Abstract
Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.
Highlights
The global obesity and diabetes crises have prompted a concerted effort to identify effective novel treatments
Given the conflicting results surrounding the co-targeting of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) signalling pathways, we investigated the metabolic benefits of co-administration of peptide-based GIP receptor (GIPR) antagonists with a GLP1 agonist, liraglutide
Acute in vivo effects of GIPR peptide antagonists in lean mice. Having established both GIPA-1 and GIPA-2 as potent mouse GIPR antagonists in vitro, we aimed to determine their acute actions on oral glucose tolerance in lean mice
Summary
The global obesity and diabetes crises have prompted a concerted effort to identify effective novel treatments. Gut hormones exhibit well-characterised physiological roles ranging from effects on pancreatic islet hormone secretion, glucose concentrations, lipid metabolism, energy storage, gut motility, appetite, and body weight. These properties have drawn attention to their potential to treat metabolic disease, and the glucagon-like peptide-1 (GLP-1) drug class is a well-established treatment for Type 2 diabetes (T2D) and obesity. Two key glucoregulatory gut hormones, GIP and GLP-1, are secreted respectively by K cells, located predominately in the proximal small intestine, and by L cells, most densely located in the distal small intestine and colon [1] Both hormones are secreted following nutrient intake and augment insulin secretion. Together they produce the incretin effect, a 2–3 fold increase in insulin production in response to oral glucose compared with the equivalent glucose dose administered intravenously [2, 3], suggesting a combination of these two hormones could be beneficial for the treatment of T2D
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
