Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model.
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.


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 beta-subunit (IRbeta), insulin receptor substrate (IRS)-1, and IRS-2. The numbers of neurons expressing IRbeta protein were also preserved. There were trends toward early rises of mRNA levels of heat shock protein 27 (HSP27), the alpha2delta1 calcium channel subunit, and phosphatidylinositol 3-kinase in diabetes. Others were unchanged, including nuclear factor-kappaB (NF-kappaB; p50/p105) and receptor for advanced glycosylation endproducts (RAGE) as was the proportion of neurons expressing HSP27, NF-kappaB, 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.
Brussee
Valentine
V
Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Guo
GuiFang
G
Dong
YingYing
Y
Cheng
Chu
C
Martinez
José A
JA
Smith
Darrell
D
Glazner
Gordon W
GW
Fernyhough
Paul
P
Zochodne
Douglas W
DW
D000200:Action Potentials; D000818:Animals; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D008297:Male; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009431:Neural Conduction / Q000502:physiology; D010147:Pain Measurement; D012335:RNA, Ribosomal / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D011930:Reaction Time; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012335:RNA, Ribosomal; D004247:DNA