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Diabetologia
Published in: Diabetologia 11/2006

01-11-2006 | Article

Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats

Authors: H. Kamiya, W. Zhang, A. A. F. Sima

Published in: Diabetologia | Issue 11/2006

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Abstract

Aims/hypothesis

The aim of this study was to evaluate the nature and extent of neuronal loss in dorsal root ganglia (DRG) in diabetic polyneuropathy.

Materials and methods

We examined 10-month diabetic BioBreeding/Worcester (BB/Wor) rats with respect to DRG ultrastructure and morphometry, sural nerve morphometry, pro- and anti-apoptotic proteins, the expression of neurotrophic factors and their receptors, and sensory nerve functions.

Results

In diabetic rats, DRG neurons decreased to 73% of normal, owing to loss of substance P and calcitonin gene-related peptide-positive neurons. Levels of pro-apoptotic active caspase-3, Bax and low-affinity nerve growth factor (NGF) were increased in DRG. The concentration of anti-apoptotic heat shock protein (HSP) 70 in DRG was decreased, whereas concentrations of Bcl-xl and HSP27 were unaltered. Levels of poly(ADP-ribose) polymerase (PARP) and cleaved PARP were unaltered. Levels of NGF in sciatic nerve and concentrations of the high-affinity NGF receptor, insulin receptor and IGF-I receptor in DRG were significantly decreased. Sensory nerve conduction velocity decreased to 78% of normal. Hyperalgesia increased up to 6 months. Myelinated and unmyelinated fibre numbers of the sural nerve were significantly decreased in diabetic rats. DRG examinations revealed no evidence of apoptosis, mitochondrial changes or abnormalities of the endoplasmic reticulum. Instead, neurons demonstrated progressive vacuolar degenerative changes of the Golgi apparatus, with fragmentation and formation of large cytoplasmic vacuoles. These data show that sustained apoptotic stress is present in DRG of chronically diabetic BB/Wor rats, but fails to proceed to apoptotic cell death.

