A battery-less implantable glucose sensor based on electrical impedance spectroscopy.

The ability to perform accurate continuous glucose monitoring without blood sampling has revolutionised the management of diabetes. Newer methods that can allow measurements during longer periods are necessary to substantially improve patients' quality of life. This paper presents an alternative method for glucose monitoring which is based on electrical impedance spectroscopy. A battery-less implantable bioimpedance spectroscope was designed, built, and used in an in vivo study on pigs. After a recovery period of 14 days post surgery, a total of 236 subcutaneous bioimpedance measurements obtained from intravenous glucose tolerance tests, with glucose concentration ranges between 77.4 and 523.8 mg/dL, were analyzed. The results show that glucose concentrations estimated by subcutaneous bioimpedance measurements correlate very well to the blood glucose reference values. The pigs were clinically healthy throughout the study, and the postmortem examinations revealed no signs of adverse effects related to the sensor. The implantation of the sensor requires minor surgery. The implant, being externally powered, could in principle last indefinitely. These encouraging results demonstrate the potential of the bioimpedance method to be used in future continuous glucose monitoring systems.

Correction: Rydén et al. Physiological and Clinical Responses in Pigs in Relation to Plasma Concentrations during Anesthesia with Dexmedetomidine, Tiletamine, Zolazepam, and Butorphanol. Animals 2021, 11, 1482.

Text Correction [...].

Training Pigs for Oral Glucose Tolerance Test-Six Years' Experience of a Refined Model.

Animal models of human diseases are important in biomedical research. When using animals for scientific purposes, the 3Rs (replace, reduce, refine) should be considered. Refinement of animal models is essential to ensure best use of animals, which is important for ethical reasons and to retrieve reliable research data. The present publication describes improvements to an oral glucose tolerance test (OGTT) model for pigs published in 2016. Historical data from 42 pigs were used to describe improvements in the training technique over six years. Pigs of various breeds and ages can be trained to bottle-feed glucose dissolved in water to undergo OGTT. This publication describes different tips and techniques to apply for successful training and will help researchers to minimize exclusions of pigs due to unsuccessful training. The improvements are an important contribution to the 3Rs.

Physiological and Clinical Responses in Pigs in Relation to Plasma Concentrations during Anesthesia with Dexmedetomidine, Tiletamine, Zolazepam, and Butorphanol.

Reliable protocols for short-term anesthetics are essential to safeguard animal welfare during medical investigations. The aim of the study was to assess the adequacy and reliability of an anesthetic protocol and to evaluate physiological and clinical responses, in relation to the drug plasma concentrations, for pigs undergoing short-term anesthesia. A second aim was to see whether an intravenous dosage could prolong the anesthesia. The anesthesia was induced by an intramuscular injection of dexmedetomidine, tiletamine-zolazepam, and butorphanol in 12 pigs. In six of the pigs, a repeated injection intravenously of one-third of the initial dose was given after one hour. The physiological and clinical effects from induction to recovery were examined. Plasma concentrations of the drugs were analyzed and pharmacokinetic parameters were calculated. Each drug's absorption and time to maximal concentration were rapid. All pigs were able to maintain spontaneous respiration. The route of administration did not alter the half-life of the drug. The results suggest that intramuscular administration of the four-drug combination provides up to two hours of anesthesia with stable physiological parameters and an acceptable level of analgesia while maintaining spontaneous respiration. A repeated intravenous injection may be used to extend the time of anesthesia by 30 min.

Exploring the GLP-1-GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans. RESEARCH DESIGN AND METHODS: GLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract. RESULTS: High homogenous uptake of 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of 68Ga-exendin-4 in pigs scanned by PET. CONCLUSION: We identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.

The effect of housing environment on bone healing in a critical radius defect in New Zealand White rabbits.

