The Cardiac Glucagonlike Peptide-1 Receptor: Whither Art Thou?

Glucagonlike peptide-17-36NH2 (GLP-1) is an enteroendocrine hormone that plays a key role in the maintenance of glucose homeostasis through stimulation of glucose-dependent insulin secretion, the so-called incretin effect, and through inhibition of glucagon release, gastric emptying, and food intake. As a consequence, GLP-1–derivative drugs were successfully implemented into the clinic >10 years ago, reducing glycemia, HbA1c levels, and, in some cases, body weight in patients with type 2 diabetes. Given the increased incidence of cardiovascular disease in this population, several large clinical trials have recently reported that at least some GLP-1–based therapeutics also provide cardioprotection, reducing both fatal and nonfatal cardiovascular events in subjects with type 2 diabetes (1). GLP-1 receptor (GLP-1R) agonists have also been reported to increase heart rate in proportion to the pharmacokinetic profile of the individual agonist (2). When taken with both clinical and preclinical data showing effects of GLP-1 to improve left ventricular function after an ischemic insult (3, 4), these findings suggest that GLP-1 may exert direct effects on cells within the heart and cardiovascular system. However, how these effects are exerted has remained enigmatic, largely because of low-level GLP-1R expression as well as technical issues in the field. The biological actions of GLP-1 are mediated through a single known GLP-1R, which is a 7-transmembrane, G protein–coupled member of the glucagon receptor superfamily. Original reports described expression of GLP-1R in a variety of peripheral tissues, including β cells, the gastrointestinal tract, kidneys, lungs, cells of the immune system, heart and blood vessels, and the central nervous system. Although the localization of the receptor in many of these tissues is consistent with known effects of GLP-1, controversy in the field arose with the demonstration that several commonly used, commercially available GLP-1R antisera are nonspecific, detecting expression in tissues from GLP-1R knockout models as well as in cells not known to express GLP-1R messenger RNA (mRNA) (5); hence, numerous studies using these nonvalidated reagents to report GLP-1R expression in diverse tissues were rendered suspect. Furthermore, given the high degree of sequence similarity within the glucagon family of receptors, short-sequence (as compared with full-length) polymerase chain reaction (PCR)–based analyses of transcript expression are prone to detection of related G protein–coupled receptors or transcripts that do not encode the full-length GLP-1R. Some of these problems have been circumvented by the validation of a highly specific GLP-1R antiserum, whereby GLP-1R expression has been detected in myocytes of the sinoatrial node in a single primate heart (6). Conversely, cells of the murine atrial myocardium, but not of the ventricles, were labeled in GLP-1R reporter mice (7). In this issue of Endocrinology, Baggio et al. (8) have used multiple approaches, including quantitative PCR, full-length reverse transcription PCR, immunohistochemistry with a validated antiserum, and in situ hybridization, to provide a detailed analysis of GLP-1R expression and localization in multiple human hearts. Baggio et al. (8) now report detection of full-length GLP1R transcripts (1.46 kb of open-reading frame) in all 4 chambers of hearts from 15 different individuals. Indicating the specificity of these findings, expression of structurally related G protein–coupled receptors, including those for GLP-2 and glucose-dependent insulinotropic polypeptide was also detected, although that for the GLP-2R was lower and more variable; conversely, despite rodent data to the contrary, glucagon receptor expression could not be demonstrated in any of the samples from the left ventricle. Although these findings were consistent with biological effects of GLP-1 on the human heart, localization of the receptor to specific cell types proved more problematic. Hence, no transcripts were detected in coronary artery endothelial and vascular smooth muscle cells or in cardiac fibroblasts. Furthermore, although two antisera were validated by Western blotting and one was able to detect the human GLP-1R in tissues known to express the receptor, including human islets, the sensitivity was insufficient to detect protein by Western blotting in cardiac samples from 35 subjects. Similarly, in situ hybridization for GLP1R transcripts from the same hearts demonstrated expression in the sinoatrial node but, again, did not detect GLP1R mRNA in histological sections from the ventricles. When taken together, this well-controlled study by Baggio et al. (8) clearly demonstrates the expression of GLP1R mRNA in all chambers of the human heart. The finding of transcripts in the sinoatrial node confirms a previous observation (6) and is consistent with the known ability of GLP-1 to increase heart rate (2). Notwithstanding detection of ventricular GLP1R RNA, the identity of the GLP-1R+ ventricular cell(s) mediating the effects of GLP-1 remain to be discovered. Curiously, preclinical studies have suggested the possible existence of a second GLP-1R. Thus, GLP-19-36NH2, a product of dipeptidylpeptidase IV–mediated GLP-1 degradation that does not activate the known GLP-1R, has been reported to improve ventricular function in both normal and GLP-1R null mice (4). Collectively, therefore, these findings leave open the intriguing possibility that some of the actions of native GLP-1 on human ventricular function are mediated through extremely rare cells that express very low levels of GLP-1R protein and/or may be mediated through another, currently unknown, cardiac GLP-1R. glucagonlike peptide-17-36NH2 glucagonlike peptide-17-36NH2receptor messenger RNA polymerase chain reaction Financial Support: P.L.B. is supported by a Canada Research Chair in Vascular and Metabolic Biology. Studies on GLP-1 in the Brubaker laboratory are supported by an operating grant from the Canadian Institutes of Health Research (PJT-15308). Disclosure Summary: The author has nothing to disclose.

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