title: Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy.
abstract: BACKGROUND
  Recent studies indicate that impaired glucose tolerance (IGT) in man is a causative factor in idiopathic sensory neuropathy, and that insulinopenia may contribute substantially to the severity of diabetic peripheral neuropathy. The effect of sustained IGT and progressive insulinopenia in the absence of overt hyperglycemia on peripheral nerve abnormalities was examined in the Goto-Kakizaki (GK)-rat.
  
  
  METHODS
  Two and eighteen-month-old GK rats with decreased glucose tolerance and overt insulinopenia, respectively, were examined with respect to nerve function, structure, morphometry and molecular integrity, and were compared to age-matched control rats.
  
  
  RESULTS
  Both 2-(p < 0.001) and 18-month-old (p < 0.001) GK rats showed reduced body weight. Blood glucose levels following glucose tolerance tests were elevated in both the 2-month and the 18-month-old GK rats. Fasting plasma insulin levels in the 2-month GK rats were increased threefold (p < 0.05) but decreased by 71% (p < 0.001) in the 18-month GK rats. The two-month GK rats showed a normal nerve conduction velocity, whereas in the 18-month GK rats it was reduced to 76% (p < 0.001) of control values. No morphometric abnormalities were found in the 2-month GK rats, whereas the 18-month GK rats showed loss of small myelinated fibers (p < 0.001), atrophy and loss of unmyelinated axons (p < 0.05) and an increased (p < 0.01) frequency of regenerating fibers. In the older GK rats, both mRNA and protein expression of nerve growth factor (NGF) in the sciatic nerve were significantly reduced (p < 0.001 and p < 0.05), and NGFR TrkA (high affinity NGF receptor) and NGFRp75 (low affinity NGF-receptor) protein expression was reduced in dorsal root ganglia (DRG) (both p < 0.05). These changes were accompanied by significantly reduced protein expressions of substance P (SP) and calcitonin gene-related protein (CGRP) in DRG's (both p < 0.001) as well as a 40% (p < 0.001) decrease in SP and a 62% (p < 0.001) decrease in CGRP-positive DRG neurons. In the sciatic nerve, SP and CGRP protein expression was decreased by 71% (p < 0.01) and 79% (p < 0.01), respectively.
  
  
  CONCLUSIONS
  IGT combined with hyperinsulinemia for 2 months have no detectable effect on peripheral nerve function or structure. In contrast, IGT and subsequent insulinopenia result in a functional and structural neuropathy associated with impaired NGF support and neuropeptide synthesis. We suggest that these abnormalities are mainly due to insulinopenia rather than hyperglycemia.
authors.affiliation: Department of Pathology, Wayne State University, School of Medicine, Detroit, MI, USA.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakawa
authors.forename: Weixian
authors.initials: W
authors.lastname: Zhang
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Tom
authors.initials: T
authors.lastname: Brismar
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Ostenson
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.forename: Anders A F
authors.initials: AA
authors.lastname: Sima
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D008297:Male; D016555:Matched-Pair Analysis; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D010525:Peripheral Nerves / Q000503:physiopathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D013373:Substance P; D020932:Nerve Growth Factor; D011972:Receptor, Insulin; D020917:Receptor, trkA; D015740:Calcitonin Gene-Related Peptide