Original Data

Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide

Anders A.F. Sima^1,2, Weixian Zhang¹, Christian W. Kreipke³, José A. Rafols³, William H. Hoffman⁴

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.

Fulltext: HTML , PDF (379KB)

This article has been cited by other articles:

	C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells Cifarelli V, Geng X, Styche A, Lakomy R, Trucco M, Luppi P Diabetologia 2011. 54(10):2702-2712
	Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells Lindahl E, Nordquist L, Müller P, El Agha E, Friederich M, Dahlman-Wright K, Palm F, Jörnvall H Diabetes Metab Res Rev 2011. 27(7):697-704
	Oxidative damage is present in the fatal brain edema of diabetic ketoacidosis Hoffman WH, Siedlak SL, Wang Y, Castellani RJ, Smith MA Brain Res 2011. 1369:194-202
	C-peptide and long-term complications of diabetes Luppi P, Cifarelli V, Wahren J Pediatr Diabetes 2011. 12(3Pt2):276-292
	Anti-inflammatory effects of C-peptide prevent endothelial dysfunction in type 1 diabetes Cifarelli V, Trucco M, Luppi P Immunol Endocr Metab Agents Med Chem 2011. 11(1):59-70
	Encephalopathies: the emerging diabetic complications Sima AA Acta Diabetol 2010. 47(4):279-293
	Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema Hoffman WH, Andjelkovic AV, Zhang W, Passmore GG, Sima AA Brain Res 2010. 1343:168-177
	Neuroprotection in diabetic encephalopathy Fazeli SA Neurodegener Dis 2009. 6(5-6):213-218
	Sequential abnormalities in type 1 diabetic encephalopathy and the effects of C-Peptide Sima AA, Zhang W, Muzik O, Kreipke CW, Rafols JA, Hoffman WH Rev Diabet Stud 2009. 6(3):211-222
	The beneficial effects of C-Peptide on diabetic polyneuropathy Kamiya H, Zhang W, Sima AA Rev Diabet Stud 2009. 6(3):187-202
	Anti-inflammatory properties of C-Peptide Haidet J, Cifarelli V, Trucco M, Luppi P Rev Diabet Stud 2009. 6(3):168-179
	Breakthrough in diabetes therapy ... Just around the corner? Rudert WA, Trucco M Rev Diabet Stud 2009. 6(2):76-80