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When exposed to a hyperglycemic milieu, the GIPR was found to downregulate in a study of pancreatic islet cells (59) and the patients with T2DM might express a small amount of GIPR or defective GIPR (60, 61)

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As shown in Table 1 [1,8,12-19] , because of the critical role of this pathway in energy regulation, functional abnormalities caused by mutations in any of its critical genes (e.g., LEP , LEPR , POMC , PCSK1 , MC4R ) can lead to severe early-onset obesity and extreme hyperphagia and are often accompanied by endocrine abnormalities due to deficiencies in related hormones, such as hypogonadism and hypothyroidism [12,20]

Protein kinases are highly druggable and are the second most targeted group of drug targets after G-protein-coupled receptors [211]