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Rev Diabet Stud, 2009, 6(1):37-42 DOI 10.1900/RDS.2009.6.37

Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide

Anders A.F. Sima1,2, Weixian Zhang1, Christian W. Kreipke3, José A. Rafols3, William H. Hoffman4

1Department of Pathology, Wayne State University, Detroit, MI, USA
2Department of Neurology, Wayne State University, Detroit, MI, USA
3Department of Anatomy, Wayne State University, Detroit, MI, USA
4Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA
Address correspondence to: Anders A.F. Sima, e-mail: asima@med.wayne.edu

Manuscript submitted May 18, 2009; resubmitted June 8, 2009; accepted June 9, 2009.

Keywords: type 1 diabetes, BB/Wor-rat, encephalopathy, inflammation, C-peptide, hippocampus, NF-kappaB, RAGE

Abstract

Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-κB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-α, IL-1β, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-κB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.

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