Abstract
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) analogues are approved for treating type 2 diabetes, but are known to activate GLP-1R signaling globally and constitutively. Active compound N55, previously isolated from fenugreek, enhances the potency of GLP-1 without activating GLP-1R. Here we investigated if N55 lowers plasma glucose base on physiological levels of GLP-1. N55 was found to dose-dependently lower plasma glucose in non-fasted mice but not in the fasted mice, with the effect attenuated by GLP-1R antagonist exendin-(9–39) (Ex-9). On the other hand, when co-administered with dipeptidyl peptidase-IV (DPP4) -resistant [Aib8]-GLP-1(7–36) amide (GLP-1′), hypoglycemic response to N55 was observed in the fasted mice. This enhancement was also found to display dose dependency. N55 enhancement of the hypoglycemic and insulinotropic action of GLP-1′ was eliminated upon Ex-9 treatment. Both exendin-4 (Ex-4) and DPP4-resistant GLP-1 mutant peptide ([Aib8, E22, E30]-GLP-1(7–36) amide) activated GLP-1R and improved glucose tolerance but the enhancement effect of N55 was not observed in vivo or in vitro. In conclusions, N55 lowers plasma glucose according to prandial status by enhancing the response of physiological levels of GLP-1 and is much less likely to disrupt tight regulation of GLP-1R signaling as compare to GLP-1 analogues.
Highlights
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1 or by neuron-secreted GLP-1
To test if N55 would affect the plasma glucose, we examined glycemic response of N55 during intraperitoneal glucose tolerance test (IPGTT) in non-fasted mice
The hypoglycemic action of N55 was completely eliminated by GLP-1R antagonist exendin-(9–39) (Ex-9) (Fig. 1c)
Summary
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1 or by neuron-secreted GLP-1. GLP-1 analogues have been approved for treatment of type 2 diabetes. The target tissues and physiological message transmission pathways of the pharmacological level of GLP-1 analogues may be quite different from those of physiological levels of GLP-12,5,6. All these features disrupt the tight regulation of GLP-1R signaling and may lead to adverse effects. To explore whether N55 is able to improve glucose tolerance without disrupting tight regulation of GLP-1R, we analyzed the responses of N55 in animal studies. Glycemic responses of N55 in non-fasted mice and in fasted mice were used to address these concerns. Examining the effect of N55 on hypoglycemic response of GLP-1′, Ex-4 and [Aib, E22, E30]-GLP-1(7–36) amide allowed us to specify the primary target of N55 in vivo
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