In animal studies on bone healing, the effect of housing space and physical activity are seldom taken into account. Bone formation was evaluated in New Zealand White rabbits (mean ± SEM BW: 3.9 ± 0.11 kg) with a critical bone defect after 12 weeks of rehabilitation in pair-housing in 3 m2 large floor pens (Floor, n = 10) or standard single housing in 0.43 m2 cages (Cage, n = 10). In the randomised full-factorial study, a bone replica of calcium phosphate cement (CPC, n = 10) or autologous bone (AB, n = 10) was implanted in the unilateral 20 mm radius defect. Post-mortem, the oxidative capacity was measured by citrate synthase (CS) activity in M. quadriceps and the defect filling volume and density evaluated by microcomputer tomography (µ-CT). Histology sections were evaluated by subjective scoring and histomorphometry. Fourteen rabbits remained until the end of the study. Group Floor (n = 7; 3 CPC + 4 AB) had a higher CS activity and a larger bone defect filling volume and lower density by µ-CT measurements than group Cage (n = 7; 3 CPC + 4 AB). Three out of four rabbits in AB-Floor presented fusion of the defect with reorganisation of trabecular bone, whereas three of four in AB-Cage showed areas of incomplete healing. Floor rabbits had a higher score of bony fusion between the radius and ulna than Cage rabbits. There were no differences between groups in histomorphometry. The study found that a larger housing space increased physical activity and promoted bone formation.

Nursing and training of pigs used in renal transplantation studies.

The pig is commonly used in renal transplantation studies since the porcine kidney resembles the human kidney. To meet the requirements of intense caretaking and examination without stress, a 2-week socialisation and training programme was developed. Conventional cross-breed pigs (n = 36) with high health status were trained for 15 min/day in a four-step training programme before kidney transplantation. The systematic training resulted in calm animals, which allowed for ultrasound examination, blood sampling and urine sampling without restraint. When a 2-methacryloyloxyethyl phosphorylcholine polymer-coated jugular catheter introduced via the auricular vein was used for post-operative blood sampling, clotting was avoided. To assess renal function, urinary output was observed and creatinine and cystatin C were measured; the latter was not found to be useful in recently transplanted pigs. The results presented contribute to the 3Rs (refine, reduce, replace).

Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI.

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique. METHODS: Pigs (n = 4) were examined by [15O]H2O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose. RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [15O]H2O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [15O]H2O PET and IVIM MRI (r = 0.81, R2 = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [15O]H2O PET was within a 15% error of margin of the microsphere technique. CONCLUSION: Pancreatic perfusion by [15O]H2O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [15O]H2O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

Validation of an MPC Polymer Coating to Attenuate Surface-Induced Crosstalk between the Complement and Coagulation Systems in Whole Blood in In Vitro and In Vivo Models.

Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model.

OBJECTIVES: The aim of this study was to investigate if a synthetic granular calcium phosphate compound (CPC) and a composite bisphosphonate-linked hyaluronic acid-calcium phosphate hydrogel (HABP·CaP) induced similar or more amount of bone as bovine mineral in a modified sinus lift rabbit model. MATERIAL AND METHODS: Eighteen adult male New Zeeland White rabbits, received randomly one of the two test materials on a random side of the face, and bovine mineral as control on the contralateral side. In a sinus lift, the sinus mucosa was elevated and a titanium mini-implant was placed in the alveolar bone. Augmentation material (CPC, HABP·CaP or bovine bone) was applied in the space around the implant. The rabbits were euthanized three months after surgery and qualitative and histomorphometric evaluation were conducted. Histomorphometric evaluation included three different regions of interest (ROIs) and the bone to implant contact on each installed implant. RESULTS: Qualitative assessment (p = <.05), histomorphometric evaluations (p = < .01), and implant incorporation (p = <.05) showed that CPC and bovine mineral induced similar amount of bone and more than the HABP·CaP hydrogel. CONCLUSION: CPC induced similar amount of bone as bovine mineral and both materials induced more bone than HABP·CaP hydrogel. CLINICAL SIGNIFICANCE: The CPC is suggested as a synthetic alternative for augmentations in the maxillofacial area.

In Vivo Visualization of ß-Cells by Targeting of GPR44.

GPR44 expression has recently been described as highly ß-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [11C]AZ12204657, was evaluated for visualization of ß-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess ß-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [11C]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [11C]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [11C]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [11C]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic ß-cells by targeting the protein GPR44.

Anaesthesia and changes in parameters that reflect glucose metabolism in pigs - a pilot study.

