👤 Angela Irwin

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. Show less

Effects of sustained activation of glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) as well as antagonism of receptors for glucose-dependent insulinotropic peptide (GIP) on intestinal morphology and related gut hormone populations have not been fully investigated. The present study assesses the impact of 21-days twice daily treatment with the GLP-1R agonist exendin-4 (Ex-4), or the GIP receptor (GIPR) antagonist mGIP(3-30), on these features in obese mice fed a high fat diet (HFD). HFD mice presented with reduced crypt depth when compared to normal diet (ND) controls, which was reversed by Ex-4 treatment. Both regimens lead to an enlargement of villi length in HFD mice. HFD mice had increased numbers of GIP and PYY positive ileal cells, with both treatment interventions reversing the effect on PYY positive cells, but only Ex-4 restoring GIP ileal cell populations to ND levels. Ex-4 and mGIP (3-30) marginally decreased GLP-1 villi immunoreactivity and countered the reduction of ileal GLP-1 content caused by HFD. As expected, HFD mice presented with elevated pancreatic islet area. Interestingly, mGIP(3-30), but not Ex-4, enhanced islet and beta-cell areas in HFD mice despite lack of effect of beta-cell turnover, whilst Ex-4 increased delta-cell area. Co-localisation of islet PYY or GLP-1 with glucagon was increased by Ex-4, whilst islet PYY co-immunoreactivity with somatostatin was enhanced by mGIP(3-30) treatment. These observations highlight potential new mechanisms linked to the metabolic benefits of GLP-1R agonism and GIPR antagonism in obesity. Show less

Obesity is recognized as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist, recently approved for management of type 2 diabetes mellitus. Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarizes experimental, preclinical, and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritizing clinical research published within the last 10 years where possible. GLP-1R mimetics are often discontinued within 24 months meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy. Show less

Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB1 moderated the effects of a lifestyle intervention on weight change among breast cancer survivors. 151 breast cancer survivors with a body mass index ≥ 25 kg/m Women in the intervention group achieved significantly greater weight loss than the usual care group (5.9% vs 0.4%, p < 0.001), regardless of genotype. Changes in weight and percent body fat did not differ significantly between carriers of the FTO rs9939609, MC4R rs6567160, BDNF rs11030104, and CREB1 rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each single-nucleotide polymorphisms). Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may achieve significant and clinically meaningful weight loss through healthy eating and exercise. NCT02863887 (Date of Registration: August 11, 2016); NCT02110641 (Date of Registration: April 10, 2014). Show less

Receptors to glucose-dependent insulinotropic polypeptide (GIP), have been identified on bone and GIP receptor (GIPr) knockout mice exhibit reduced bone strength and quality. Despite this, little is known on the potential beneficial bone effects of exogenous GIP on bone physiology. The aim of the present study was to assess whether stable GIP analogues were capable of ameliorating bone strength in mice with diet-induced obesity. The stable GIP analogue (D-Ala²)-GIP, and (D-Ala²)-GIP-Tag, a specific GIP analogue homing exclusively to bone, were employed. In vitro studies were used to assess effects of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag on bone mineralization, lysyl oxidase activity, collagen maturity as well as osteoclast formation and activity. Subsequent in vivo studies employed obese-prediabetic Swiss NIH mice subjected to a 42-day period of daily administration of saline, (D-Ala²)-GIP or (D-Ala²)-GIP-Tag. In vitro studies confirmed that (D-Ala²)-GIP and (D-Ala²)-GIP-Tag had similar beneficial biological effects on bone cells. Administration of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag resulted in lower blood glucose levels without any effects on body weight. Both GIP analogues augmented bone strength to a similar extent. Trabecular or cortical bone microarchitecture were not changed over the time course of the study. However, (D-Ala²)-GIP and (D-Ala²)-GIP-Tag augmented enzymatic collagen crosslinking as well as the heterogeneity of enzymatic collagen crosslinking, mineral-to-matrix ratio and significantly reduced the heterogeneity in mineral bone crystallite size. This study demonstrates that activation of skeletal GIPr by stable GIP analogues enhance bone strength in prediabetes and suggest that these analogues may be beneficial in the treatment of bone disease. Show less

Gastric inhibitory polypeptide (GIP) is a 42 amino acid hormone secreted from intestinal K-cells in response to nutrient ingestion. Despite a recognised physiological role for GIP as an insulin secretagogue to control postprandial blood glucose levels, growing evidence reveals important actions of GIP on adipocytes and promotion of fat deposition in tissues. As such, blockade of GIP receptor (GIPR) action has been proposed as a means to counter insulin resistance, and improve metabolic status in obesity and related diabetes. In agreement with this, numerous independent observations in animal models support important therapeutic applications of GIPR antagonists in obesity-diabetes. Sustained administration of peptide-based GIPR inhibitors, low molecular weight GIPR antagonists, GIPR neutralising antibodies as well as genetic knockout of GIPR's or vaccination against GIP all demonstrate amelioration of insulin resistance and reduced body weight gain in response to high fat feeding. These observations were consistently associated with decreased accumulation of lipids in peripheral tissues, thereby alleviating insulin resistance. Although the impact of prolonged GIPR inhibition on bone turnover still needs to be determined, evidence to date indicates that GIPR antagonists represent an exciting novel treatment option for obesity-diabetes. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a product of the Gip gene and acts as an incretin hormone in mammals. Gip is most closely related to the proglucagon (Gcg) and Exendin genes and diverged from these very early in vertebrate evolution. In mammals, GIP acts through its specific receptor, encoded by the Gipr gene, which belongs to a subfamily of 7-transmembrane G-protein coupled receptor (GPCR) genes that also includes those for the proglucagon-derived peptides (Gcgr, Glp1r, and Glp2r), and the receptor for Exendin (Grlr). Gip, Gipr, Exendin, and Grlr genes are found in species from most vertebrate classes. While most species that have a Gip gene also have a Gipr gene, two classes of vertebrates, cartilaginous fish and birds, retain conserved Gip genes but lack Gipr genes. This raises the possibility the GIP signals through other receptors in some vertebrates. Exendin genes and the gene for its receptor, Grlr, are also found in diverse vertebrates, with the notable exception of mammals. Both GIP and Exendin likely have important roles in vertebrate physiology, but their roles are either dispensable or can be replaced by other hormones. Show less

Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weight-reducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial Show less

HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local Show less

Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(d-Ala Show less

ChREBP and MondoA are glucose-sensitive transcription factors that regulate aspects of energy metabolism. Here we performed a phylogenomic analysis of Mlxip (encoding MondoA) and Mlxipl (encoding ChREBP) genes across vertebrates. Analysis of extant Mlxip and Mlxipl genes suggests that the most recent common ancestor of these genes was composed of 17 coding exons. Single copy genes encoding both ChREBP and MondoA, along with their interacting partner Mlx, were found in diverse vertebrate genomes, including fish that have experienced a genome duplication. This observation suggests that a single Mlx gene has been retained to maintain coordinate regulation of ChREBP and MondoA. The ChREBP-β isoform, the more potent and constitutively active isoform, appeared with the evolution of tetrapods and is absent from the Mlxipl genes of fish. Evaluation of the conservation of ChREBP and MondoA sequences demonstrate that MondoA is better conserved and potentially mediates more ancient function in glucose metabolism. Show less

It has been previously demonstrated that compromise of glucose-dependent insulinotropic polypeptide receptor (GIPR) action and chronic consumption of a high-fat diet can independently impair memory and learning ability, however, the underlying pathology remain to be elucidated. The present study investigated the effects of GIPR knockout (KO), alone and in combination with a high-fat diet, on aspects of cognitive function and hippocampal gene expression in mice. In object recognition tests, normal mice exhibited effective memory, preferring to investigate the novel over the familiar object. However, wild-type (WT) mice fed a high-fat diet and GIPR KO mice fed a standard or high-fat diet demonstrated no such discrimination, suggesting the impairment of memory function. This decline in cognitive function was associated with marked changes in the expression levels of hippocampal genes involved in memory and learning. The chronic consumption of a high-fat diet decreased the hippocampal gene expression levels of mammalian target of rapamycin (mTOR), neurotrophic tyrosine kinase receptor type 2 (NTRK2) and synaptophysin. Notably, the GIPR KO mice fed a high-fat diet exhibited no reduction in the hippocampal expression of synaptophysin expression, however, the GIPR KO mice fed a standard rodent maintenance diet exhibited reduced hippocampal expression of mTOR compared with the WT controls. These data highlighted the importance of intact GIPR signalling and dietary composition in modulating memory and learning, and hippocampal pathways involved in the maintenance of synaptic plasticity, including mTOR and NTRK2, appear to be key in this regard. Show less

Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr(2))Oxm, (Asp(3))Oxm, (Aib(2))Oxm, (d-Ser(2))Oxm, (N-acetyl)Oxm and (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr(2))Oxm and (Asp(3))Oxm were rapidly degraded by DPP-4, while (Aib(2))Oxm, (d-Ser(2))Oxm, (N-acetyl)Oxm and (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P<0.01 to P<0.001) in GLP-1-R, but not in GIP-R, transfected cells. In glucagon-R transfected cells, all peptides except (N-acetyl)Oxm and (Thr(2))Oxm evoked significant cAMP generation. Similarly, all analogues, except (N-acetyl)Oxm, exhibited prominent (P<0.05 to P<0.001) insulinotropic activity in BRIN BD11 cells. When administered in conjunction with glucose to normal mice only native Oxm, (Aib(2))Oxm and (d-Ser(2))Oxm significantly (P<0.05 to P<0.01) increased overall plasma insulin levels. The corresponding glycaemic excursion was significantly (P<0.05 to P<0.001) lowered by all Oxm peptides, barring (N-acetyl)Oxm. Further investigations revealed persistent glucose-lowering and insulin-releasing actions of (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL. Studies in GIP- and GLP-1-receptor KO mice with (Aib(2))Oxm, (d-Ser(2))Oxm, and (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL highlighted the importance of GLP-1 receptor signalling for the beneficial glucose homoeostatic actions of these analogues. All peptides, except (N-acetyl)Oxm, possessed significant appetite suppressive effects in mice. These data highlight the significant therapeutic promise of enzymatically stable Oxm-based peptides, particularly with position 2 modifications, for the treatment of obesity-diabetes. Show less

The genes encoding the peptide precursors for glucagon (GCG), glucose-dependent insulinotropic peptide (GIP), and ortholog of exendin belong to the same family as shown by sequence similarity. The peptides similar to glucagon encoded by these genes signal through a closely related subfamily of G-protein coupled receptors. A total of five types of genes for receptors for these peptides have been identified, three for the products of GCG (GCGR, GLP1R, and GLP2R) and one each for the products of GIP (GIPR) and the ortholog of exendin (Grlr). Phylogenetic and genomic neighborhood analyses clearly show that these genes originated very early in vertebrate evolution and all were present in the common ancestor of tetrapods and bony fish. Despite their ancient origins, some of these genes are dispensable, with the Glp1r, Gipr, and Grlr being lost on the lineages leading to bony fish, birds, and mammals, respectively. The loss of the genes for these receptors may have been driving forces in the evolution of new functions for these peptides similar to glucagon. Show less

The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors. Show less

Gastric inhibitory polypeptide (GIP) is a gut derived peptide with multiple emerging physiological actions. Effects of pregnancy and lactation on GIP secretion and related gene expression were studied in Wistar rats. Pregnancy moderately increased feeding (p<0.05), whilst lactation substantially increased food intake (p<0.01 to p<0.001). Circulating GIP was unchanged during pregnancy, but non-fasting plasma glucose was significantly (p<0.01) decreased and insulin increased (p<0.05). Lactation was associated with elevated circulating GIP concentrations (p<0.001) without change of glucose or insulin. Oral glucose resulted in a significantly (p<0.001) decreased glycaemic excursion despite similar glucose-induced GIP and insulin concentrations in lactating rats. Pregnant rats had a similar glycaemic excursion but exhibited significantly lowered (p<0.05) GIP accompanied by elevated (p<0.001) insulin levels. Pregnant rats exhibited increased (p<0.001) islet numbers and individual islet areas were enlarged (p<0.05). There were no significant differences in islet alpha-cell areas, but all groups of rats displayed co-expression of glucagon and GIP in alpha-cells. Lactating rats exhibited significantly (p<0.01) increased intestinal weight, whereas intestinal GIP stores were significantly (p<0.01) elevated only in pregnant rats. Gene expression studies in lactating rats revealed prominent (p<0.01 to p<0.001) increases in mammary gland expression of genes involved in energy turnover, including GIP-R. GIP was present in intestines and plasma of 17 day old foetal rats, with substantially raised circulating concentrations in neonates throughout the period of lactation/suckling. These data indicate that changes in the secretion and action of GIP play an important role in metabolic adaptations during pregnancy and especially lactation. Show less

Bone is permanently remodeled by a complex network of local, hormonal and neuronal factors that affect osteoclast and osteoblast biology. In this context, a role for gastro-intestinal hormones has been proposed based on evidence that bone resorption dramatically falls after a meal. Glucose-dependent insulinotropic polypeptide (GIP) is one of the candidate hormones as its receptor, glucose-dependent insulinotropic polypeptide receptor (GIPR), is expressed in bone. In the present study we investigated bone strength and quality by three-point bending, quantitative x-ray microradiography, microCT, qBEI and FTIR in a GIPR knockout (GIPR KO) mouse model and compared with control wild-type (WT) animals. Animals with a deletion of the GIPR presented with a significant reduction in ultimate load (--11%), stiffness (-16%), total absorbed (-28%) and post-yield energies (-27%) as compared with WT animals. Furthermore, despite no change in bone outer diameter, the bone marrow diameter was significantly increased and as a result cortical thickness was significantly decreased by 20% in GIPR deficient animals. Bone resorption at the endosteal surface was significantly increased whilst bone formation was unchanged in GIPR deficient animals. Deficient animals also presented with a pronounced reduction in the degree of mineralization of bone matrix. Furthermore, the amount of mature cross-links of collagen matrix was significantly reduced in GIPR deficient animals and was associated with lowered intrinsic material properties. Taken together, these data support a positive effect of the GIPR on bone strength and quality. Show less

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality. Show less

GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding. Show less

Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro3)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in a streptozotocin (STZ)-induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro(3))GIP to STZ-treated mice. Swiss TO mice received once-daily injection of (Pro3)GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. (Pro3)GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro3)GIP. These effects were observed on an STZ-induced background characterized by severe reductions of circulating insulin, beta-cell mass and pancreatic insulin stores. These data indicate that the beneficial actions of the GIP-R antagonist, (Pro3)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both peptides are believed to play a key role in glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, (Pro(3))GIP (25 nmol/kg) and the endogenous truncated form of PYY, PYY(3-36) (50 nmol/kg), in mice fed with a high fat diet. Daily i.p. injection of (Pro(3))GIP, PYY(3-36) or combined peptide administration over 24 days significantly (P<0.05-0.01) decreased body weight compared with saline-treated controls without change in food intake. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by (Pro(3))GIP treatment alone, and in combination with PYY(3-36). These changes were accompanied by a slight improvement of insulin sensitivity in all of the treatment groups. (Pro(3))GIP treatment significantly reduced plasma corticosterone (P<0.05), while combined administration with PYY(3-36) significantly lowered serum glucagon (P<0.05). No appreciable changes were observed in either circulating or glucose-stimulated insulin secretion in all treatment groups. (Pro(3))GIP-treated mice had significantly (P<0.01) lowered fasting glucose levels and an improved (P<0.05) glycemic response to feeding. These comparative data indicate that chemical ablation of GIP receptor action using (Pro(3))GIP provides an especially effective means of countering obesity and related abnormalities induced by consumption of high fat energy rich diet. Show less

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes. Show less