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Diabetes Obes Metab. 2018 May;20(5):1223-1234. doi: 10.1111/dom.13222. Epub 2018 Feb 20.

A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents.

Author information

1
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Chemistry, Syracuse University, Syracuse, New York.
3
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York.
5
Center for Integrative Brain Research, Seattle Children's Research Institute, Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, Washington.

Abstract

AIMS:

While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.

MATERIALS AND METHODS:

We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.

RESULTS:

B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4.

CONCLUSION:

These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

KEYWORDS:

antidiabetic drug; appetite control; drug development; exenatide

PMID:
29327400
PMCID:
PMC5899935
DOI:
10.1111/dom.13222
[Indexed for MEDLINE]
Free PMC Article

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