Mouse models of diabetic neuropathy

Sullivan, Kelli A.; Hayes, John M.; Wiggin, Timothy D.; Backus, Carey; Oh, Sang Su; Lentz, Stephen I.; Brosius, Frank C.; Feldman, Eva L.

doi:10.1016/j.nbd.2007.07.022

Cited by 165 publications

(202 citation statements)

References 106 publications

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“…Thermal sensitivities were determined with an analgesia apparatus (Model 336TG; Life Sciences) as previously described (33). Tail flick responses were elicited with an adjustable red light emitter (range 60-170°C), and the time for the animal to respond was recorded electronically.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that Akita diabetic mice on a C57BL/6 genetic background are resistant to diabetic neuropathy, as judged by the minimal effects of Akita diabetes on latencies of heat sensation and nerve conduction velocity at age 24 weeks (33). Nevertheless, at the same age and on the same genetic background, the response times to a thermal stimulus (tail flick and hind paw withdrawal) are prolonged in the BRKO-Akita mice relative to the Akita, BRKO, or WT mice (Fig.…”

Section: Effect Of Lack Of Bradykinin Receptors and Akita Diabetes Onmentioning

confidence: 99%

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Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Kakoki¹,

Sullivan

Backus

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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110

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An insertion polymorphism of the angiotensin-I converting enzyme gene (ACE) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The ACE polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (Ins2). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.diabetes mellitus complications | kinins T he angiotensin-I converting enzyme (ACE) is a dipeptidyl carboxypeptidase, named because it removes two amino acids from the carboxyl terminus of the inactive peptide angiotensin I and converts it into the active blood pressure-raising peptide, angiotensin II. However, ACE is also a kininase and converts the active vasodilatory kinins into inactive metabolites by removing two amino acids from their carboxyl termini (1). Prior experimental findings (2) and computer simulations (3) show that modest changes in ACE levels affect the levels of its substrates much more than its products, indicating that relatively small changes in the levels of ACE affect kinin levels more than angiotensin II levels.The common insertion/deletion (I/D) polymorphism of the ACE gene in humans is due to the presence or absence of an Alu retrotransposon in the 16th intron of the gene. The polymorphism is associated with up to a twofold difference in relative plasma ACE levels (4), but the polymorphism does not significantly affect blood pressure or angiotensin II or aldosterone levels (5). Nevertheless, the I and D human ACE alleles are associated with different risks for developing diabetic complications including nephropathy (6

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Section: Methodsmentioning

confidence: 99%

Section: Effect Of Lack Of Bradykinin Receptors and Akita Diabetes Onmentioning

confidence: 99%

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Kakoki¹,

Sullivan

Backus

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

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“…Sensorimotor diabetic polyneuropathy (DPN) affects both large and small sensory afferent nerve fibers. The majority of research focuses on small-fiber neuropathy leading to increased or decreased pain and temperature sensations (2)(3)(4)(5). Consequently, there is a shortage of animal model research exploring large-fiber DPN, which can cause deficits in lower-limb proprioception, decreased tactile sensitivity and vibration sense, and incoordination due to balance abnormalities (1,6).…”

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confidence: 99%

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

et al. 2008

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OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.RESEARCH DESIGN AND METHODS-Behavioral assessments were performed in untreated and treated streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Quantification of Ia axon innervation of spindles was carried out using immunohistochemistry and confocal microscopy on STZ-injected C57BL/6 and db/db mice.RESULTS-STZ-injected C57BL/6 mice displayed significant and progressive sensorimotor dysfunction. Analysis of Ia innervation patterns of diabetic C57BL/6 spindles revealed a range of abnormalities suggestive of Ia axon degeneration and/or regeneration. The multiple abnormal Ia fiber morphologies resulted in substantial variability in axonal width and inter-rotational distance (IRD). Likewise, db/db mice displayed significant variability in their IRDs compared with db ϩ mice, suggesting that damage to Ia axons occurs in both type 1 and type 2 diabetes models. Insulin treatment improved behavioral deficits and restored Ia fiber innervation in comparison with nondiabetic mice.CONCLUSIONS-Similar to small fibers, Ia axons are vulnerable to diabetes, and their damage may contribute to balance and gait deficits. In addition, these studies provide a novel method to assay therapeutic interventions designed for diabetes-induced large-fiber dysfunction. Diabetes 57:1693-1701, 2008 E stimates from the Centers for Disease Control and Prevention suggest that 60 -70% of diabetic patients develop neuropathy. In addition, diabetes is the leading cause of neuropathy in the U.S. and Western countries (1). Sensorimotor diabetic polyneuropathy (DPN) affects both large and small sensory afferent nerve fibers. The majority of research focuses on small-fiber neuropathy leading to increased or decreased pain and temperature sensations (2-5). Consequently, there is a shortage of animal model research exploring large-fiber DPN, which can cause deficits in lower-limb proprioception, decreased tactile sensitivity and vibration sense, and incoordination due to balance abnormalities (1,6).The sensorimotor deficits resulting from large-fiber DPN, while sometimes subtle in nature, can lead to significant impairment. Numerous human studies report that patients with DPN are at increased risk for falls due to decreased postural control, altered gait and balance, and increased body sway (7-9). The underlying neurologic mechanisms involved in large-fiber DPN remain poorly understood. It has been hypothesized that large-fiber DPN instability could be ca...

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“…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 (http://www.amdcc.org) and developed an independent set of phenotyping parameters to classify and categorize mouse models of diabetes with regard to the development and severity of DN [13,14]. The current review suggests a definition of murine DN, summarizes the published data on mouse models of DN and recommends a set of standardized criteria to define DN in mice.…”

mentioning

confidence: 99%

“…Methods used to assess neuropathy include a careful neurological examination of tendon reflexes, the ability to sense hot, cold or vibratory stimuli, and in select cases, nerve conduction studies using surface electrodes and skin biopsies [10,13,14,28]. These measures have been successfully adapted and applied to mouse models of neuropathy including DN [13,14,[29][30][31][32].DN is described in mice with type 1 or 2 diabetes including spontaneous (genetic) and chemically induced (streptozotocin, STZ) models (Tables 1-3). The earliest reports of DN in mouse models centered on the BKS.Cg-m+/+Lepr db /J mouse (BKS-db/db) a spontaneous model of type 2 diabetes.…”

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confidence: 99%

Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

Sullivan

Lentz²,

Roberts

et al. 2008

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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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Mouse models of diabetic neuropathy

Cited by 165 publications

References 106 publications

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy

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