The Effect of C-Peptide on Cognitive Dysfunction and Hippocampal Apoptosis in Type 1 Diabetic Rats

  1. Anders A.F. Sima123 and
  2. Zhen-guo Li13
  1. 1Department of Pathology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
  2. 2Department of Neurology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
  3. 3Morris Hood Jr. Comprehensive Diabetes Center, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
  1. Address correspondence and reprint requests to Anders A.F. Sima, MD, PhD, Wayne State University, Department of Pathology, 540 E. Canfield Ave., Detroit, MI 48201. E-mail: asima{at}med.wayne.edu

Abstract

Primary diabetic encephalopathy is a recently recognized late complication of diabetes resulting in a progressive decline in cognitive faculties. In the spontaneously type 1 diabetic BB/Wor rat, we recently demonstrated that cognitive impairment was associated with hippocampal apoptotic neuronal loss. Here, we demonstrate that replacement of proinsulin C-peptide in this insulinopenic model significantly prevented spatial learning and memory deficits and hippocampal neuronal loss. C-peptide replacement prevented oxidative stress–, endoplasmic reticulum–, nerve growth factor receptor p75–, and poly(ADP-ribose) polymerase–related apoptotic activities. It partially ameliorated apoptotic stresses mediated via impaired insulin and IGF activities. These findings were associated with the prevention of increased expression of Bax and active caspase 3 and the frequency of caspase 3–positive neurons. The results show that several partially interrelated apoptotic mechanisms are involved in primary encephalopathy and suggest that impaired insulinomimetic action by C-peptide plays a prominent role in cognitive dysfunction and hippocampal apoptosis in type 1 diabetes. Although these abnormalities were not fully prevented by C-peptide replacement, the findings suggest that this regime will substantially prevent cognitive decline in the type 1 diabetic population.

Footnotes

    • Accepted January 24, 2005.
    • Received August 11, 2004.
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