Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of Show more
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor-GLP-1 receptor (GIPR-GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil-induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity. Show less
Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-f Show more
Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR ( Show less
An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the rol Show more
An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca Show less