Development of diabetic neuropathy in the C57BL/Ks (db/db) mouse and its treatment with gangliosides

Norido, F.; Canella, R.; Zanoni, R.; Gorio, A.

doi:10.1016/s0014-4886(84)90094-3

Cited by 101 publications

(36 citation statements)

References 27 publications

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“…The BBZDR/Wor rat (9) had more mild electrophysiological changes and structural changes of nerves than related BB/Wor type 1 rats despite similar levels and durations of hyperglycemia. Furthermore, type 2 models have included the TSOD mouse exhibiting severe axon and myelin changes after 14 months of diabetes (28); the Goto-Kakizaki (GK) rat that demonstrated motor nerve conduction slowing, mild axonal atrophy, low-level demyelination, and axonal degeneration at 18 but not 2 months of diabetes (29); the db/db mouse with slowed sciatic nerve conduction velocity, axonal atrophy, and epidermal axon fiber loss up to 6 months of age (30,31); and the leptin-deficient (ob/ob) mouse with motor nerve conduction slowing, thermal hyperalgesia, mechanical allodynia, and loss of epidermal axons at 11 weeks of age (32). The diabetic rats exhibited substantial mechanical allodynia without evidence of thermal hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

et al. 2008

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OBJECTIVE-Peripheral neuropathy associated with type 2 diabetes (DPN) is not widely modeled. We describe unique features of DPN in type 2 diabetic Zucker diabetic fatty (ZDF) rats.RESEARCH DESIGN AND METHODS-We evaluated the structural, electrophysiological, behavioral, and molecular features of DPN in ZDF rats and littermates over 4 months of hyperglycemia. The status of insulin signaling transduction molecules that might be interrupted in type 2 diabetes and selected survival-, stress-, and pain-related molecules was emphasized in dorsal root ganglia (DRG) sensory neurons.RESULTS-ZDF rats developed slowing of motor sciatic-tibial and sensory sciatic digital conduction velocity and selective mechanical allodynia with preserved thermal algesia. Diabetic sural axons, preserved in number, developed atrophy, but there was loss of large-calibre dermal and small-calibre epidermal axons. In diabetic rats, insulin signal transduction pathways in lumbar DRGs were preserved or had trends toward upregulation: mRNA levels of insulin receptor ␤-subunit (IR␤), insulin receptor substrate (IRS)-1, and IRS-2. The numbers of neurons expressing IR␤ protein were also preserved. There were trends toward early rises of mRNA levels of heat shock protein 27 (HSP27), the ␣2␦1 calcium channel subunit, and phosphatidylinositol 3-kinase in diabetes. Others were unchanged, including nuclear factor-B (NF-B; p50/p105) and receptor for advanced glycosylation endproducts (RAGE) as was the proportion of neurons expressing HSP27, NF-B, and RAGE protein.CONCLUSIONS-ZDF type 2 diabetic rats develop a distal degenerative sensory neuropathy accompanied by a selective long-term pain syndrome. Neuronal insulin signal transduction molecules are preserved.

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Section: Discussionmentioning

confidence: 99%

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

et al. 2008

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“…Galactocerebroside, a lipid element in axo-glial junctions (37), is depleted from myelin isolated from the BB rat (38). Membrane glycolipids are further implicated in chronic conduction slowing by studies in the spontaneously diabetic db/ db mouse, where ganglioside treatment selectively improves nerve conduction during the structural phase of diabetic neuropathy (39). Lastly, altered membrane phosphoinositide composition, and/or associated changes in protein kinase C activity and/or inositol-(1,4,5)-tris-phosphate-mediated Ca mobilization might directly influence the integrity of axo-glial junctional complexes (40), as might other abnormalities in the endoneurial extracellular environment in diabetes (41).…”

Section: Discussionmentioning

confidence: 99%

Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat.

Sima¹,

Lattimer²,

Yagihashi³

et al. 1986

J. Clin. Invest.

171

117

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Biochemical abnormalities in peripher, nerve are thought to precede and condition the development of diabetic neuropathy, but metabolic intervention in chronic diabetic neuropathy produces only limited acute clinical response. The residual, metabolically unresponsive neurological deficits have never been rigorously defined in terms of either persistent metabolic derangements or irreversible structural defects because (a) human nerve tissue is rarely accessible for anatomical and biochemical study and (b) experimentally diabetic animals do not develop the structural hallmarks of human diabetic neuropathy. Detailed neuroanatomical-functional-biochemical correlation was therefore undertaken in long-term spontaneously diabetic BB-Wistar rats that functionally and structurally model human diabetic neuropathy. Vigorous insulin replacement in chronically diabetic BB rats essentially normalized both the sural nerve fiber caliber spectrum and the decreased sciatic nerve myo-inositol and (Na,K)-ATPase levels generally associated with conduction slowing in diabetic animals; yet, nerve conduction was only partially restored toward normal. Morphometric analysis revealed a striking disappearance of paranodal axo-glial junctional complexes that was not corrected by insulin replacement. Loss of these strategic junctional complexes, which are thought to limit lateral migration of axolemmal Na channels away from nodes of Ranvier, correlates with and can account for the diminished nodal Na permeability and resultant nodal conduction delay characteristic of chronic diabetic neuropathy in this animal model.

