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  • br Acknowledgments The authors would

    2022-07-27


    Acknowledgments The authors would like to thank principal investigator Edward John Pratt, MD (Lilly-NUS Centre for Clinical Pharmacology, Singapore) and study investigator Martha Hernandez-Illas MD (QPS-MRA) along with site staff, and trial participants and their families. We thank Zvonko Milicevic, MD for reviewing the studies, Yongming Qu, PhD for the statistical review, Parag Garhyan, PhD, for pharmacokinetics review, Melissa Thomas, MD, PhD for discussions on biomarkers, and Chrisanthi Karanikas, MS and Oralee Varnado, PhD for writing and editorial support (all from Eli Lilly and Company). We also thank Jude Onyia, PhD (Eli Lilly and Company) for scientific discussions and continued support throughout the course of this project. Technical support was provided by Robert Cummins, BS, Hongchang Qu, PhD, Libbey O'Farrell, BS, Meghan Hayes, MS, Alexis Bennett, MS, James Ficorilli, BS, Jennifer Martin, MS, Aaron Showalter, MS, Xiaoping Ruan, BS, Ajit Regmi, MS, Wenzhen Ma, MA, Alexander Efanov, PhD, Charity Zink, BS, Brad Wainscott, MS, Francis Willard, PhD, Steve Kahl, MS, and Hui-Rong Qian, PhD (all from Eli Lilly and Company). Funding was provided by Eli Lilly and Company.
    The entero-insular axis The entero-insular axis encompasses all the nutrient, neural and hormonal signals that activate pancreatic beta cells. A series of classical experiments in the 1960s provided the first evidence that intestinal hormonal factors were involved in postprandial insulin release. These experiments revealed that the insulin response to an oral glucose load was much greater than that stimulated by an intravenous injection of glucose.2, 3 Presently, two hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are believed to contribute to the incretin effect, linking the function of the gastrointestinal (GI) tract and the pancreatic beta cells. Incretin hormones are peptides which are released in response to nutrients that stimulate insulin secretion at physiological concentrations. GLP-1 is produced by post-translational processing of preproglucagon gene products in enteroendocrine L-cells. The predominant active form of GLP-1 in human plasma is GLP-1(7–36)amide. GIP is a 42-amino-acid peptide hormone secreted from the enteroendocrine K PRIMA-1 mg whose biosynthesis results from the proteolytic processing of a larger precursor comprising 153 amino acids. An epidemic of diabetes is a major problem in affluent and developing societies, fuelled by obesity and insulin resistance, which now results in increasing numbers of children presenting with type 2 diabetes. Recent projections indicate that by 2030 over 366 million people will be affected by diabetes. There are two major forms of diabetes, type 1 and type 2. Type 2 diabetes constitutes more than 90% of these cases and is characterised by beta-cell decline, insulin resistance and increased hepatic glucose production. Importantly, this form of diabetes is also associated with a defect in the endogenous incretin system. Thus, the study of incretin hormones has been driven by the hope of a better understanding of the pathogenesis of type 2 diabetes and possible elucidation of new gut-derived therapeutic agents. This article focusses on the role and potential of GIP in type 2 diabetes and obesity.
    GIP physiology GIP was initially isolated from porcine intestinal extract and characterised for its ability to inhibit histamine-induced gastric acid secretion, hence the name ‘gastric inhibitory polypeptide’ was proposed. However, subsequent studies evaluating wider physiological actions indicated that GIP stimulated glucose-dependent insulin secretion. As a result, the hormone is also referred to as ‘glucose-dependent insulinotropic polypeptide’.10, 11, 12 GIP exerts its effects through binding to a specific G-protein-coupled GIP receptor (GIP-R) of the glucagon–secretin family of peptides. Moreover, molecular biology studies have opened up a much wider appreciation of GIP actions, with demonstration of GIP-R not only in pancreas, but also in adipose tissue, small intestine, adrenal cortex, lung, pituitary, heart, testis, bone and brain. The action of GIP at many of these targets is, for the large part, unknown. However, the effects of GIP on bone resorption14, 15, proliferation of hippocampal progenitor cells, locomotor activity, stimulation of intestinal GLP-1 release and glucocorticoid secretion have been demonstrated. Several of these actions may prove to offer therapeutic potential for various conditions, including bone and neurodegenerative disorders. However, the use of GIP analogues in such circumstances has received little attention to date.14, 20