Pigs are commonly used in diabetes research due to their many physiological similarities to humans. They are especially useful in imaging procedures because of their large size. However, to achieve imaging procedures the pig must lie completely still, and thus needs to be anaesthetized. Most anaesthetic drugs used in laboratory animals affect carbohydrate metabolism by the inhibition of insulin release. The aim of this pilot study was primarily to develop an anaesthetic protocol for pigs that did not have an effect on blood glucose levels throughout the 3 h of anaesthesia; and secondly, to evaluate the most promising protocol in combination with an oral glucose tolerance test (OGTT). Two anaesthetic protocols were used in four growing pigs. Intravenous propofol infusion caused hyperglycaemia in three out of four pigs within 5-10 min after induction and was therefore excluded. Intravenous infusion with tiletamine, zolazepam and butorphanol (TZB) for 3 h did not affect blood glucose levels. The pigs underwent OGTT twice, once without anaesthesia and once with TZB induction after glucose intake. Anaesthesia during OGTT resulted in a lower area under the curve (AUC) of glucose ( P < 0.05), higher AUC of glucagon ( P < 0.05) and an insulin response less than 10% of that during OGTT without anaesthesia. In conclusion, long-term infusion anaesthesia with TZB does not affect glucose homeostasis in pigs. However, the protocol is not effective when combined with OGTT, as glucose, insulin and glucagon levels are affected.

Carprofen neither reduces postoperative facial expression scores in rabbits treated with buprenorphine nor alters long term bone formation after maxillary sinus grafting.

In connection with bilateral maxillary sinus augmentation, the acute effects of the nonsteroidal anti-inflammatory drug carprofen on facial expressions and long-term effects on bone formation were evaluated in 18 male New Zealand White rabbits. A 10×10mm bone window was drilled in the maxilla, the sinus membrane elevated and a titanium mini-implant inserted. One of two test materials was randomly inserted unilaterally and bovine bone chips (control) on the contralateral side in the created space. Rabbits were randomly allocated to receive buprenorphine plus carprofen (n=9) or buprenorphine plus saline (n=9) postoperatively. Buprenorphine was administered subcutaneously every 6h for 3days in a tapered dose (0.05-0.01mg/kg) and carprofen (5mg/kg) or saline administered subcutaneously 1h before, and daily for 4days postoperatively. To assess pain, clinical examination, body weight recording and scoring of facial expressions from photos taken before, and 6-13h after surgery were performed. Twelve weeks after surgery the rabbits were euthanized and sections of maxillary bones and sinuses were analysed with histomorphometry and by qualitative histology. Carprofen had no effect on mean facial expression scores, which increased from 0.0 to 3.6 (carprofen) and 4.3 (saline), of a maximum of 8.0. Neither did carprofen have an effect on bone formation or implant incorporation, whereas the test materials had. In conclusion, treatment with 5mg/kg carprofen once daily for 5days did not reduce facial expression scores after maxillary sinus augmentation in buprenorphine treated rabbits and did not affect long term bone formation.

Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs.

INTRODUCTION: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of ß-cells and in experimental animal research. Exendin-4 can be radiolabeled with (68)Ga, (111)In or (99m)Tc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic ß-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D). The compound, which is administered subcutaneously (SC) may cause nausea, vomiting and a minor increase in the heart rate (HR). However, possible side-effects on cardiovascular functions after intravenous (IV) administration have not been reported. This study describes the Exendin-4 dose at which cardiovascular side-effects occur in pigs and cynomolgus monkeys. The IV effect of the tracer on insulin secretion is also investigated in pigs. METHODS: Seven clinically healthy littermate pigs (40days old) were used; three of them were made diabetic by streptozotocin (STZ). All pigs underwent PET imaging under general anesthesia to examine the glucagon-like peptide-1 receptor (GLP-1R) in ß-cells with radiolabeled Exendin-4. A baseline tracer dose IV [(68)Ga]Exendin-4 (0.025±0.010µg/kg) followed by a competition dose IV [(68)Ga]Exendin-4 (3.98±1.33µg/kg) 60min later were administered. Blood samples were taken and analyzed for insulin secretion by using ELISA. Cardiovascular and respiratory variables were monitored throughout the experiment. RESULTS: Immediately after administration of the high dose [(68)Ga]Exendin-4 the HR rose from 122±14 to 227±40bpm (p<0.01) and from 100±5 to 181±13bpm (p<0.01) in healthy non-diabetic and diabetes-induced pigs, respectively. The tachycardia was observed for >2h and one healthy non-diabetic pig suffered cardiac arrest 3h after the IV [(68)Ga]Exendin-4. Arrhythmia was detected by listening to the heart with a stethoscope up to 4days after the [(68)Ga]Exendin-4 injection. In all animals, no effect on the cardiovascular system was registered after the low dose of IV [(68)Ga]Exendin-4. Insulin secretion increased (p<0.05) when IV [(68)Ga]Exendin-4 was given in dosages ≥0.14µg/kg. CONCLUSIONS: Intravenous administration of ≥2.8µg/kg [(68)Ga]Exendin-4 resulted in severe tachycardia and arrhythmias in healthy non-diabetic and diabetes-induced pigs, and the insulin secretion was stimulated in healthy non-diabetic animals when ≥0.14µg/kg [(68)Ga]Exendin-4 was given.

