GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes.
BACKGROUND
Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28-36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11.


RESULTS
Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress.


CONCLUSIONS
These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes.
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, MA 02114, United States.
Eva
E
Tomas
Violeta
V
Stanojevic
Joel F
JF
Habener
D000818:Animals; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000378:metabolism
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C560057:glucagon-like peptide-1(28-36)amide; D052216:Glucagon-Like Peptide 1; D005947:Glucose