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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.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.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.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.

Objectives To examine outcome for hip fracture patients treated by a hemiarthroplasty (HA) but who actually met the United Kingdom, National Institute for Health and Care Excellence (NICE) criteria for receiving a total hip arthroplasty (THA). Design Match Cohort Study. Setting Level 1, Academic Trauma Centre (UK Major Trauma Centre)Patients/Participants: 398 patients underwent either a HA or THA for a non-pathological displaced intra-capsular fractured neck of femur (OTA/AO 31 B3 (garden 3-4), having met the NICE criteria for THA. Intervention HA versus THA. Two analyses were performed, the first comparing the outcome in a cohort of patients who either received a THA or HA, but who all had met the NICE criteria to receive a THA (n=398). The second analysis assessed the outcome of THA versus HA, in a matched cohort of patients who all met the NICE criteria for a THA (n=44 matched pairs). All patients in the matched cohort were able to walk independently outdoors (WIO) prior to injury. Main outcome Mobility and functional outcome, one year following surgery. Results Of the 398 patients who met the criteria for THA, only 78 (19.6%) patients actually received a THA. Within the matched cohort, significantly more THA patients (92.9%, 39/42) maintained the ability to walk independently outdoors at 1-year compared to HA patients (56.4%. 22/39; p=0.001). There was no difference in mortality, re-operation or complication rates for our matched population at 1 year. Conclusion Patients who meet the NICE criteria for THA and are able to walk independently outdoors pre-injury are more likely to have a higher level of independent mobility and a better functional outcome at 1-year if they receive a THA, as opposed to receiving a HA. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.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.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).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.

With respect to survivorship following total knee arthroplasty (TKA), joint registries consistently demonstrate higher revision rates for both sexes in those less than 55 years of age. The current 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.This was a retrospective review of 500 consecutive TKAs performed in patients under the age of 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 non-revision procedures, clinical, functional, and radiological outcomes.An all-cause survival rate of 98.4% and an aseptic survival rate of 99.2% at a median time of 10.7 years (IQR 7.3-14.9, Range 0.2-27.7) was 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 non-revision procedure with manipulation under anesthetic (MUA) accounting for 27. On multivariate analysis, pre-operative ROM and female gender were negatively associated with postoperative range of motion (p0.001 and p=0.003, respectively). Sixty-seven patients (17.3%) had RLL's and on multivariate analysis, there were no significant predictors of radiolucent lines.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.

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.

Introduction The enhanced recovery after surgery (ERAS) concept in arthroplasty surgery has led to a reduction in postoperative length of stay in recent years. Patients with prolonged length of stay (PLOS) add to the burden of a strained NHS. Our aim was to identify the main reasons. Methods A PLOS was arbitrarily defined as an inpatient hospital stay of four days or longer from admission date. A total of 2,000 consecutive arthroplasty patients between September 2017 and July 2018 were reviewed. Of these, 1,878 patients were included after exclusion criteria were applied. Notes for 524 PLOS patients were audited to determine predominant reasons for PLOS. Results The mean total length of stay was 4 days (1 to 42). The top three reasons for PLOS were social services, day-before-surgery admission, and slow to mobilize. Social services accounted for 1,224 excess bed days, almost half (49.2%, 1,224/2,489) of the sum of excess bed days. Conclusion A preadmission discharge plan, plus day of surgery admission and mobilization on the day of surgery, would have the potential to significantly reduce length of stay without compromising patient care. Cite this article: Bone Joint Open 2020;1-8:488–493.

Background Particularly in broach-only uncemented total hip arthroplasty, a narrow femoral canal presents a technical challenge. Traditionally such femurs have been considered to be Dorr A. To our knowledge, however, no study has reported on the relationship between isthmus width and the Dorr classification. Method We reviewed 500 high-quality, hard copy radiographs. Dorr classification and isthmus canal width were measured using an electronic caliper by 5 independent observers with intraobserver and interobserver error calculated. For this study, we defined a narrow canal as being 10 mm at its narrowest point (isthmus). Results Eight percent (40) were Dorr A, 85% (424) Dorr B, and 7% (36) Dorr C. With respect to isthmus width for Dorr A, 63% (25) were 10 mm compared to just 13% (55) of Dorr B. However, overall because there were more Dorr B femurs, 69% of those with an isthmus of 10 mm were Dorr B. Conclusions In this population, almost 70% of patients with an isthmus 10 mm were Dorr B, with only 30% being Dorr A. When using a broach-only technique, isthmus width should be routinely measured on the preoperative anteroposterior radiographs so as to alert the surgeon to potential problems.

AimsUp to one in five patients undergoing primary total hip (THA) and knee arthroplasty (TKA) require contralateral surgery. This is frequently performed as a staged procedure. This study aimed to determine if outcomes, as determined by the Oxford Hip Score (OHS) and Knee Score (OKS) differed following second-side surgery.MethodsOver a five-year period all patients who underwent staged bilateral primary THA or TKA utilizing the same type of implants were studied. Eligible patients had both preoperative and one year Oxford scores and had their second procedure completed within a mean (2 SDs) of the primary surgery. Patient demographics, radiographs, and OHS and OKS were analyzed.ResultsA total of 236 patients met the inclusion criteria, of which 122 were THAs and 114 TKAs. The mean age was 66.5 years (SD 9.4), with a 2:1 female:male ratio. THAs showed similar significant improvements in outcomes following first- and second-side surgery, regardless of sex. In contrast for TKAs, although male patients demonstrated the same pattern as the THAs, female TKAs displayed significantly less improvement in both OKS and its pain component following second-side surgery.ConclusionFemale patients undergoing second-side TKA showed less improvement in Oxford and pain scores compared to the first-side. This difference in outcome following second-side surgery did not apply to male patients undergoing TKA, or to either sex undergoing THA. Cite this article: Bone Jt Open 2021;2(4):243–254.

