| Project/Area Number |
21590609
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Hirosaki University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
YASUJIMA Minoru 弘前大学, 大学院・医学研究科, 教授 (90142934)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | 糖尿病 / 神経障害 / 表皮内神経線維 / 3次元画像解析 / 痛覚 / 病期分類 / インスリンシグナル異常 / 病期 / インスリンシグナル / インスリン作用 / 共焦点レーザー顕微鏡 |
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| Research Abstract |
Skin biopsies for analysis of intraepidermal nerve fibers (IENFs) represent a recently introduced technique for assessment of patients with suspected painful sensory neuropathy. Recent studies using skin biopsy specimen have indicated that the pre-diabetic state of impaired glucose tolerance (IGT) is associated with painful sensory neuropathy that is indistinguishable from the typical phenotype of early diabetic neuropathy, showing loss of IENFs. IGT is one component of metabolic syndrome, which consists of a constellation of specific metabolic derangements associated with insulin resistance (IR). It is reported that patients with painful sensory neuropathy have significantly higher serum insulin with greater IR than control subjects, indicating a linkage between insulin dysmetabolism and small fiber dysfunction. However, time course and molecular mechanism of IENF loss at different stages of severity of neuropathy associated with insulin resistant type 2 diabetes remain to be explored
… More
. In the present study, we characterized longitudinal trends in IENF density and alterations in peripheral nerve insulin signaling at the specific stages of neuropathy in type 2 diabetic Zucker diabetic fatty (ZDF) rats. ZDF rats at 8-10 weeks of age showed compensatory hyperinsulinemia and developed thermal hyperalgesia prior to the onset of overt hyperglycemia. These animals also exhibited progression from thermal hyperalgesia to hypoalgesia and developed mechanical hyperalgesia after 18 weeks of age when hyperglycemia was no longer accompanied by compensatory hyperinsulinemia. Despite the abnormal nociceptive behaviors, the IENF density was unaltered at 23 and 39 weeks of age, whereas it insignificantly increased by 26% at 10 weeks of age in ZDF rats, compared with age-matched lean rats. Immunofluorescence studies revealed significant decreases in insulin receptor and phosphorylated insulin receptor immunoreactivities in dorsal root ganglion neurons in 23 week-old ZDF rats compared with age-matched lean rats. In western blot analyses, insulin receptor and Akt protein levels were reduced by 70 % and 25%, respectively, whereas the phospho/total p44 and p42 MAP kinase ratios were increased by 33% and 52%, respectively, in the sciatic nerves of diabetic animals. In summary, the present study demonstrated progressive nociceptive dysfunction and aberrant peripheral nerve insulin signaling with preserved skin innervation up to 39 weeks of age in ZDF rats. ZDF rats may not be an appropriate animal model for studying IENF loss associated with type 2 diabetes. Less
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