Early changes in insulin receptor signaling and pain sensation in streptozotocin-induced diabetic neuropathy in rats.
The objective of the present study was to evaluate the time course of changes in peripheral nerve insulin receptor (IR) signaling and compare observed findings with behavioral responses to noxious mechanical and thermal stimuli in streptozotocin (STZ)-diabetic rats over 12 weeks of diabetes. Diabetic rats developed mechanical hyperalgesia, as indicated by decreased paw withdrawal thresholds to mechanical stimuli that were detectable after 2 weeks of diabetes; they also developed thermal hypoalgesia, as indicated by increased tail flick latencies to thermal stimuli that were detectable at 1 week of diabetes. Western blot analysis revealed decreased phosphorylated: total IR protein ratio that was detectable as early as 2 weeks of diabetes, whereas phosphorylated:total Akt protein ratio was decreased at 2 weeks and increased at 12 weeks of diabetes with unchanged PI-3K protein levels. To our knowledge, the present study is the first to demonstrate that impaired peripheral nerve IR signaling, as indicated by decreased phosphorylated:total IR protein ratio, coincides with early mechanical hyperalgesia and thermal hypoalgesia in STZ-diabetic rats. This finding may improve understanding of how altered pain sensation develops rapidly in this model.


CONCLUSIONS
This study examined peripheral nerve IR signaling during the early course of altered nociception in STZ-diabetic rats. In diabetic rats, impaired peripheral nerve IR signaling is observed shortly after STZ injection, as is altered nociception. This finding suggests a possible role of impaired IR signaling in diabetic sensory neuropathy.
Sugimoto
Kazuhiro
K
Department of Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. sugimoto@cc.hirosaki-u.ac.jp
Rashid
Irena B
IB
Shoji
Masaru
M
Suda
Toshihiro
T
Yasujima
Minoru
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D001786:Blood Glucose; D014443:Tyrosine; D013311:Streptozocin; D011972:Receptor, Insulin