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Diabetes 54:1497-1505, 2005
© 2005 by the American Diabetes Association, Inc.
The Effect of C-Peptide on Cognitive Dysfunction and Hippocampal Apoptosis in Type 1 Diabetic Rats
1 Department of Pathology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
2 Department of Neurology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
3 Morris Hood Jr. Comprehensive Diabetes Center, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan
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.
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
Abbreviations:
8-OHdG, 8-hydroxyl-2'-deoxyguanosine; AIF, apoptosis-inducing factor; NF-
B, nuclear factor-B; NGF, nerve growth factor; NGFR, nerve growth factor receptor; PARP, poly(ADP-ribose) polymerase; PI-3, phosphatidyinositol-3; ROS, reactive oxygen species; TBS, tris-buffered saline; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling
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