Decision regret after primary hip and knee replacement surgery.

BACKGROUND: Decision regret (DR) is a recognised patient centered outcome measure following a therapeutic intervention. This study aimed to measure DR following primary total hip and knee arthroplasty (THA/TKA), to assess for differences between these patients and explore possible contributory factors. METHOD: DR was measured using the DR scale in a group of THA and TKA patients, between February 2017 and December 2018, who had made a decision to have joint replacement surgery within the previous year and were able to reflect on their outcomes. RESULTS: On analysis a significantly greater proportion of TKA patients reported moderate or severe (Mod/Sev) DR [17.1% (56/328)] compared to THA patients [4.8% (18/376)]. Conversely, a significantly reduced proportion of TKA patients reported having No DR [42.1% (138/328)] compared to THA patients [66.7% (251/376)]. On multivariate logistic regression analysis joint replacement type (TKA/THA) and change in Oxford score were significant predictors of DR with gender, age, BMI and ASA grade not significantly associated. TKA patients were more than twice as likely to have Mod/Sev DR compared THA patients (Odds Ratio = 2.33 (95% CI 1.24-4.39)). Patients with poorer improvements in pain and function 1-year post-operatively (measured by Oxford scores) reported greater levels of DR. CONCLUSION: TKA patients were significantly more likely to report greater levels of DR 1-year following surgery compared to THA patients. For both TKA and THA patients, greater levels of DR were associated with poorer Oxford scores. The use of decision aids to reduce post-operative DR in joint replacement patients should be examined especially for knee replacement patients.

Survivorship of 500 Cementless Total Knee Arthroplasties in Patients Under 55 Years of Age.

BACKGROUND: With respect to survivorship following total knee arthroplasty (TKA), joint registries consistently demonstrate higher revision rates for both genders in those aged less than 55 years. The present study analyzed the survivorship of 500 cementless TKAs performed in this age group in a high-volume primary joint unit where cementless TKA has traditionally been used for the majority of patients. METHODS: This was a retrospective review of 500 consecutive TKAs performed in patients aged less than 55 years between March 1994 and April 2017. The primary outcome measures for the study were survivorship and all-cause revisions. Secondary outcome measures included nonrevision procedures, clinical, functional, and radiological outcomes. RESULTS: An all-cause survival rate of 98.4% and an aseptic survival rate of 99.2% at a median time of 10.7 years (interquartile range 7.3-14.9, range 0.2-27.7) were found. Four patents were revised for infection, 2 for stiffness, 1 for aseptic loosening of the tibial component, and 1 for a patella that was resurfaced for anterior knee pain. Thirty four patients (6.8%) had a nonrevision procedure with manipulation under anesthetic accounting for 27. On a multivariate analysis, preoperative range of motion and female gender were negatively associated with postoperative range of motion (P < .001 and P = .003, respectively). Sixty seven patients (17.3%) had radioluscent lines and on a multivariate analysis, there were no significant predictors of radiolucent lines. CONCLUSION: Cementless TKA in the young patient can achieve excellent clinical and functional outcomes. At a median of 10.7 years, aseptic revision rates are exceptionally low at 0.8% for the entire cohort.

Is Cementless Total Knee Arthroplasty Safe in Women Over 75 Y of Age?

BACKGROUND: Cementless total knee arthroplasty (TKA) is the subject of renewed interest. Previous concerns about survivorship have been addressed and there is an appeal in terms of biological fixation and surgical efficiency. However, even surgeon advocates have concerns about the risk of marked subsidence when using this technology in older patients at risk for osteoporosis. METHODS: This was a retrospective analysis of 1,000 consecutive fully cementless mobile bearing TKAs performed at a single institution on women over 75 years of age who had postoperative and 1-year x-rays. The primary outcome was the incidence of subsidence. RESULTS: There were three asymptomatic cases with definite subsidence and change in alignment. In a fourth symptomatic case, the femoral component subsided into varus and the tibia into valgus, thus maintaining alignment which facilitated nonoperative treatment in a 92-year-old. Overall, at 1 year, there were two- liner revisions for infection without recurrence. Five patients had further surgery, of which three were washouts and two were for periprosthetic fractures sustained postoperatively within 1 year. Seven patients had further anesthesia, of which five were manipulations and two were nonrecurrent closed reductions for spinouts. CONCLUSION: Cementless TKA did not have a high risk of subsidence in this at-risk population. In the hands of experienced surgeons, these procedures can be used safely irrespective of bone quality.

