title: The role of impaired insulin/IGF action in primary diabetic encephalopathy.
abstract: We have previously shown that hippocampal neuronal apoptosis accompanied by impaired cognitive functions occurs in type 1 diabetic BB/Wor rats. To differentiate the contribution by insulin deficiency vs. that by hyperglycemia on neuronal apoptosis, we examined the activities of various apoptotic pathways in hippocampi from type 1 diabetic BB/Wor rats (hyperglycemic and insulinopenic) and type 2 diabetic BBZDR/Wor rats (hyperglycemic and hyperinsulinemic). DNA fragmentation was demonstrated by LM-PCR in type 1 diabetic BB/Wor rats, but was not detectable in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. Of various apoptotic pathways, Fas activations, 8-OHdG expression, and caspase-12 were demonstrated in type 1 diabetic BB/Wor rats only. In contrast, perturbations of the IGF and NGF systems and PARP activation were demonstrated in type 1 and to a lesser extent in type 2 diabetes. Expressions of Bax and active caspase-3 were significantly increased in type 1, but not in type 2, diabetic rats. These data suggest a lesser apoptogenic stress in type 2 vs. type 1 diabetes. These differences translated into a more profound neuronal loss in the hippocampus of type 1 rats. The results demonstrate that caspase-dependent apoptotic activities dominate in type 1 diabetes, whereas PARP-mediated caspase-independent apoptotic stress is present in both type 1 and type 2 diabetes. The findings suggest that insulin deficiency plays a compounding role to that of hyperglycemia in neuronal apoptosis underpinning primary diabetic encephalopathy.
authors.affiliation: Department of Pathology, Wayne State University, School of Medicine, H.G. Scott Hall, Room 9275, 540 East Canfield Avenue, Detroit, MI 48201, USA.
authors.forename: Zhen-Guo
authors.initials: ZG
authors.lastname: Li
authors.forename: Weixian
authors.initials: W
authors.lastname: Zhang
authors.forename: Anders A F
authors.initials: AA
authors.lastname: Sima
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology; D053938:DNA Fragmentation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D006624:Hippocampus / Q000473:pathology; D006943:Hyperglycemia / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000097:blood / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013002:Somatomedins / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D007328:Insulin; D018124:Receptors, Tumor Necrosis Factor; D013002:Somatomedins; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases; D020794:Receptor Protein-Tyrosine Kinases; D020169:Caspases