Neuropathological study of C57BL/6Akita mouse, type 2 diabetic model: Enhanced expression of αB‐crystallin in oligodendrocytes

Yaguchi, Masamitsu; Nagashima, Kazuaki; Izumi, Tetsuro; Okamoto, Koichi

doi:10.1046/j.1440-1789.2003.00475.x

Cited by 21 publications

(13 citation statements)

References 28 publications

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“…Similarly to the previously described characterization of Ins2 Akita/+ mice [36] we found a progressive increase in blood glucose level starting between three and four weeks of age. Interestingly, our experimental design allowed us to detect the presence of a DPN much earlier than previously reported [27].…”

Section: Discussionsupporting

confidence: 88%

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

et al. 2010

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While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2Akita/+ mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2Akita/+ and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2Akita/+ mice and sex-matched littermate controls. Our phenotypic analysis of Ins2Akita/+ mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

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Section: Discussionsupporting

confidence: 88%

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

et al. 2010

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“…Akita mice further showed enhanced expression of ␣␤-crystallin in oligodendrocytes, suggesting a role for hyperglycemia or insulin deficiency in diabetic neuropathy (44). Although Ins2…”

Section: Barber Et Al (2) Demonstrated That Ins2mentioning

confidence: 99%

“…Akita mice to examine diabetic complications including retinopathy, nephropathy and neuropathy (2,10,44).…”

mentioning

confidence: 99%

Nonobese, insulin-deficient Ins2^Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

Hong

Jung

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2Akita mice leads to pancreatic β-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2Akita and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2Akita mice developed insulin resistance, as indicated by an ∼80% reduction in glucose infusion rate during clamps. Insulin resistance was due to ∼50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCε levels in Ins2Akita mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCε levels in Ins2Akita mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2Akita mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects.

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“…Hyperglycemia-induced flux through the polyol pathway has many stressful consequences for cellular metabolism (22), and it is plausible that this could induce local secretion of hyperalgesia-inducing substances from oligodendrocytes. Indeed, oligodendrocytes in the brain of diabetic mice show enhanced expression of ␣B-crystallin, a heat shock protein upregulated under various pathological conditions (23), and oligodendrocytes in vitro secrete inflammatory lipid products, including PGE 2 , in response to sublethal injury with complement complexes (24). In diabetes, exaggerated polyol pathway flux in oligodendrocytes may induce COX-2 activity, resulting in local secretion of PGE 2 that could diffuse to dorsal horn neurons and sensitize them to nociceptive input from primary afferents (25).…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

Ramos

Jiang²,

Svensson³

et al. 2007

Diabetes

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Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalinevoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats. Diabetes 56: [1569][1570][1571][1572][1573][1574][1575][1576] 2007 A proportion of diabetic patients experience chronic pain that severely degrades their quality of life. The pathogenesis of painful diabetic neuropathy is unclear, and treatment options are currently limited to palliatives that do not target a pathogenic mechanism specific to painful diabetic neuropathy and provide limited efficacy before side effects become intolerable (1). Experimental models of diabetic neuropathy can spur development of novel therapies by providing an understanding of how diabetes alters sensory processing.Diabetic rats display abnormal pain-associated behaviors, measured as exaggerated responses to painful stimuli (hyperalgesia) or nocifensive responses to normally innocuous stimuli (allodynia). Hyperalgesia to paw formalin injection (2,3) and allodynia to tactile stimulation of the paw (4) develop within weeks of induction of hyperglycemia, and, as overt structural pathology in peripheral nerves is minimal, attention has focused on biochemical disorders that could exaggerate sensory processing.The formalin test is used to investigate spinal sensitization in animals (5) and allows investigation of sensory processing beyond peripheral nociceptive pathways. Diabetic rats exhibit increased nocifensive behavior during periods of the formalin test associated with spinal sensitization (6,7) in concert with paradoxically decreased spinal release of excitatory neurotransmitters (8,9). This suggests that hyperalgesia is not caused by increased primary afferent input and, toge...

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Neuropathological study of C57BL/6Akita mouse, type 2 diabetic model: Enhanced expression of αB‐crystallin in oligodendrocytes

Cited by 21 publications

References 28 publications

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

Nonobese, insulin-deficient Ins2^Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

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Neuropathological study of C57BL/6Akita mouse, type 2 diabetic model: Enhanced expression of αB‐crystallin in oligodendrocytes

Cited by 21 publications

References 28 publications

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

Nonobese, insulin-deficient Ins2Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

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Nonobese, insulin-deficient Ins2^Akitamice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling