Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide

Abstract

■ AbstractEncephalopathy 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 neurobehavioral 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.

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

“…We have previously observed that C-peptide interferes with glucose-induced nuclear translocation of the NF-κB p65/p50 subunits in HAEC, and reduces endothelial dysfunction [29]. An effect of C-peptide on NF-κB and consequent decreased inflammatory cytokine production has also been reported in the brain of diabetic BB/Wor rats and found to be associated with reduced neuronal apoptosis [31,45,46]. Here, we add significant pieces of information, by showing that C-peptide decreases intracellular ROS generation, a crucial upstream signalling event in the NF-κB pathway.…”

“…C-peptide has been shown to improve endothelial dysfunction and systemic inflammation in several in vivo and in vitro models of inflammation-mediated vascular injury by reducing expression of genes encoding endothelial cell adhesion molecules, inflammatory cytokine production and adherence and transmigration of leucocytes [27][28][29][30]. Although the exact mechanism(s) underlying the antiinflammatory activity of C-peptide is not known, there is evidence that C-peptide affects NF-κB activation [29,31]. However, which NF-κB-dependent upstream signalling event is affected by C-peptide in endothelial cells is not clear.…”

Diabetic encephalopathy: the role of oxidative stress and inflammation in type 2 diabetes

“…18 Although the brain was described before as an insulin-insensitive organ, there is now an increasing body of evidence demonstrating that insulin is widely distributed in this organ. 33 Furthermore, insulin plays a critical role in numerous mechanisms in the brain, such as metabolic, neurotrophic, neuromodulatory, and neuroendocrine, 34 as well as in memory and learning processes.…”

“…33 Furthermore, insulin plays a critical role in numerous mechanisms in the brain, such as metabolic, neurotrophic, neuromodulatory, and neuroendocrine, 34 as well as in memory and learning processes. 35,36 Additionally, insulin operates in the CNS through binding to specific cell receptorsinsulin and insulin growth factor 1 receptor (IGF-1R) -which are highly abundant and selectively distributed throughout the CNS (eg, hypothalamus, hippocampus). 37,38 Once bound to these receptors, insulin triggers signaling cascades that include phosphoinositide 3-kinase (PI3K) and MAPK, 39,40 which are the most relevant ones involved in learning and memory processes ( Figure 2).…”

“…13,17 Oxidative stress and inflammation, which underlie multiple cellular pathways that can ultimately lead to the onset and progression of subsequent complications of T2DM, are being envisioned as two key players in diabetic encephalopathy, an emerging and pressing type 2 diabetic complication ( Figure 1). [18][19][20][21] Additionally a correlation was unequivocally drawn between hallmarks of T2DM, including hyperglycemia, impaired insulin signaling, free fatty acids (FFAs), oxidative stress, and inflammation.…”