Abstract
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Highlights
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D)
We have investigated the role of receptor trafficking in glucagon-like peptide-1 receptor (GLP-1R) agonism, an important treatment modality for type 2 diabetes (T2D) which improves pancreatic beta cell function and insulin sensitivity[8]
We found that prolonged exendin-4-induced insulin secretion was increased in INS-1 832/3 and MIN6B1 cells after treatment with small interfering RNA to silence both β-arrestins, and in human EndoC-βH140 beta cells lentivirally transduced with β-arrestin-1 and β-arrestin-2 small hairpin RNA (Fig. 4g–i, Supplementary Fig. 7a-e)
Summary
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. We develop a series of peptides closely related to the GLP1 homolog exendin-4, used clinically as exenatide[12], but with widely varying trafficking properties We use these to establish a robust relationship between GLP-1R trafficking and insulin release in a manner not predicted by the standard pharmacological potency testing for cyclic adenosine monophosphate (cAMP), a primary second messenger coupling GLP-1R activation to insulin secretion[13]. By selectively augmenting insulin release, modulation of GLP-1R trafficking may be a viable strategy to achieve greater metabolic control in T2D without increasing the rate of unwanted side effects, such as nausea
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