Hippocampal Apoptosis Is Ameliorated By C‐Peptide Replacement In Type 1 BB/W‐Rat

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It has been suggested that perturbed insulin‐like growth factors (IGFs) may be involved in CNS complications of diabetes. We examined IGF messages, hippocampal apoptosis and the effect of C‐peptide replacement on encephalopathy in type‐1 diabetic BB/Wor‐rats. By Northern blot analysis, we found decreased (50%) mRNA expression of IGF‐I, IGF‐II and IGF‐I receptor (IGF‐IR) in 2‐month diabetic rats. In 6‐month diabetic rats, these changes were associated with positive TUNEL staining, nucleosomal DNA fragmentation and an elevated (∼2.5‐fold) ratio of Bax/Bcl‐xL in hippocampus as assessed by Western blotting and LM‐PCR assays. C‐peptide replacement (75 ng/kg body weight/day) partially corrected the expression of IGF‐I, IGF‐II and IGF‐IR and eliminated hippocampal apoptosis. To investigate the mechanisms by which C‐peptide exerts its antiapoptotic effect, human neuroblastoma SH‐SY5Y cells were incubated in high concentrations of glucose (300 mM), which caused significant apoptosis of SH‐SY5Y cells as shown by nuclear shrinkage, positive TUNEL staining and DNA laddering. This increased apoptotic activity was delayed in SH‐SY5Y cells to which 10 nM C‐peptide had been added. In the same cell system, the insulin‐induced effect on PI‐3 kinase activity was enhanced by C‐peptide, in keeping with the notion that PI‐kinase plays a role in antiapoptotic signaling. We therefore conclude that insulin and C‐peptide deficiencies in type‐1 diabetic BB/Wor‐rats are associated with hippocampal apoptosis, which can be prevented by C‐peptide replacement.

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