The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats.
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.
Sima
Anders A F
AA
Wayne State University School of Medicine, Department of Pathology, 540 E. Canfield Ave., Detroit, MI 48201, USA. asima@med.wayne.edu
Li
Zhen-guo
ZG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002096:C-Peptide / Q000494:pharmacology*; D053454:Caspase 12; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D003072:Cognition Disorders / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000523:psychology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011236:Prediabetic State / Q000473:pathology / Q000523:psychology; D051381:Rats; D011913:Rats, Inbred BB
D002096:C-Peptide; C506443:Casp12 protein, rat; D053454:Caspase 12; D020169:Caspases