vitamin C were measured in nonsmoking diabetic patients without PN and CAN (PN−/CAN− group; n = 62), in a group with PN but without CAN (PN+/CAN− group; n = 105), in those with both PN and CAN (PN+/CAN+ group; n = 22), and in healthy control subjects (n = 85). RESULTS—All three markers of oxidative stress were significantly increased, and both markers of antioxidant defense were decreased in the PN+/CAN− group compared with the control group (all P < 0.05). PN−/CAN− subjects showed a significant increase compared with control subjects for 8-iso-PGF2α, O2·−, and ONOO− and a decrease for the vitamin E-to-lipid ratio (all P < 0.05). In the PN+/CAN− group, a significant increase compared with the PN−/CAN− group was noted for O2·−, whereas the vitamin E-to-lipid ratio and vitamin C were reduced (all P < 0.05). No significant differences were noted between the PN+/CAN− and PN+/CAN+ groups for each of the five markers of oxidative stress. In multivariate models, O2·− and ONOO− were independently associated with neuropathic deficits, but diabetes duration and triglyceride levels were also independent determinants. CONCLUSIONS—Oxidative stress is enhanced in diabetic patients before the development of PN but to an even higher degree in those with PN, without further significant increase in relation to superimposed autonomic neuropathy. However, apart from oxidative stress, diabetes duration and triglyceride levels are also related to the severity of PN.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 55%

Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy

2004

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“…There is an active vasodilative mechanism of skin blood vessels that is dependent on C-fiber nociceptors, which accounts for 75% of their dilative capacity (11), and there is an alternate pathway regulating blood flow that is associated with lipid levels, blood pressure, hematocrit, WBC count, and resistance to the action of insulin in diabetes and the metabolic syndrome. This in- crease in NO production has now been reported by other authors (24) and is thought possibly to be due to an excess of a circulating antagonist (asymmetric dimethylarginine). The suggestion has been made that this unbridled production results in NO reacting with reactive oxygen species (ROS) to form peroxynitrite (ONOO Ϫ ), which is damaging to blood vessel structure and function (25).…”

Section: Statisticssupporting

confidence: 76%

Pioglitazone Treatment Improves Nitrosative Stress in Type 2 Diabetes

et al. 2006

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OBJECTIVE -The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -This was a randomized, parallel, cross-over, double-blind, within-and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 Ϯ 30.8 years, HbA 1c 7.9 Ϯ 00.4%, BMI 31.3 Ϯ 1.2 kg/m 2 ). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks.RESULTS -The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 Ϯ 1.0 vs. 2.8 Ϯ 0.8, P Ͻ 0.01), after local heat stimulation at 40°C (12.9 Ϯ 2.2 vs. 5.7 Ϯ 1.7, P Ͻ 0.01), and after nociceptor stimulated flow with local heating at 44°C (36.4 Ϯ 6.3 vs. 16.6 Ϯ 3.4). Differences were not significant in the placebotreated group.CONCLUSIONS -Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation. Diabetes Care 29:869 -876, 2006W e have previously described both impaired peripheral vasoconstriction and vasodilatation in cutaneous vessels of people with diabetes, which strongly resembles the normal aging effects seen in peripheral vasculature (1). We have suggested both an endothelial and a neuronal component to these defects (2). The neuronal component is only activated at noxious temperatures (Ͼ40°C) or after tissue damage. Endothelial integrity is a major component under normal tissue demands for oxygenation after ischemia. Other investigators have also proposed the notion that there is specific damage to vascular endothelium and/or smooth muscle in diabetes, but localization of such a defect remains elusive.Insulin is a vasodilator hormone and facilitates endothelial release of nitric oxide (NO) and prostacyclin as well as upregulation of prostacyclin receptors on vascular smooth muscle (3). Resistance to the action of insulin could theoretically contribute to impaired neurovascular function. Jaap et al. (4) showed an endothelial or smooth muscle defect associated with insulin resistance that may precede the development of diabetes. We also showed that defective neurovascular function correlates with features of the metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and obesity (2). Diabetes is now recognized to be part of the metabolic syndrome an...

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“…Enhanced oxidative stress has been documented in peripheral nerve (4,5,8,(12)(13)(14), dorsal root and sympathetic ganglia (15), and vasculature (16,17) of the peripheral nervous system and has been implicated in neurovascular dysfunction and motor and sensory nerve conduction velocity (MNCV and SNCV) deficits, impaired neurotrophic support, nerve metabolic and signal transduction changes, and morphologic abnormalities characteristic for diabetes (4,5,12,14,16 -20). Evidence for the pathophysiologic role of reactive nitrogen species in PDN is also emerging (16,21).…”

mentioning

confidence: 99%

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

et al. 2004

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Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mechanisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP ؊/؊ ) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP ؉/؉ ) diabetic or galactose-fed mice. Two structurally unrelated PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induced diabetic rats. Sciatic nerve immunohistochemistry revealed enhanced poly(ADP-ribosyl)ation in all experimental groups manifesting neuropathic changes. Poly(ADP-ribose) accumulation was localized in both endothelial and Schwann cells. Thus, the current work identifies PARP activation as an important mechanism in diabetic neuropathy and provides the first evidence for the potential therapeutic value of PARP inhibitors in this devastating complication of diabetes. Diabetes 53: 711-720, 2004 D iabetic distal symmetric sensorimotor polyneuropathy affects up to 60 -70% of diabetic patients and is the leading cause of foot ulceration and amputation (1). Improved blood glucose control reduces the risk of peripheral diabetic neuropathy (PDN), thereby implicating hyperglycemia as a leading causative factor. Diabetic hyperglycemia causes PDN via several mechanisms, among which increased aldose reductase (AR) activity (2-5), nonenzymatic glycation/glycoxidation (6,7), and activation of protein kinase C (2,8) are the best studied. All three mechanisms contribute to enhanced oxidative and nitrosative stress (4,5,7,9 -11) resulting from imbalance between production and neutralization of reactive oxygen species. Enhanced oxidative stress has been documented in peripheral nerve (4,5,8,(12)(13)(14), dorsal root and sympathetic ganglia (15), and vasculature (16,17) of the peripheral nervous system and has been implicated in neurovascular dysfunction and motor and sensory nerve conduction velocity (MNCV and SNCV) deficits, impaired neurotrophic support, nerve metabolic and signal transduction changes, and morphologic abnormalities characteristic for diabetes (4,5,12,14,16 -20). Evidence for the pathophysiologic role of reactive nitrogen species in PDN is also emerging (16,21).The question of how oxidative and nitrosative stress causes PDN remains open. We explored the role for poly(ADP-ribose) (PAR) polymerase (PARP-1; EC 2.4.2.30), a nuclear enzyme that is activated by oxidant-induced DNA single-strand breakage and transfers ADP-ribose residues from NAD ϩ to nuclear proteins (22-25). PARP-1 is present in both endothelial cells (22,23) and Schwann cells of the peripheral nerve (26). PARP-1 activation is clearly manifest in diabetes and contributes to diabetic end...

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Nitrosative Stress, Uric Acid, and Peripheral Nerve Function in Early Type 1 Diabetes

Cited by 94 publications

References 49 publications

Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy

Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy

Pioglitazone Treatment Improves Nitrosative Stress in Type 2 Diabetes

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

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