Effects of diet-induced weight gain and turnout to pasture on insulin sensitivity in moderately insulin resistant horses.

OBJECTIVE: To quantify insulin sensitivity and monitor glucose, insulin, and lipid concentrations in a group of moderately insulin-resistant horses during induction of obesity by use of a forage diet supplemented with fat and during subsequent turnout to pasture. ANIMALS 9 adult Standardbred mares (11 to 20 years old). PROCEDURES: Weight gain of horses was induced during 22 weeks by use of a forage diet supplemented with fat fed in gradually increasing amounts, followed by feeding of that fat-supplemented diet at 2.5 times the daily maintenance requirements. Horses were then turned out to pasture. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method before and after weight gain and after 4 weeks at pasture. Body weight, body condition score, and cresty neck score as well as fasting and postprandial concentrations of plasma insulin, plasma glucose, serum triglyceride, and serum nonesterified fatty acids were measured during the study. RESULTS: Body weight typically increased by 10%, and body condition score (scale, 1 to 9) increased by > 1.5 from the start to the end of the weight-gain period. There was no difference in insulin sensitivity or metabolic clearance rate of insulin during the weight-gain period. Four weeks at pasture generally improved insulin sensitivity and metabolic clearance rate of insulin by 54% and 32%, respectively, but there was no change in body weight or body condition score. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that dietary composition played a more important role than did short-term weight gain on alterations in insulin sensitivity of horses.

Establishment of a Refined Oral Glucose Tolerance Test in Pigs, and Assessment of Insulin, Glucagon and Glucagon-Like Peptide-1 Responses.

Diabetes mellitus is increasing worldwide and reliable animal models are important for progression of the research field. The pig is a commonly used large animal model in diabetes research and the present study aimed to refine a model for oral glucose tolerance test (OGTT) in young growing pigs, as well as describing intravenous glucose tolerance test (IVGTT) in the same age group. The refined porcine OGTT will reflect that used in children and adolescents. Eighteen pigs were obtained one week after weaning and trained for two weeks to bottle-feed glucose solution, mimicking the human OGTT. The pigs subsequently underwent OGTT (1.75 g/kg BW) and IVGTT (0.5 g/kg BW). Blood samples were collected from indwelling vein catheters for measurements of glucose and the diabetes related hormones insulin, glucagon and active glucagon-like peptide-1. The study confirmed that pigs can be trained to bottle-feed glucose dissolved in water and thereby undergo an OGTT more similar to the human standard OGTT than previously described methods in pigs. With the refined method for OGTT, oral intake only consists of glucose and water, which is an advantage over previously described methods in pigs where glucose is given together with feed which will affect glucose absorption. Patterns of hormonal secretion in response to oral and intravenous glucose were similar to those in humans; however, the pigs were more glucose tolerant with lower insulin levels than humans. In translational medicine, this refined OGTT and IVGTT methods provide important tools in diabetes research when pigs are used as models for children and adolescents in diabetes research.

Intravenous sufentanil-midazolam versus sevoflurane anaesthesia in medetomidine pre-medicated Himalayan rabbits undergoing ovariohysterectomy.

