Rapid selection of a novel GLP-1/GIP dual receptor agonist with prolonged glycemic control and weight loss in rodent animals

Jun 30, 2020Life sciences

Fast identification of a new drug that activates two hormone receptors to improve blood sugar control and reduce weight in rodents

AI simplified

GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗

Abstract

XEL32 demonstrated significant insulinotropic and glucose-lowering activities in diabetic db/db mice.

XEL17 showed balanced activation potency on GLP-1R and GIPR in stable cell lines.
Preclinical assessments indicated that XEL32 maintained prolonged antidiabetic effects in diabetic db/db mice.
XEL32 also resulted in notable reductions in hemoglobin A1C (HbA1C) and improved glucose tolerance.
Chronic treatment of XEL32 in diet-induced obesity (DIO) rats led to effective body weight control and fat loss.
The findings suggest that XEL32 could be a promising option for glycemic control and weight management.

AI simplified

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists have emerged as treatment options for reversing diabetes and obesity. Here, we screened the high potency receptor-biased GLP-1R agonists via a newly designed high-throughput GLP-1R extracellular domain (ECD)-based system and demonstrated its in vitro and in vivo therapeutic characters.

METHODS: Twelve 9-mer peptides (named XEL1-XEL12) which were screened from a large phage-displayed peptide library were fused to the N-terminus of GIP (3-30) to generate another twelve fusion peptides, termed XEL13-24. Using the six lysine-altered XEL17 as leading sequences, eighteen fatty chain modified fusion peptides were further assessed via in vitro GLP-1R/GIPR-based cell assay. Moreover, the acute and long-acting in vivo effects of selected candidate on diabetic db/db mice and diet-induced obesity (DIO) rats were both carefully evaluated.

RESULTS: XEL17 exhibited balanced activation potency on GLP-1R/GIPR in stable cell lines, and further assessment was performed to evaluate the XEL32, a fatty chain modified XEL17 derivative. Preclinical pharmacodynamic results in diabetic db/db mice demonstrated that XEL32 held outstanding insulinotropic and glucose-lowering activities. In addition, protracted antidiabetic effects of XEL32 were also proved by the hypoglycemic test and multiple oral glucose tolerance test. Furthermore, chronic treatment of XEL32 in DIO rats exhibited outstanding beneficial effects on body weight control, fat loss, food intake control, hemoglobin A1C (HbA1C) reduction as well as the glucose tolerance.

CONCLUSIONS: XEL32, as a novel GLP-1/GIP dual receptor agonist, may supply efficient glycemic control and weight loss.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Rapid selection of a novel GLP-1/GIP dual receptor agonist with prolonged glycemic control and weight loss in rodent animals

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief