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Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to assess the long‐term therapeutic efficacy of a recently discovered 28 amino acid peptide, Δ‐theraphotoxin‐Ac1 (Δ‐TRTX‐Ac1), originally isolated from venom of the Aphonopelma chalcodes tarantula. Δ‐TRTX‐Ac has previously been shown to improve pancreatic beta‐cell function and suppress appetite. Materials and Methods: Δ‐TRTX‐Ac1 was administered twice daily in high‐fat fed (HFF) mice with streptozotocin (STZ)‐induced insulin deficiency, namely HFF/STZ mice, for 28 days both alone and in combination with the venom‐derived glucagon‐like peptide‐1 (GLP‐1) mimetic, exenatide. Results: Initial pharmacokinetic profiling of ΔTRTX‐Ac1 revealed a plasma half‐life of 2 h in mice, with ΔTRTX‐Ac1 also evidenced in the pancreas 12 h post‐injection. Accordingly, HFF‐STZ mice received twice‐daily injections of Δ‐TRTX‐Ac1, exenatide or a combination of both peptides for 28 days. As anticipated, HFF/STZ mice presented with hyperglycaemia, impaired glucose tolerance, decreased plasma and pancreatic insulin and disturbed pancreatic islet morphology. Administration of ΔTRTX‐Ac1 reduced body weight, improved glucose tolerance and augmented pancreatic insulin content while decreasing glucagon content. Exenatide had similar benefits on body weight and pancreatic hormone content while also reducing circulating glucose. ΔTRTX‐Ac1 decreased energy expenditure on day 28 whereas exenatide had no impact. All treatment regimens restored pancreatic islet and beta‐cell area towards lean control levels, which was linked to significantly elevated beta‐cell proliferation rates. In terms of benefits of combined ΔTRTX‐Ac1 and exenatide treatment over individual agents, there was augmentation of glucose tolerance and ambulatory activity with combination therapy, and these mice presented with increased pancreatic glucagon. Conclusion: These data highlight the therapeutic promise of ΔTRTX‐Ac1 for diabetes, with suggestion that benefits could be enhanced through combined administration with exenatide. [ABSTRACT FROM AUTHOR]

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, ([Pro.sup.3])GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of ([Pro.sup.3])GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. ([Pro.sup.3])GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in ([Pro.sup.3])GIP-treated high-fat-fed mice. ([Pro.sup.3])GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro3)GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet. gastric inhibitory polypeptide; antagonist; high-fat feeding

This study examines the actions of the novel enzyme-resistant, N[H.sub.2]-terminally modified GIP analog ([Hyp.sup.3])GIP and its fatty acid-derivatized analog ([Hyp.sup.3])[GIPLys.sup.16]PAL. Acute effects are compared with the established GIP receptor antagonist ([Pro.sup.3])GIP. All three peptides exhibited DPP IV resistance, and significantly inhibited GIP stimulated cAMP formation and insulin secretion in GIP receptor-transfected fibroblasts and in clonal pancreatic BRIN-BD11 cells, respectively. Likewise, in obese diabetic ob/ob mice, intraperitoneal administration of GIP analogs significantly inhibited the acute antihyperglycemic and insulin-releasing effects of native GIP. Administration of once daily injections of ([Hyp.sup.3])GIP or ([Hyp.sup.3])[GIPLys.sup.16]PAL for 14 days resulted in significantly lower plasma glucose levels (P < 0.05) after ([Hyp.sup.3])GIP on days 12 and 14 and enhanced glucose tolerance (P < 0.05) and insulin sensitivity (P < 0.05 to P < 0.001) in both groups by clay 14. Both ([Hyp.sup.3])GIP and ([Hyp.sup.3])[GIPLys.sup.16]PAL treatment also reduced pancreatic insulin (P < 0.05 to P < 0.01) without affecting islet number. These data indicate that ([Hyp.sup.3])GIP and ([Hyp.sup.3])[GIPLys.sup.16]PAL function as GIP receptor antagonists with potential for ameliorating obesity-related diabetes. Acylation of ([Hyp.sup.3])GIP to extend bioactivity does not appear to be of any additional benefit. glucose-dependent insulinotropic polypeptide receptor antagonists; insulin secretion; antihyperglycemic activity; dipeptidyl peptidase IV; fatty acid conjugation doi: 10.1152/ajpendo.00391.2006