Mouse models of diabetic neuropathy

doi:10.1016/j.nbd.2007.07.022

Neurobiology of Disease

Volume 28, Issue 3, December 2007, Pages 276-285

https://doi.org/10.1016/j.nbd.2007.07.022 Get rights and content

Abstract

Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. We examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2^Akita] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db]. Despite persistent hyperglycemia, the STZ-treated B6 and B6Ins2^Akita mice were resistant to the development of DN. In contrast, DN developed in both type 2 diabetes models: the B6-db/db and BKS-db/db mice. The persistence of hyperglycemia and development of DN in the B6-db/db mice required an increased fat diet while the BKS-db/db mice developed severe DN and remained hyperglycemic on standard mouse chow. Our data support the hypothesis that genetic background and diet influence the development of DN and should be considered when developing new models of DN.

Introduction

Over 20 million Americans are diabetic and the incidence is increasing by 5% per year. The most common complication of diabetes is neuropathy (DN) which occurs in approximately 60% of diabetic patients (Vincent and Feldman, 2004). In the United States, DN is the leading cause of diabetes-related hospital admissions and nontraumatic amputations (Boulton et al., 2005) (http://www.diabetes.org).

There are no accepted treatments for DN beyond glucose control. In part, the lack of effective therapies stems from the lack of animal models of DN. The Animal Models of Diabetic Complications Consortium (AMDCC) was formed by the NIH to develop new animal models of diabetic complications; its goal is to identify the most appropriate animal models to study the etiology, prevention and treatment of diabetic complications, including DN.

The most useful mouse model of DN should exhibit the key features present in human pathology (Feldman et al., 2003) including (1) sensory loss, (2) electrophysiological measures of nerve impairment and (3) anatomical evidence of nerve fiber loss. Neuropathy phenotyping begins with evaluation of sensory loss by quantitative assessment of thermal sensitivity. Electrophysiological measures of nerve impairment are the “gold standard” for determining sensory and motor nerve function and include assessment of motor and sensory nerve conductions in the tail and sciatic nerve. Finally, analysis of the number of small fibers in the mouse footpad lends insight into function. Anatomical evidence of nerve fiber loss is measured by assessment of intraepidermal nerve fiber (IENF) density in the footpad.

The current study examined DN in 4 inbred strains of mice. Our goal was to identify mouse models that closely resemble neural changes present in patients with DN. We hypothesize that development of DN is multifactorial and is influenced by background strain and diet. We determined that the most robust model for DN was the db/db mouse on the C57BLKS background. This model remained hyperglycemic without dietary intervention and developed progressive loss of sensory function, slowed nerve conductions and loss of intraepidermal nerve fibers. Our finding that the development of DN varies across mouse models of diabetes agrees with the recent report by Qi et al. (Qi et al., 2005).

Section snippets

Mice

Mice (Table 1) were purchased from Jackson Laboratories (Bar Harbor, Maine). Breeding colonies were established at the University of Michigan to provide the animals used in this study and were genotyped 4 weeks after birth. Mice were housed in a pathogen-free environment, with continuous access to food (see below) and water on a 12-h light–dark schedule and were cared for following the University of Michigan Committee on the Care and Use of Animals guidelines.

Induction or onset of diabetes

In the following text, mice are

Metabolic parameters

Pancreatic beta cell destruction with STZ is a commonly used model of type 1 diabetes. This strategy was employed in the C57BL/6J strain of mice. STZ-treated C57BL/6J developed significantly higher levels of fasting blood glucose than vehicle injected mice. Elevated blood glucose levels were consistent throughout the experimental period and reflected by elevated GHb measured at the end of 24 weeks (Table 2). C57BL/6J STZ-treated mice lost weight compared to the nontreated control mice (Table 2

Discussion

A relevant mouse model of DN must demonstrate key features of human disease including (1) loss of sensory function, (2) electrophysiological measures of nerve impairment and (3) nerve fiber loss (Ad Hoc Panel on Endpoints for Diabetic Neuropathy Trials, 2001). In the current study, thermal sensitivity in the tail and hind paw, NCV and IENF density are used to determine if diabetic mouse models develop DN. In the current study, these measures were used to assess 4 mouse models of diabetes for

Acknowledgments

The authors wish to acknowledge Ms. Julie Erwin for expert manuscript preparation and Drs. Tracy Schwab and Andrea Vincent for expert editorial advice. These studies were conducted within the Morphometry Core of the JDRF Center for the Study of Complications in Diabetes and the Michigan Diabetes Research and Training Center (NIH5P60 DK20572).