The feasibility of achieving Elective Care Framework targets for total hip arthroplasty and total knee arthroplasty in Northern Ireland.

AIMS: Waiting times for arthroplasty surgery in Northern Ireland are among the longest in the NHS, which have been further lengthened by the onset of the COVID-19 global pandemic in March 2020. The Department of Health in Northern Ireland has announced a new Elective Care Framework (ECF), with the framework proposing that by March 2026 no patient will wait more than 52 weeks for inpatient/day case treatment. We aimed to assess the feasibility of achieving this with reference to total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Mathematical modelling was undertaken to calculate when the ECF targets will be achieved for THA and TKA, as well as the time when waiting lists for THA and TKA will be cleared. The number of patients currently on the waiting list and percentage operating capacity relative to pre-COVID-19 capacity was used to determine future projections. RESULTS: As of May 2021, there were 3,757 patients awaiting primary THA and 4,469 patients awaiting primary TKA in Northern Ireland. Prior to April 2020, there were a mean 2,346 (2,085 to 2,610) patients per annum boarded for primary THA, a mean 2,514 (2,494 to 2,514) patients per annum boarded for primary TKA, and there were a mean 1,554 primary THAs and 1,518 primary TKAs performed per annum. The ECF targets for THA will only be achieved in 2030 if operating capacity is 200% of pre COVID-19 pandemic capacity and in 2042 if capacity is 170%. For TKA, the targets will be met in 2034 if capacity is 200% of pre-COVID-19 pandemic capacity. CONCLUSION: This modelling demonstrates that, in the absence of major funding and reorganization of elective orthopaedic care, the targets set out in the ECF will not be achieved with regard to THA and TKA. Waiting times for THA and TKA surgery in Northern Ireland are likely to remain greater than 52 weeks for most of this decade. Cite this article: Bone Jt Open 2022;3(4):302-306.

A conservative approach to dislocation following total hip arthroplasty: a review of 8606 hips.

PATIENTS AND METHODS: We present the data on 8606 total hip arthroplasty (THA) procedures carried out in 7818 patients through a posterior approach between 1998 and 2017. RESULTS: 218 hips (2.5%) suffered at least 1 dislocation with dislocation rates declining from 6.2% from 1998 to 2002 to 1.5% from 2003 to 2017. Overall, 92 hips (1.06%) required revision surgery but of these, only 5 (0.06%) had a full revision of both components with the remaining 87 requiring intervention only on the acetabular side. None have had a pseudo-arthrosis; none were left dislocated and all remain stable to date. CONCLUSIONS: In patients who have a second dislocation within 3 months of their primary surgery we recommend a spica or long leg cylinder cast to reduce the need for revision surgery. We propose an algorithm to manage instability with less aggressive operative treatment in this often-elderly patient population with the potential for less physiological insult and significant cost savings.

Should isolated morbid obesity influence the decision to operate in hip and knee arthroplasty?

