GUB06-046, a novel secretin/glucagon-like peptide 1 co-agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice.
Søren B van WitteloostuijnLouise S DalbøgeGitte HansenSøren Roi MidtgaardGrethe Vestergaard JensenKnud Jørgen JensenNiels VrangJacob JelsingSøren L PedersenPublished in: Journal of peptide science : an official publication of the European Peptide Society (2017)
Bariatric surgery is currently the most effective treatment of obesity, which has spurred an interest in developing pharmaceutical mimetics. It is thought that the marked body weight-lowering effects of bariatric surgery involve stimulated secretion of appetite-regulating gut hormones, including glucagon-like peptide 1. We here report that intestinal expression of secretin is markedly upregulated in a rat model of Roux-en-Y gastric bypass, suggesting an additional role of secretin in the beneficial metabolic effects of Roux-en-Y gastric bypass. We therefore developed novel secretin-based peptide co-agonists and identified a lead compound, GUB06-046, that exhibited potent agonism of both the secretin receptor and glucagon-like peptide 1 receptor. Semi-acute administration of GUB06-046 to lean mice significantly decreased cumulative food intake and improved glucose tolerance. Chronic administration of GUB06-046 to diabetic db/db mice for 8 weeks improved glycemic control, as indicated by a 39% decrease in fasting blood glucose and 1.6% reduction of plasma HbA1c levels. Stereological analysis of db/db mice pancreata revealed a 78% increase in beta-cell mass after GUB06-046 treatment, with no impact on exocrine pancreas mass or pancreatic duct epithelial mass. The data demonstrate beneficial effects of GUB06-046 on appetite regulation, glucose homeostasis, and beta-cell mass in db/db mice, without proliferative effects on the exocrine pancreas and the pancreatic duct epithelium. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Keyphrases
- weight loss
- glycemic control
- blood glucose
- roux en y gastric bypass
- bariatric surgery
- gastric bypass
- high fat diet induced
- obese patients
- type diabetes
- single cell
- body weight
- insulin resistance
- cell therapy
- weight gain
- poor prognosis
- wild type
- adipose tissue
- electronic health record
- blood pressure
- stem cells
- liver failure
- physical activity
- long non coding rna
- intensive care unit
- artificial intelligence
- extracorporeal membrane oxygenation
- body mass index