Grant support: This work was supported by the National Institutes of Health (NS38849, U54-DA021519 and DK60994), the Juvenile Diabetes Research Foundation

References (57)

H.-L. Cheng et al.
Immunohistochemical localization of insulin-like growth factor binding protein-5 in the developing rat nervous system
Brain Res. Dev. Brain Res.
(1996)
C. Choeiri et al.
Longitudinal evaluation of memory performance and peripheral neuropathy in the Ins2C96Y Akita mice
Behav. Brain Res.
(2005)
J.A. Christianson et al.
Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice
Exp. Neurol.
(2003)
J.A. Christianson et al.
Beneficial actions of neurotrophin treatment on diabetes-induced hypoalgesia in mice
J. Pain
(2003)
B.H. Gabra et al.
Absence of diabetic hyperalgesia in bradykinin B1 receptor-knockout mice
Regul. Pept.
(2005)
N.S. Gibran et al.
Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus
J. Surg. Res.
(2002)
B.E. Layton et al.
Differences between collagen morphologies, properties and distribution in diabetic and normal BioBreeding and Sprague–Dawley rat sciatic nerves
J. Biomech.
(2004)
J.H. Lee et al.
Effect of hyperglycemia on pain threshold in alloxan-diabetic rats
Pain
(1990)
E.H. Leiter et al.
Dietary control of pathogenesis in C57BL/KsJ db/db diabetes mice
Metabolism
(1981)
H.Z. Mao et al.
Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains
Biochim. Biophys. Acta
(2006)

M. Matsuda et al.

Possible contribution of adipocytokines on diabetic neuropathy

Diabetes Res. Clin. Pract.

(2004)

S.M. Miller et al.

Leptin receptor immunoreactivity in sympathetic prevertebral ganglion neurons of mouse and rat

Neurosci. Lett.

(1999)

F. Norido et al.

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

Exp. Neurol.

(1984)

J.W. Russell et al.

Neurons undergo apoptosis in animal and cell culture models of diabetes

Neurobiol. Dis.

(1999)

M.J. Stevens et al.

Acetyl-l-carnitine deficiency as a cause of altered nerve myo-Inositol content, Na, K-ATPase activity and motor conduction velocity in the streptozotocin-diabetic rat

Metabolism

(1996)

R.S. Surwit et al.

Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice

Metabolism

(1995)

N. Tsunoda et al.

High-monounsaturated fat diet-induced obesity and diabetes in C57BL/6J mice

Metabolism

(1998)

I. Vareniuk et al.

Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice

Exp. Neurol.

(2007)

S.M. Watkins et al.

Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone

J. Lipid Res.

(2002)

Ad Hoc Panel on Endpoints for Diabetic Neuropathy Trials, 2001. Positive neuropathic sensory symptoms as endpoints in...

A.J. Barber et al.

The Ins2Akita mouse as a model of early retinal complications in diabetes

Invest. Ophthalmol. Visual Sci.

(2005)

R. Bianchi et al.

Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity

Clin. Cancer Res.

(2006)

A.J. Boulton et al.

Diabetic neuropathies: a statement by the American Diabetes Association

Diabetes Care

(2005)

M.D. Breyer et al.

Diabetic nephropathy: leveraging mouse genetics

Curr. Opin. Nephrol. Hypertens.

(2006)

M. Brownlee

The pathobiology of diabetic complications: a unifying mechanism

Diabetes

(2005)

H.P. Chen et al.

Detection and estrogen regulation of leptin receptor expression in rat dorsal root ganglion

Histochem. Cell Biol.

(2006)

R.C. Davis et al.

Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility

Diabetes

(2005)

S. Doss et al.

Cis-acting expression quantitative trait loci in mice

Genome Res.

(2005)

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Mouse models of diabetic neuropathy

Abstract

Introduction

Section snippets

Mice

Induction or onset of diabetes

Metabolic parameters

Discussion

Acknowledgments

Brain Res. Dev. Brain Res.

Behav. Brain Res.

Exp. Neurol.

J. Pain

Regul. Pept.

J. Surg. Res.

J. Biomech.

Pain

Metabolism

Biochim. Biophys. Acta

Diabetes Res. Clin. Pract.

Neurosci. Lett.

Exp. Neurol.

Neurobiol. Dis.

Metabolism

Metabolism

Metabolism

Exp. Neurol.

J. Lipid Res.

The Ins2Akita mouse as a model of early retinal complications in diabetes

Invest. Ophthalmol. Visual Sci.

Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity

Clin. Cancer Res.

Diabetic neuropathies: a statement by the American Diabetes Association

Diabetes Care

Diabetic nephropathy: leveraging mouse genetics

Curr. Opin. Nephrol. Hypertens.

The pathobiology of diabetic complications: a unifying mechanism

Diabetes

Detection and estrogen regulation of leptin receptor expression in rat dorsal root ganglion

Histochem. Cell Biol.

Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility

Diabetes

Cis-acting expression quantitative trait loci in mice

Genome Res.