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    • br Conclusion br Conflict of

    2022-01-17


    Conclusion
    Conflict-of-Interest JJH has collaborated with several different pharmaceutical companies during the last 30 years; is currently receiving speaker honoraria from NovoNordisk and MSD and is on advisory boards for NovoNordisk. The author is currently supported by an independent grant from the NovoNordisk Foundation to the NNF Center for Basic Metabolic Research.
    Gastrointestinal hormone-based therapies are currently used for treating human obesity and NB-598 hydrochloride sale () and are explored as a potential therapy for treating feline diabetes mellitus. Of these hormones, the incretins - glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have received much attention. Notably, GLP-1 analogs were reported to decrease body weight, fasting blood glucose, increase circulating insulin and decrease glucagon concentrations in healthy cats (; ). Although these analogs prevented weight gain, they were ineffective in altering plasma glucose and insulin in healthy obese () or diabetic cats (). We previously reported that GLP-1, GIP and peptide YY (PYY) plasma concentrations were increased postprandially in lean, overweight and diabetic cats, with GLP-1 and GIP being greater in diabetic than healthy lean and overweight cats (). It has also been reported that plasma GLP-1, but not GIP, increase after an oral or gastric glucose challenge in healthy cats (; ). However, whether these hormones play direct roles in the control of feeding, glucose metabolism and body weight regulation in cats remains unknown. As a fundamental step towards understanding the physiology of GLP-1, GIP and PYY in cats, it is crucial to first demonstrate the expression of transcripts for these hormones, and their cognate receptors, in various peripheral tissues to guide further research. Therefore, we determined the distribution of transcripts for proglucagon (; which encodes for glucagon-like peptides), glucagon-like peptide-1 receptor (), glucose-dependent insulinotropic peptide (), glucose-dependent insulinotropic peptide receptor (), peptide YY () and peptide YY receptor () in feline peripheral tissues using polymerase chain reaction (qPCR).
    Introduction The two major incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following nutrient intake leading to insulin secretion and glucose control [1]. This mode of action is currently used for the treatment of patients with type 2 diabetes [2]. Beyond its glucoregulatory role GLP-1 has been found to mediate various protective pleiotropic effects in different organ systems [3]. For example, we and others found GLP-1 to reduce and stabilize atherosclerotic lesions in ApoE−/− mice by directly blocking monocyte migration and preventing inflammatory activation of monocytes/macrophages [4], [5]. Two recent clinical trials (LEADER and SUSTAIN-6) showed improved cardiovascular outcomes in diabetic patients at high cardiovascular risk after treatment with the GLP-1-receptor agonists liraglutide and semaglutide on top of standard antidiabetic therapy [6], [7]. Interestingly, in both studies, GLP-1-receptor agonists reduced cardiovascular endpoints most likely through a reduction in atherosclerosis-related events. However, the role of the other main incretin hormone, GIP, in the cardiovascular system, beyond its insulinotropic function, is still largely unknown. Experimental work by Nagashima et al. demonstrated that infusion of GIP into non-diabetic ApoE−/− mice on an atherogenic diet for 4 weeks was able to reduce lesion size [6], [7]. A study by Nogi and colleagues could reproduce the anti-atherosclerotic effects of GIP also in diabetic ApoE−/− mice [6], [7], which was mechanistically linked to a reduction of plaque macrophages and direct GIP-receptor-mediated inhibition of foam cell formation. However, evidence is lacking on the effects of GIP on composition and stability of atherosclerotic plaques. Experimental and clinical imaging studies identified atherosclerotic plaques of patients with diabetes compared to non-diabetic patients to be more instable due to a thin fibrous cap and less collagen content with high amounts of proinflammatory macrophages, thus leading to high susceptibility of early plaque rupture and life threatening cardiovascular complications like consecutive myocardial infarction [10], [11]. Therefore, identifying new approaches to target plaque morphology and stability is of particular importance to improve cardiovascular outcomes in patients with diabetes. Here we investigated the role of GIP in atherosclerotic cardiovascular disease with a focus on plaque morphology.