Conclusions/interpretation

Progressive DRG neuronal loss, particularly of small neurons, occurs in the type 1 diabetic BB/Wor rat. This is associated with neurotrophic withdrawal and progressive degeneration of the Golgi apparatus.
Appendix
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Literature
1.
Sima AAF (2003) New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci 60:2445–2464PubMedCrossRef
2.
Scott JN, Clark AW, Zochodne DW (1999) Neurofilament and tubulin gene expression in progressive experimental diabetes: failure of synthesis and export by neurons. Brain 122:2109–2117PubMedCrossRef
3.
Tomlinson DR, Fernyhough P (2000) Neurotrophism in diabetic neuropathy. In: Sima AAF (ed.) Frontiers in animal diabetes research. Chronic complications in diabetes. Harwood Academic, Amsterdam, pp 167–182
4.
Huang TJ, Price SA, Chilton L et al (2003) Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes 52:2129–2136PubMed
5.
Sayers NM, Beswick LJ, Middlemas A et al (2003) Neurotrophin-3 prevents the proximal accumulation of neurofilament proteins in sensory neurons of streptozocin-induced diabetic rats. Diabetes 52:2372–2780PubMed
6.
Brussee V, Cunningham FA, Zochodne DW (2004) Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 53:1824–1830PubMed
7.
Kamiya H, Zhang W, Sima AAF (2004) C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 56:827–835PubMedCrossRef
8.
Sima AAF, Kamiya H (2004) Insulin, C-peptide and diabetic neuropathy. Sci Med 10:308–319
9.
Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL (1999) Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 6:347–363PubMedCrossRef
10.
Srinivasan S, Stevens M, Wiley JW (2000) Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 49:1932–1938PubMed
11.
Schmeichel AM, Schmetzer JD, Low PA (2003) Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 52:165–171PubMed
12.
Yagihashi S, Kamijo M, Ido Y, Mirrlees DJ (1990) Effects of long-term aldose reductase inhibition on development of experimental diabetic neuropathy. Ultrastructural and morphometric studies of sural nerve in streptozocin-induced diabetic rats. Diabetes 39:690–696PubMed
13.
Zochodne DW, Verge VM, Cheng C, Sun H, Johnston J (2001) Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes. Brain 124:2319–2334PubMedCrossRef
14.
Kishi M, Tanabe J, Schmelzer JD, Low PA (2002) Morphometry of dorsal root ganglion in chronic experimental diabetic neuropathy. Diabetes 51:819–824PubMed
15.
Kamiya H, Zhang W, Sima AAF (2005) Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of DRGs in subacute type 1 diabetic BB/Wor-rats. Diabetes 54:3288–3295PubMed
16.
Mordes JP, Bortell R, Groen H, Guberski D, Rossini AA, Greiner DL (2001) Autoimmune diabetes mellitus in the BB rat. In: Sima AAF, Shafrir E (eds) Animal models of diabetes. Harwood Academic, Amsterdam, pp 1–42
17.
Sima AAF, Bouchier M, Christensen H (1983) Axonal atrophy in sensory nerves of the diabetic BB–Wistar rat, a possible early correlate of human diabetic neuropathy. Ann Neurol 13:264–272PubMedCrossRef
18.
Kamiya H, Zhang W, Sima AAF (2005) Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes. Diabetes Metab Res Rev 21:448–458PubMedCrossRef
19.
Sima AAF, Ristic H, Merry A et al (1996) Primary preventive and secondary interventionary effects of acetyl-l-carnitine on diabetic neuropathy in the Bio-breeding Worcester rat. J Clin Invest 97:1900–1907PubMedCrossRef
20.
21.
Farquhar MG, Palade GE (1998) The Golgi apparatus: 100 years of progress and controversy. Trends Cell Biol 8:2–10PubMedCrossRef
22.
23.
24.
Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3:E255–E263PubMedCrossRef
25.
Arvan P, Zhao X, Ramos-Castaneda J, Chang A (2002) Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems. Traffic 3:771–780PubMedCrossRef
26.
Hicks SW, Machamer CE (2005) Golgi structure in stress sensing and apoptosis. Biochim Biophys Acta 1744:406–414PubMedCrossRef
27.
Mancini M, Machamer CE, Roy S et al (2000) Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis. J Cell Biol 149:603–612PubMedCrossRef
28.
Jones SJ, Ledgerwood EC, Prins JB et al (1999) TNF recruits TRADD to the plasma membrane but not the trans-Golgi network, the principal subcellular location of TNF-R1. J Immunol 162:1042–1048PubMed
29.
Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P (1998) Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282:290–293PubMedCrossRef
30.
Recio-Pinto E, Rechler MM, Ishii DN (1986) Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci 6:1211–1219PubMed
31.
Pierson CR, Zhang W, Sima AAF (2003) Proinsulin C-peptide replacement in type 1 diabetic BB/Wor-rats prevents deficits in nerve fiber regeneration. J Neuropathol Exp Neurol 62:765–779PubMed
32.
Cheng C, Zochodne DW (2003) Sensory neurons with activated caspase-3 survive long-term experimental diabetes. Diabetes 52:2363–2371PubMed
33.
Burnand RC, Price SA, McElhaney M, Barker D, Tomlinson DR (2004) Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes. Brain Res Mol Brain Res 132:235–240PubMedCrossRef
34.
Lewis SE, Mannion RJ, White FA et al (1999) A role for HSP27 in sensory neuron survival. J Neurosci 19:8945–8953PubMed
35.
Benn SC, Perrelet D, Kato AC et al (2002) Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron 36:45–56PubMedCrossRef
36.
Mehlen P, Schulze-Osthoff K, Arrigo AP (1996) Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1- and staurosporine-induced cell death. J Biol Chem 271:16510–16514PubMedCrossRef
37.
Greenbaum D, Richardson PC, Salmon MW, Urich H (1964) Pathologic aberrations on six cases of diabetic neuropathy. Brain 87:201–214PubMed
38.
Sima AAF, Zhang W, Li ZG, Murakawa Y, Pierson CR (2004) Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Diabetes 53:1556–1563PubMed
39.
Ishii DN (1995) Implication of insulin-like growth factors in the pathogenesis of diabetic neuropathy. Brain Res Brain Res Rev 20:47–67PubMedCrossRef
40.
Zhuang HX, Wuarin L, Fei ZJ, Ishii DN (1997) Insulin-like growth factor (IGF) gene expression is reduced in neural tissues and liver from rats with non-insulin-dependent diabetes mellitus, and IGF treatment ameliorates diabetic neuropathy. J Pharmacol Exp Ther 283:366–374PubMed
41.
Xu G, Pierson CR, Murakawa Y, Sima AAF (2002) Altered tubulin and neurofilament expression and impaired axonal growth in diabetic nerve regeneration. J Neuropathol Exp Neurol 61:164–175PubMed
42.
Pierson CR, Zhang W, Murakawa Y, Sima AAF (2002) Early gene responses of trophic factors in nerve regeneration differ in experimental type 1 and type 2 diabetic polyneuropathies. J Neuropathol Exp Neurol 61:857–871PubMed
43.
Li ZG, Zhang W, Sima AAF (2003) C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes Metab Res Rev 19:375–385PubMedCrossRef
44.
Averill S, McMahon SB, Clary DO, Reichardt LF, Priestley JV (1995) Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons. Eur J Neurosci 7:1484–1494PubMedCrossRef
45.
Sugimoto K, Murakawa Y, Sima AAF (2002) Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst 7:44–53PubMedCrossRef
46.
Wright DE, Snider WD (1995) Neurotrophin receptor mRNA expression defines distinct populations of neurons in rat dorsal root ganglia. J Comp Neurol 351:329–338PubMedCrossRef
47.
Singleton JR, Smith AG, Bromberg MB (2001) Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 24:1448–1453PubMed
48.
Novella SP, Inzucchi SE, Goldstein JM (2001) The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 24:1229–1231PubMedCrossRef
49.
Murakawa Y, Zhang W, Pierson CR et al (2002) Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev 18:473–483PubMedCrossRef
Metadata
Title
Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats
Authors
H. Kamiya
W. Zhang
A. A. F. Sima
Publication date
01-11-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0379-0

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