C-peptide activates AMPKα and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes.

Abstract

Vasculopathy is a major complication of diabetes; however, molecular mechanisms mediating the development of vasculopathy and potential strategies for prevention have not been identified. We have previously reported that C-peptide prevents diabetic vasculopathy by inhibiting reactive oxygen species (ROS)-mediated endothelial apoptosis. To gain further insight into ROS-dependent mechanism of diabetic vasculopathy and its prevention, we studied high glucose-induced cytosolic and mitochondrial ROS production and its effect on altered mitochondrial dynamics and apoptosis. For the therapeutic strategy, we investigated the vasoprotective mechanism of C-peptide against hyperglycemia-induced endothelial damage through the AMP-activated protein kinase α (AMPKα) pathway using human umbilical vein endothelial cells and aorta of diabetic mice. High glucose (33 mmol/L) increased intracellular ROS through a mechanism involving interregulation between cytosolic and mitochondrial ROS generation. C-peptide (1 nmol/L) activation of AMPKα inhibited high glucose-induced ROS generation, mitochondrial fission, mitochondrial membrane potential collapse, and endothelial cell apoptosis. Additionally, the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside and the antihyperglycemic drug metformin mimicked protective effects of C-peptide. C-peptide replacement therapy normalized hyperglycemia-induced AMPKα dephosphorylation, ROS generation, and mitochondrial disorganization in aorta of diabetic mice. These findings highlight a novel mechanism by which C-peptide activates AMPKα and protects against hyperglycemia-induced vasculopathy.

• Authors: Mahendra Prasad Bhatt, Young-Cheol Lim, Young-Myeong Kim, Kwon-Soo Ha
• Journal: Diabetes (Diabetes) Vol. 62 Issue 11 Pg. 3851-62 (Nov 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23884890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• C-Peptide
• Reactive Oxygen Species
• Aminoimidazole Carboxamide
• Metformin
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Aminoimidazole Carboxamide (pharmacology)
• Animals
• Apoptosis (drug effects)
• C-Peptide (pharmacology, therapeutic use)
• Cells, Cultured
• Cytosol (metabolism)
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetic Angiopathies (etiology)
• Enzyme Activation
• Glucose (administration & dosage, pharmacology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Metformin (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mitochondrial Dynamics (drug effects)
• Reactive Oxygen Species (metabolism, pharmacology)