AIMS: We studied the outcomes of hip and knee arthroplasties in a high-volume arthroplasty centre to determine if patients with morbid obesity (BMI ≥ 40 kg/m2) had unacceptably worse outcomes as compared to those with BMI < 40 kg/m2. METHODS: In a two-year period, 4,711 patients had either total hip arthroplasty (THA; n = 2,370), total knee arthroplasty (TKA; n = 2,109), or unicompartmental knee arthroplasty (UKA; n = 232). Of these patients, 392 (8.3%) had morbid obesity. We compared duration of operation, anaesthetic time, length of stay (LOS), LOS > three days, out of hours attendance, emergency department attendance, readmission to hospital, return to theatre, and venous thromboembolism up to 90 days. Readmission for wound infection was recorded to one year. Oxford scores were recorded preoperatively and at one year postoperatively. RESULTS: On average, the morbidly obese had longer operating times (63 vs 58 minutes), longer anaesthetic times (31 vs 28 minutes), increased LOS (3.7 vs 3.5 days), and significantly more readmissions for wound infection (1.0% vs 0.3%). There were no statistically significant differences in either suspected or confirmed venous thromboembolism. Improvement in Oxford scores were equivalent. CONCLUSION: Although morbidly obese patients had less favourable outcomes, we do not feel that the magnitude of difference is clinically significant when applied to an individual, particularly when improvement in Oxford scores were unrelated to BMI. Cite this article: Bone Jt Open 2021;2(7):515-521.

Risk Factors for Significant Radiolucent Line Development in a Fully Coated Hydroxyapatite Stem.

BACKGROUND: The risk factors for and clinical impact of radiolucent lines (RLLs) in cementless total hip arthroplasty remain contentious. The aim of this work was to describe a method of classification that has clinical significance and to identify risk factors. METHODS: A cohort of 288 subjects with unrevised Corail stems (DePuy Synthes, Warsaw, IN) were reviewed with radiographs and Oxford Hip Scores at 10 years. Based on clinical experience, three groups were defined; those with no RLLs (NoRLLs), those considered to have benign RLLs (BenRLLs), and those considered to have significant RLLs (SigRLLs). SigRLLs were then compared to BenRLLs and NoRLLs to determine the validity of this classification. RESULTS: One hundred and nine (37.8%) had NoRLLs, 111 (38.5%) had BenRLLs, and 68 (23.6%) had SigRLLs. No significant difference apart from gender was noted between the occurrence of BenRLLs and NoRLLs after multinomial regression analysis, consequently the NoRLLs and BenRLLs groups were combined (NoSigRLLs) and compared to SigRLLs. Non-cross-linked polyethylene (odds ratio = 4.6, P < .001), collarless stem design (odds ratio = 9.4, P < .001), undersizing (odds ratio = 1.2, P = .028), and male sex (odds ratio = 2.1, P = .008) were risk factors for SigRLLs. Regression analysis also revealed that increasing age at operation decreased the likelihood of SigRLLs (P < .001). Patients with SigRLLs had significantly higher pain scores (P = .005) although overall Oxford Hip Scores were not significantly different (P = .364). CONCLUSION: The definition of SigRLLs proposed in this study was significantly associated with that of non-cross-linked polyethylene, absence of a collar, undersizing, and higher pain scores.

Increased fat depth is not associated with increased risk of surgical complications following total hip arthroplasty.

AIMS: Previous research has demonstrated increased early complication rates following total hip arthroplasty (THA) in obese patients, as defined by body mass index (BMI). Subcutaneous fat depth (FD) has been shown to be an independent risk factor for wound infection in cervical and lumbar spine surgery, as well as after abdominal laparotomy. The aim of this study was to investigate whether increased peritrochanteric FD was associated with an increased risk of complications in the first year following THA. METHODS: We analyzed prospectively collected data on a consecutive series of 1,220 primary THAs from June 2013 until May 2018. The vertical soft tissue depth from the most prominent part of the greater trochanter to the skin was measured intraoperatively using a sterile ruler and recorded to the nearest millimetre. BMI was calculated at the patient's preoperative assessment. All surgical complications occuring within the initial 12 months of follow-up were identified. RESULTS: Females had a significantly greater FD at the greater trochanter in comparison to males (median 3.0 cm (interquartile range (IQR) 2.3 to 4.0) vs 2.0 cm (IQR 1.7 to 3.0); p < 0.001) despite equivalent BMI between sexes (male median BMI 30.0 kg/m2 (IQR 27.0 to 33.0); female median 29.0 kg/m2 (IQR 25.0 to 33.0)). FD showed a weak correlation with BMI (R² 0.41 males and R² 0.43 females). Patients with the greatest FD (upper quartile) were at no greater risk of complications compared with patients with the lowest FD (lower quartile); 7/311 (2.3%) vs 9/439 (2.1%); p = 0.820 . Conversely, patients with the highest BMI (≥ 40 kg/m2) had a significantly increased risk of complications compared with patients with lower BMI (< 40 kg/m2); 5/60 (8.3% vs 18/1,160 (1.6%), odds ratio (OR) 5.77 (95% confidence interval (CI) 2.1 to 16.1; p = 0.001)). CONCLUSION: We found no relationship between peritrochanteric FD and the risk of surgical complications following primary THA. Cite this article: Bone Joint J 2020;102-B(9):1146-1150.

