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A functioning entero\u2010insular (gut\u2010endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to \u201cisoglycaemic\u201d intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP\u20101 have additive effects on insulin secretion. Local production of GIP and\/or GLP\u20101 in islet \u03b1\u2010cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP\u20101 suppresses, and GIP increases glucagon secretion, both in a glucose\u2010dependent manner. GIP plays a greater physiological role as an incretin. In type 2\u2010diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP\u20101. While insulinotropic effects of GLP\u20101 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP\u20101 have additional biological functions: GLP\u20101 at pharmacological concentrations reduces appetite, food intake, and\u2014in the long run\u2014body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP\u20101 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP\u20101, play a role in bone remodelling. GLP\u20101, but not GIP slows gastric emptying, which reduces post\u2010meal glycaemic increments. For both GIP and GLP\u20101, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP\/GLP\u20101 receptor co\u2010agonists like tirzepatide have superior efficacy compared to selective GLP\u20101 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long\u2010term interaction of GIP and GLP\u20101 receptor signalling. A GLP\u20101 receptor antagonist (exendin [9\u201039]) and, more recently, a GIP receptor agonist (GIP [3\u201030] NH\n                    <jats:sub>2<\/jats:sub>\n                    ) and, hopefully, longer\u2010acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin\u2010based diabetes drugs.\n                  <\/jats:p>","DOI":"10.1111\/dom.14496","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T09:19:12Z","timestamp":1627291152000},"page":"5-29","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":383,"title":["The evolving story of incretins (\n                    <scp>GIP<\/scp>\n                    and\n                    <scp>GLP<\/scp>\n                    \u20101) in metabolic and cardiovascular disease: A pathophysiological update"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-6954","authenticated-orcid":false,"given":"Michael A.","family":"Nauck","sequence":"first","affiliation":[{"name":"Diabetes Division Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Quast","sequence":"additional","affiliation":[{"name":"Diabetes Division Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Wefers","sequence":"additional","affiliation":[{"name":"Diabetes Division Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas F. 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