Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

Sullivan, Kelli A.; Lentz, Stephen I.; Roberts, John L.; Feldman, Eva L.

doi:10.2174/138945008783431763

Cited by 66 publications

(35 citation statements)

References 83 publications

(149 reference statements)

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“…In our well-characterized model of type 2 diabetes with diabetic neuropathy, the 24 wk old BKLS db/db mouse [32, 33], the increase in the number of axonal mitochondria agrees with our recent report of increased mitochondrial density in the cell bodies of the DRG neurons [7]. Mitochondrial density was never different between samples in younger 12 wk db/db animals, an age at which neuropathy has not yet developed [32, 41].…”

Section: Discussionsupporting

confidence: 88%

Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy

et al. 2010

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Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.

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Section: Discussionsupporting

confidence: 88%

Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy

et al. 2010

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“…Two site combinations, SP1F and ZBPF, and a configuration of two EGRF sites were found to be significant by both approaches [57]. We and others are now making a comprehensive effort to establish the molecular signatures of neural tissues including peripheral nerve and sensory and sympathetic ganglia, from genome wide screening of RNA from human patients and animal models with and without diabetic neuropathy [55, 145]. Our approach for diabetic neuropathy is presented in Figure 3.…”

Section: The Search For Novel Therapeutic Targetsmentioning

confidence: 99%

Mechanisms of disease: The oxidative stress theory of diabetic neuropathy

Figueroa‐Romero

Sadidi

Feldman

2008

Rev Endocr Metab Disord

235

175

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Diabetic neuropathy is the most common complication of diabetes, affecting 50% of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of Poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets.

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“…Finally, since both human and db/db mouse kidneys mainly express leptin receptor Ob-Ra [145], and since the db/db mutation is in the Ob-Rb receptor, the leptin deregulation in this model may play a role in the pathogenesis of diabetic nephropathy that is not relevant to the conditions in humans. With regard to neuropathy, while db/db mice develop fiber atrophy [146] and profound neuropathy at 24 weeks after the onset of diabetes [147], they do not have increased sorbitol in the sciatic nerve [148], which is suggested to play an important role in the development of diabetic neuropathy in humans [149]. …”

Section: Introductionmentioning

confidence: 99%

“…The short lifespan of rodents makes it difficult to study these complications. There is also a lack of uniformity in the diagnosis and monitoring of diabetic neuropathy in murine models due to substantial variability in the background strains, animal age and gender, and the type of diabetes present (including induction method and duration) [147]. …”

Section: Introductionmentioning

confidence: 99%

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

Wang¹,

Chandrasekera

Pippin

2014

CDR

433

348

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Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

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Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

Cited by 66 publications

References 83 publications

Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy

Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy

Mechanisms of disease: The oxidative stress theory of diabetic neuropathy

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

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