Seventeen to Twenty Years of Follow-Up of the Low Contact Stress Rotating-Platform Total Knee Arthroplasty With a Cementless Tibia in All Cases.

BACKGROUND: Total knee arthroplasty designs can be categorized by bearing design and fixation method. The mobile-bearing concept was developed with the aim of increasing longevity and improving function by reduced polyethylene wear and closer replication of physiological knee motion. Cementless fixation has the goal of achieving a long-lasting "biological" fixation between prosthesis and bone. METHODS: Prospective analysis of the survivorship and patient-reported functional outcomes of a series of 500 low contact stress rotating-platform mobile-bearing total knee arthroplasties with a cementless tibial component with a minimum 17-year follow-up. RESULTS: Five hundred primary total knee arthroplasties were conducted in 467 patients. Mean follow-up was 18.1 (17.0-21.8) years and 141 (28.2%) knees were alive and available for review. Using revision for any cause as the end point, cumulative survivorship was 97.4%. Thirteen knees required revision: 3 for deep infection, 3 bearing only revisions for spinout, 3 for tibial tray subsidence, 2 secondary patella resurfacings, 1 aseptic loosening, and 1 for suspected aseptic loosening that was found to be well fixed. Mean American Knee Society Scores were 83 (evaluation) and 48 (function), Mean Oxford Knee Score was 32.1, and the mean Bartlett Patellar Score was 21.6. CONCLUSION: This series demonstrates excellent survivorship and acceptable patient-reported functional outcome scores of a mobile-bearing total knee arthroplasty with a cementless tibial tray at minimum 17-year follow-up.

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix.

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-ß3) and inflammatory (IL-10, IL-1ß, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3ß and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP.

Increasing evidence from both clinical and experimental studies indicates that the insulin-releasing hormone, glucagon-like peptide-1 (GLP-1) may exert additional protective/reparative effects on the cardiovascular system. The aim of this study was to examine vasorelaxant effects of GLP-1(7-36)amide, three structurally-related peptides and a non-peptide GLP-1 agonist in rat aorta. Interestingly, all GLP-1 compounds, including the established GLP-1 receptor antagonist, exendin (9-39) caused concentration-dependent relaxation. Mechanistic studies employing hyperpolarising concentrations of potassium or glybenclamide revealed that these relaxant effects are mediated via specific activation of ATP-sensitive potassium channels. Further experiments using a specific membrane-permeable cyclic AMP (cAMP) antagonist, and demonstration of increased cAMP production in response to GLP-1 illustrated the critical importance of this pathway. These data significantly extend previous observations suggesting that GLP-1 may modulate vascular function, and indicate that this effect may be mediated by the GLP-1 receptor. However, further studies are required in order to establish whether GLP-1 related agents may confer additional cardiovascular benefits to diabetic patients.

Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by endocrine K-cells in response to nutrient absorption. This study has utilised numerous well-characterised dipeptidyl peptidase IV-resistant GIP analogues to evaluate the glucagonotropic actions of GIP in Wistar rats and isolated rat islets. Intraperitoneal administration of GIP analogues (25 nmol/kg body weight) in combination with glucose had no effect on circulating glucagon concentrations compared to controls in Wistar rats. However, plasma glucose concentrations were significantly (p<0.05 to p<0.001) lowered by the GIP-receptor agonists, N-AcGIP, GIP(Lys37)PAL and N-AcGIP(Lys37)PAL. The GIP antagonist, (Pro3)GIP, caused a significant (p<0.05) reduction in glucagon levels following concurrent administration with saline in Wistar rats. In isolated rat islets native GIP induced a significant (p<0.01) enhancement of glucagon release at basal glucose concentrations, which was completely annulled by (Pro3)GIP. Furthermore, glucagon release in the presence of GLP-1, GIP(Lys37)PAL, N-AcGIP(Lys37)PAL and (Pro3)GIP was significantly (p<0.05 to p<0.001) decreased compared to native GIP in isolated rat islets. These data indicate a modest effect of GIP on glucagon secretion from isolated rat islets, which was not observed in vivo. However, the GIP agonists N-AcGIP, GIP(Lys37)PAL and N-AcGIP(Lys37)PAL had no effect on glucagon release demonstrating an improved therapeutic potential for the treatment of type 2 diabetes.

GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet.

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(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(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(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(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.

Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide.

BACKGROUND: The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. METHODS: The present study examined the sub-chronic (14 days) anti-diabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. RESULTS: Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. In addition, no significant effects were observed on body weight and food intake in any of the treatment groups. CONCLUSIONS: The results illustrate significant anti-diabetic potential of N-AcGIP alone and in combination with exendin(1-39)amide.

Long-term administration of PACAP receptor antagonist, PACAP(6-27), impairs glucose tolerance and insulin sensitivity in obese diabetic ob/ob mice.

Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous peptide of the glucagon superfamily that is involved in glucose homeostasis and regulation of insulin secretion. This study employed the PACAP receptor antagonist, PACAP(6-27) to evaluate the role of endogenous PACAP in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob mice. Acute in vivo antagonistic potency of PACAP(6-27) was confirmed in ob/ob mice by blockade of the insulin-releasing action but not hyperglycaemia. In longer-term studies, ob/ob mice were given once daily injections of PACAP(6-27) or vehicle for 14 days. Feeding activity, body weight, basal plasma glucose and plasma insulin concentrations were not significantly affected by chronic PACAP(6-27) treatment. However, PACAP(6-27) treatment impaired glucose tolerance, insulin sensitivity and the glycaemic response to feeding. Plasma glucagon and lipids were unchanged. These observations indicate a role of endogenous PACAP for normal glucose homeostasis, but indicate a minor involvement in the regulation of insulin secretion in ob/ob mice.

Effects on glucose homeostasis and insulin secretion of long term activation of the glucose-dependent insulinotropic polypeptide (GIP) receptor by N-AcGIP(LysPAL37) in normal mice.

Glucose-dependent insulinotropic polypeptide (GIP) is a key hormone of the enteroinsular axis. The present study was designed to assess the metabolic effects in healthy mice of long term activation of the GIP receptor by N-AcGIP(LysPAL37), a potent long-acting GIP receptor agonist. Daily injection of N-AcGIP(LysPAL37) (25 nmol/kg body weight) for 14 days had no significant effect on food intake, body weight, glycated hemoglobin levels, non-fasting plasma glucose and insulin concentrations compared to saline treated controls. No significant differences in post-prandial plasma glucose and insulin concentrations were observed between the two groups following 15 min feeding. However, after 14 days, the glycemic response to intraperitoneal (i.p.) glucose was significantly improved in the N-AcGIP(LysPAL37) treated mice compared to controls (P < 0.01). In keeping with this, glucose-mediated insulin secretion was significantly enhanced in the N-AcGIP(LysPAL37) treated group (P < 0.05). No changes in insulin sensitivity or pancreatic insulin content of the N-AcGIP(LysPAL37) treated mice were detected. No adverse reactions were noted and the effects of N-AcGIP(LysPAL37) were reversed by 14 days cessation of treatment. These data indicate that long term activation of the GIP receptor by daily treatment with N-AcGIP(LysPAL37) improved glucose tolerance due to enhancement of pancreatic beta cell glucose responsiveness and insulin secretion.