An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis through multiple mechanisms including direct actions on the endocrine pancreas and indirect activation of central nervous system circuits regulating gastric emptying, satiety, and body weight. Because native GLP-1 is rapidly degraded, there is considerable interest in development of more potent GLP-1 receptor (GLP-1R) agonists with sustained activity; however, the extent to which much larger GLP-1R agonists will mimic some or all of the actions of smaller peptides remains uncertain.


METHODS
We studied the actions of CJC-1134-PC, a recombinant human serum albumin-exendin-4 conjugated protein, at the GLP-1R using heterologous cells expressing the GLP-1R in vitro and both wild-type and Glp1r(-/-) mice in vivo.


RESULTS
CJC-1134-PC activated GLP-1R-dependent signaling in baby hamster kidney-GLP-1R cells and acutely lowered blood glucose in wild-type but not in Glp1r(-/-) mice. Moreover, acute administration of CJC-1134-PC rapidly activated c-Fos expression in multiple regions of the central nervous system, acutely inhibited gastric emptying, and produced sustained inhibition of food intake in a GLP-1R-dependent manner. Furthermore, chronic daily treatment of high-fat diet-fed wild-type mice with CJC-1134-PC for 4 weeks led to improved glucose tolerance, increased levels of glucose-stimulated insulin, decreased HbA1c, and weight loss associated with decreased hepatic triglyceride content.


CONCLUSIONS
These findings illustrate that a high-molecular-weight exendin-4-albumin conjugate retains the ability to mimic a full spectrum of GLP-1R-dependent actions, including activation of central nervous system circuits regulating gastric emptying, food intake, and body weight.
Baggio
Laurie L
LL
Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, Canada.
Huang
Qingling
Q
Cao
Xiemin
X
Drucker
Daniel J
DJ
D000818:Animals; D015992:Body Mass Index; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D004734:Energy Metabolism / Q000187:drug effects*; D000077270:Exenatide; D005746:Gastric Emptying / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D000081410:Germinal Center Kinases; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018027:Receptors, Glucagon / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014688:Venoms / Q000494:pharmacology*
C000593833:GLP1R protein, human; D000081410:Germinal Center Kinases; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D017346:Protein Serine-Threonine Kinases; D005947:Glucose