OBJECTIVE: To compare physiological effects of sufentanil-midazolam with sevoflurane for surgical anaesthesia in medetomidine premedicated rabbits. STUDY DESIGN: Prospective, randomized controlled experimental study. ANIMALS: Eighteen female Himalayan rabbits, weight 2.1 ± 0.1 kg. METHODS: Premedication with 0.1 mg kg(-1) medetomidine and 5 mg kg(-1) carprofen subcutaneously, was followed by intravenous anaesthetic induction with sufentanil (2.3 µg mL(-1)) and midazolam (0.45 mg mL(-1)). After endotracheal intubation, anaesthesia was maintained with sufentanil-midazolam (n = 9) or sevoflurane (n = 9). Ovariohysterectomy was performed. Intermittent positive pressure ventilation was performed as required. Physiological variables were studied perioperatively. Group means of physiologic data were generated for different anaesthetic periods. Data were compared for changes from sedation, and between groups by anova. Post-operatively, 0.05 mg kg(-1) buprenorphine was administered once and 5 mg kg(-1) carprofen once daily for 2-3 days. Rabbits were examined and weighed daily until one week after surgery. RESULTS: Smooth induction of anaesthesia was achieved within 5 minutes. Sufentanil and midazolam doses were 0.5 µg kg(-1) and 0.1 mg kg(-1), during induction and 3.9 µg kg(-1) hour(-1) and 0.8 mg kg(-1) hour(-1) during surgery, respectively. End-tidal sevoflurane concentration was 2.1% during surgery. Assisted ventilation was required in nine rabbits receiving sufentanil-midazolam and four receiving sevoflurane. There were no differences between groups in physiologic data other than arterial carbon dioxide. In rabbits receiving sevoflurane, mean arterial pressure decreased pre-surgical intervention, heart rate increased 25% during and after surgery and body weight decreased 4% post-operatively. Post-operative problems sometimes resulted from catheterization of the ear artery. CONCLUSION: Sevoflurane and sufentanil-midazolam provided surgical anaesthesia of similar quality. Arterial blood pressure was sustained during sufentanil-midazolam anaesthesia and rabbits receiving sevoflurane lost body weight following ovariohysterectomy. Mechanical ventilation was required with both anaesthetic regimens. CLINICAL RELEVANCE: Anaesthesia with sufentanil-midazolam in medetomidine premedicated healthy rabbits is useful in the clinical and the research setting, as an alternative to sevoflurane.

Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs.

PURPOSE: The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in non-diabetic and streptozotocin (STZ)-induced diabetic pigs treated with insulin was investigated. METHODS: Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [(15)O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was assessed by administration of either tracer alone or by competition with 3-6.5 µg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model. RESULTS: [(15)O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR). CONCLUSION: Pancreatic uptake of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs.

Anaesthesia in medetomidine premedicated New Zealand White rabbits: a comparison between intravenous sufentanil-midazolam and isoflurane anaesthesia for orthopaedic surgery.

Eighteen female New Zealand White rabbits (3.9 ± 0.4 kg) were anaesthetized with sufentanil-midazolam by intravenous infusion (SUF-MID, n = 9) or isoflurane (ISO, n = 9) for bilateral creation of an osteochondral defect in the medial femur condyle. Subcutaneous premedication with 0.1 mg/kg medetomidine and anaesthesia induction by intravenous infusion of 1.1 µg/kg sufentanil and 0.2 mg/kg midazolam were identical in both groups. During surgery (60 min), the effects on respiratory and circulatory variables serum lactate, total protein and blood glucose were examined. Intermittent positive pressure ventilation (IPPV) was initiated if apnoea lasted>30 s or if end-tidal CO2 ≥8 kPa. The righting reflex was lost in 3 min. IPPV was necessary during most of the anaesthesia for most of the rabbits. Maintenance doses during surgery were 2.0 µg/kg/h sufentanil and 0.4 mg/kg/h midazolam, and 1.4% isoflurane, respectively. Mean arterial blood pressure (MAP) was higher in group SUF-MID than group ISO during surgery (63 ± 12 vs 50 ± 8 mmHg). In group ISO the heart rate was higher during surgery than before anaesthesia (197 ± 26 vs 158 ± 40 bpm) as was blood glucose (9 ± 2 vs 12 ± 3 mmol/L). Serum lactate levels remained unchanged whereas total protein decreased in both groups. Time to recover from anaesthesia did not differ between groups (20 min). Intravenous sufentanil-midazolam infusion provided surgical anaesthesia with a higher MAP than isoflurane anaesthesia. The protocol can be useful in situations in which gas anaesthesia cannot be used or in animals with limited cardiovascular reserves. However, IPPV is necessary.