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.

Aims Now that we are in the deceleration phase of the COVID-19 pandemic, the focus has shifted to how to safely reinstate elective operating. Regional and speciality specific data is important to guide this decision-making process. This study aimed to review 30-day mortality for all patients undergoing orthopaedic surgery during the peak of the pandemic within our region. Methods This multicentre study reviewed data on all patients undergoing trauma and orthopaedic surgery in a region from 18 March 2020 to 27 April 2020. Information was collated from regional databases. Patients were COVID-19-positive if they had positive laboratory testing and/or imaging consistent with the infection. 30-day mortality was assessed for all patients. Secondly, 30-day mortality in fracture neck of femur patients was compared to the same time period in 2019. Results Overall, 496 operations were carried out in 484 patients. The overall 30-day mortality was 1.9%. Seven out of nine deceased patients underwent surgery for a fractured neck of femur. In all, 27 patients contracted COVID-19 in the peri-operative period; of these, four patients died within 30 days (14.8%). In addition, 21 of the 27 patients in this group had a fractured neck of femur, 22 were over the age of 70 years (81.5%). Patients with American Society of Anesthesiologists (ASA) grade > 3 and/or age > 75 years were at significantly higher risk of death if they contracted COVID-19 within the study period. Conclusion Overall 30-day postoperative mortality in trauma and orthopaedic surgery patients remains low at 1.9%. There was no 30-day mortality in patients ASA 1 or 2. Patients with significant comorbidities, increasing age, and ASA 3 or above remain at the highest risk. For patients with COVID-19 infection, postoperative 30-day mortality was 14.8%. The reintroduction of elective services should consider individual patient risk profile (including for ASA grade). Effective postoperative strategies should also be employed to try and reduce postoperative exposure to the virus. Cite this article: Bone Joint Open 2020;1-7:392–397.

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.

Rapidly progressive osteoarthritis (RPO) is a rare condition which is poorly understood. Limited published literature is available. Reported here is a cohort of patients with RPO and acetabular bone loss who underwent primary THA. Risk factors, degree of acetabular bone loss and outcomes are presented. A typical case of RPO is described and investigations discussed. A retrospective audit was undertaken. 49 patients over an 18-year period were included. RPO patients were significantly older (P < 0.01) and had a lower BMI (P = 0.03). The mean acetabular bone loss in this cohort was 10.0 mm. Pathogenesis and risk factors for developing RPO remain unclear and future research is necessary. Repeat imaging in patients with deteriorating symptoms is important and urgent surgery is required maintain bone stock.

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.

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 (ppN-AcGIP, GIP(Lys37)PAL and N-AcGIP(Lys37)PAL. The GIP antagonist, (Pro3)GIP, caused a significant (pp3)GIP. Furthermore, glucagon release in the presence of GLP-1, GIP(Lys37)PAL, N-AcGIP(Lys37)PAL and (Pro3)GIP was significantly (ppin 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.

Aims/hypothesis Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro(3))GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro(3))GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets. Materials and methods Young Swiss TO mice on standard chow or high-fat, cafeteria or high-carbohydrate diets received daily injections of either saline or (Pro(3))GIP (25 nmol kg(-1)day(-1)) over 16 weeks. Food intake, body weight, and circulating glucose and insulin were measured frequently. At 16 weeks, glucose tolerance, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Adipose tissue, liver and muscle were excised and weighed, and their histology and triacylglycerol content were further examined. Results (Pro(3) )GIP significantly reduced body weight, enhanced locomotor activity, and improved HbA(1c), glucose tolerance, beta cell responsiveness and insulin sensitivity in mice fed high-fat and cafeteria diets (p

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 (14days) antidiabetic 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 NAcGIP alone and in combination with exendin(1-39)amide. Copyright (c) 2007 John Wiley & Sons, Ltd.

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-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β 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. Electronic supplementary material The online version of this article (doi:10.1007/s00395-015-0476-7) contains supplementary material, which is available to authorized users.

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.

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. (c) 2008 Elsevier Inc. All rights reserved.

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, (Pro3)GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro3)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. (Pro3)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 (Pro3)GIP-treated high-fat-fed mice. (Pro3)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.

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.

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-AcGlp(LySpAL(37)), a potent long-acting GIP receptor agonist. Daily injection of N-AcGIP(LysPAL(37)) (25 nmoVkg 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 NAcGIP(LysPAL(37)) treated mice compared to controls (P < 0.01). In keeping with this, glucose-mediated insulin secretion was significantly enhanced in the N-AcGIP(LyspAL(37)) treated group (P < 0.05). No changes in insulin sensitivity or pancreatic insulin content of the NAcGIP(LysPAL(37)) treated mice were detected. No adverse reactions were noted and the effects of N-AcGIP(LysPAL(37)) 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(LysPAL(37)) improved glucose tolerance due to enhancement of pancreatic beta cell glucose responsiveness and insulin secretion. (c) 2005 Elsevier Inc. All rights reserved.

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically-approved for glycaemic control in type 2 diabetes, which also has important cardiovascular actions. Several groups have shown that GLP-1 protects cardiomyocytes from acute ischaemic damage. Here, we investigated whether exendin-4, a stable GLP-1 mimetic, has beneficial effects on chronic cardiac remodelling following myocardial infarction (MI). Adult normoglycaemic C57BL/6J female mice (8–10 weeks) were subjected to coronary artery ligation or sham surgery and chronically-infused with exendin-4 (25 nmol/kg/day) or vehicle for 4 weeks (n‰¥18). Echocardiography indicated that exendin-4 protected against left ventricular (LV) systolic (ejection fraction: sham, 57.8±8.6 vs MI, 43.5%±6.5%, p