👤 Rola Hammoud

Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate. Show less

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

Accurate and fast dose calculation is crucial in modern radiation therapy. Four dose calculation algorithms (AAA, AXB, CCC, and MC) are available in Varian Eclipse and RaySearch Laboratories RayStation Treatment Planning Systems (TPSs). This study aims to evaluate and compare dosimetric accuracy of the four dose calculation algorithms applying to homogeneous and heterogeneous media, VMAT plans (based on AAPM TG-119 test cases), and the surface and buildup regions. The four algorithms are assessed in homogeneous (IAEA-TECDOCE 1540) and heterogeneous (IAEA-TECDOC 1583) media. Dosimetric evaluation accuracy for VMAT plans is then analyzed, along with the evaluation of the accuracy of algorithms applying to the surface and buildup regions. Tests conducted in homogeneous media revealed that all algorithms exhibit dose deviations within 5% for various conditions, with pass rates exceeding 95% based on recommended tolerances. Additionally, the tests conducted in heterogeneous media demonstrate high pass rates for all algorithms, with a 100% pass rate observed for 6 MV and mostly 100% pass rate for 15 MV, except for CCC, which achieves a pass rate of 94%. The results of gamma index pass rate (GIPR) for dose calculation algorithms in IMRT fields show that GIPR (3% /3 mm) for all four algorithms in all evaluated tests based on TG119, are greater than 97%. The results of the algorithm testing for the accuracy of superficial dose reveal variations in dose differences, ranging from -11.9% to 7.03% for 15 MV and -9.5% to 3.3% for 6 MV, respectively. It is noteworthy that the AXB and MC algorithms demonstrate relatively lower discrepancies compared to the other algorithms. This study shows that generally, two dose calculation algorithms (AXB and MC) that calculate dose in medium have better accuracy than other two dose calculation algorithms (CCC and AAA) that calculate dose to water. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation. Show less