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“…DN is reported as early as 4 weeks post onset of diabetes as measured by an increase in thermal latency. Both sensory and motor nerve conduction velocities are decreased [13,14,[33][34][35][36], axonal transport is slowed [37,38] and both neurotransmitter levels [39] and IENF densities are decreased [13,14] (Table 1). A second spontaneous model of type 2 diabetes is the B6.V-Lep ob /J or B6-ob/ob mouse.…”

Section: Mouse Models Of Dnmentioning

confidence: 99%

“…For example, nerve conduction assays are performed at 4 week intervals rather than only at 3 and 6 month time points. Assessments of MFD of the sural nerve and/or quantitation using electron microscopy of thinly myelinated and unmyelinated fibers yield additional anatomical confirmation of DN [35,44]. Biochemical measures for oxidative stress adducts and enzymes are performed in plasma and tissue extracts of DRG and peripheral nerve [47,54,[76][77][78].…”

Section: Advanced Neuropathy Phenotypingmentioning

confidence: 99%

“…The BKS-db/db mouse is an example of a spontaneous model of type 2 diabetes that develops a robust DN. Previous work in this model demonstrated clear deficits in NCV [33,34,[81][82][83][84][85] and fiber density and/or morphology [33,35,[81][82][83][86][87][88] following the development of diabetes. BKS-db/db mice develop hyperglycemia between 3-4 weeks of age (http:// jaxmice.jax.org/) and a profound neuropathy at 24 weeks post onset of diabetes [13].…”

Section: An Example Of Murine Phenotypingmentioning

confidence: 99%

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Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

Sullivan

Lentz²,

Roberts

et al. 2008

CDT

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Diabetic neuropathy (DN) is a serious and debilitating complication of both type 1 and type 2 diabetes. Despite intense research efforts into multiple aspects of this complication, including both vascular and neuronal metabolic derangements, the only treatment remains maintenance of euglycemia. Basic research into the mechanisms responsible for DN relies on using the most appropriate animal model. The advent of genetic manipulation has moved mouse models of human disease to the forefront. The ability to insert or delete genes affected in human patients offers unique insight into disease processes; however, mice are still not humans and difficulties remain in interpreting data derived from these animals. A number of studies have investigated and described DN in mice but it is difficult to compare these studies with each other or with human DN due to experimental differences including background strain, type of diabetes, method of induction and duration of diabetes, animal age and gender. This review describes currently used DN animal models. We followed a standardized diabetes induction protocol and designed and implemented a set of phenotyping parameters to classify the development and severity of DN. By applying standard protocols, we hope to facilitate the comparison and characterization of DN across different background strains in the hope of discovering the most human like model in which to test potential therapies. KeywordsNOD; Akita; ob/ob; db/db; outbred mice; nerve conduction velocity; intraepidermal nerve fiber density DIABETES MELLITUSThe term "diabetes mellitus" describes a number of conditions in which blood glucose is elevated including insulin dependent diabetes mellitus (IDDM) Beyond effective control of glucose levels, there are no treatments to prevent or cure DN. Numerous factors have impeded laboratory investigations aimed at the development of effective therapies, including an incomplete analysis of existing animal models that develop DN, lack of consistency among mouse models (diabetes induction and genetics) and lack of consensus concerning phenotyping methods. The AMDCC was formed by the NIH to develop new animal models of diabetes and its complications; its goal is to identify the most appropriate animal models to study the etiology, prevention and treatment of diabetic complications. The group has reported its findings comparing the effects of diabetes on cardiovascular disease [2], and nephropathy [12] in inbred mice from different genetic background strains and maintains a website containing its recommended phenotyping protocols. AMDCC investigators continue to refine genetic and dietary factors that affect the development of diabetes and its complications, potential interactions and overlap of complications within a genetic model, and common pathways that may influence treatment paradigms in human patients.In order to provide a consistent method of examining DN in diabetic mouse models, our laboratory implemented a standardized diabetes induction protocol used by the AMDCC (...

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Development of diabetic neuropathy in the C57BL/Ks (db/db) mouse and its treatment with gangliosides

Cited by 101 publications

References 27 publications

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat.

Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

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