Abstract
Activation of TGR5 via bile acids or bile acid analogs leads to the release of glucagon-like peptide-1 (GLP-1) from intestine, increases energy expenditure in brown adipose tissue, and increases gallbladder filling with bile. Here, we present compound 18, a non-bile acid agonist of TGR5 that demonstrates robust GLP-1 secretion in a mouse enteroendocrine cell line yet weak GLP-1 secretion in a human enteroendocrine cell line. Acute administration of compound 18 to mice increased GLP-1 and peptide YY (PYY) secretion, leading to a lowering of the glucose excursion in an oral glucose tolerance test (OGTT), while chronic administration led to weight loss. In addition, compound 18 showed a dose-dependent increase in gallbladder filling. Lastly, compound 18 failed to show similar pharmacological effects on GLP-1, PYY, and gallbladder filling in Tgr5 knockout mice. Together, these results demonstrate that compound 18 is a mouse-selective TGR5 agonist that induces GLP-1 and PYY secretion, and lowers the glucose excursion in an OGTT, but only at doses that simultaneously induce gallbladder filling. Overall, these data highlight the benefits and potential risks of using TGR5 agonists to treat diabetes and metabolic diseases.
Highlights
In 1902, Bayliss and Starling speculated that an endocrine substance arising from the gut after ingestion of nutrients induces secretions from the pancreas [1]
A TGR5 agonist that is capable of inducing the secretion of glucagon-like peptide-1 (GLP-1) as well as increasing energy expenditure may prove to be a promising incretin-based strategy for the treatment of type 2 diabetes and obesity [26,27]
While chronic treatment of obese mice with INT-777 has been shown to improve the glucose excursion in an oral glucose tolerance test (OGTT) [22], this effect on glucose is likely due to weight loss observed in these mice and not due to direct effects of TGR5 agonism on GLP-1 and indirect effects on insulin secretion
Summary
In 1902, Bayliss and Starling speculated that an endocrine substance arising from the gut after ingestion of nutrients induces secretions from the pancreas [1]. The “incretin effect” describes the phenomenon where insulin secretion is profoundly more robust following glucose ingestion compared to the insulinotropic response achieved by parenteral administration of intravenously infused glucose [2,3]. It is estimated that 50% to 70% of the secretion of insulin from the pancreas following a meal occurs due to incretin action [3]. Two hormones with known incretin activity are glucagon-like peptide-1 (GLP-1) released from intestinal Lcells and glucose-dependent insulinotropic peptide (GIP) released from intestinal K-cells [4].
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