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Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy.
Diabetes Metab Res Rev. 2002 Nov-Dec; 18(6):473-83.DM

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.

CONCLUSION

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+Show Affiliations

Department of Pathology, Wayne State University, School of Medicine, Detroit, MI, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12469361

Citation

Murakawa, Yuichi, et al. "Impaired Glucose Tolerance and Insulinopenia in the GK-rat Causes Peripheral Neuropathy." Diabetes/metabolism Research and Reviews, vol. 18, no. 6, 2002, pp. 473-83.
Murakawa Y, Zhang W, Pierson CR, et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev. 2002;18(6):473-83.
Murakawa, Y., Zhang, W., Pierson, C. R., Brismar, T., Ostenson, C. G., Efendic, S., & Sima, A. A. (2002). Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes/metabolism Research and Reviews, 18(6), 473-83.
Murakawa Y, et al. Impaired Glucose Tolerance and Insulinopenia in the GK-rat Causes Peripheral Neuropathy. Diabetes Metab Res Rev. 2002;18(6):473-83. PubMed PMID: 12469361.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. AU - Murakawa,Yuichi, AU - Zhang,Weixian, AU - Pierson,Christopher R, AU - Brismar,Tom, AU - Ostenson,Claes-Göran, AU - Efendic,Suad, AU - Sima,Anders A F, PY - 2002/12/7/pubmed PY - 2003/7/18/medline PY - 2002/12/7/entrez SP - 473 EP - 83 JF - Diabetes/metabolism research and reviews JO - Diabetes Metab. Res. Rev. VL - 18 IS - 6 N2 - 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. CONCLUSION: 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. SN - 1520-7552 UR - https://www.unboundmedicine.com/medline/citation/12469361/Impaired_glucose_tolerance_and_insulinopenia_in_the_GK_rat_causes_peripheral_neuropathy_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=1520-7552&amp;date=2002&amp;volume=18&amp;issue=6&amp;spage=473 DB - PRIME DP - Unbound Medicine ER -