Peer support for adults with type 2 diabetes starting continuous glucose monitoring-An exploratory randomised controlled trial.

AIMS: To explore the feasibility and potential benefits of a peer support programme for adults with insulin-treated type 2 diabetes (T2D) starting continuous glucose monitoring (CGM). METHODS: This part of the Steno2tech study is an exploratory, single-centre, open-labelled, prospective, randomised controlled trial (RCT). A total of 60 participants were randomised 2:1 to 12 months of CGM with or without peer support. All participants received a 3-h diabetes self-management education course including a CGM part on how to use the CGM and interpret the CGM-derived data. Peer support consisted of three 3-h peer support meetings over the first 6 months of the study period with groups of three to six people. The exploratory outcomes included the acceptability and feasibility of the peer support intervention, and the between-group difference in change in several glycaemic, metabolic and participant-reported outcomes measured at baseline, 6 and 12 months. RESULTS: The peer support intervention was found acceptable and feasible. Participants shared their experiences of using and interpreting CGM data and its association with health behaviour. While both groups had improvements in glycaemic, metabolic and participant-reported outcomes, there were no significant between-group differences. CONCLUSIONS: Although feasible, we found no measured additional benefits when adding a peer support programme after starting CGM in this exploratory RCT including adults with insulin-treated T2D. Understanding the perceived effect of and preferences for a peer support intervention from the participants' points of view, including why individuals declined to participate, would be of value for future research.

Comparing Continuous Glucose Monitoring and Blood Glucose Monitoring in Adults With Inadequately Controlled, Insulin-Treated Type 2 Diabetes (Steno2tech Study): A 12-Month, Single-Center, Randomized Controlled Trial.

OBJECTIVE: To compare the 12-month effects of continuous glucose monitoring (CGM) versus blood glucose monitoring (BGM) in adults with insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: This is a single-center, parallel, open-label, randomized controlled trial including adults with inadequately controlled, insulin-treated type 2 diabetes from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Inclusion criteria were ≥18 years of age, insulin-treated type 2 diabetes, and HbA1c ≥7.5% (58 mmol/mol). Participants were randomly assigned (1:1) to 12 months of either CGM or BGM. All participants received a diabetes self-management education course and were followed by their usual health care providers. Primary outcome was between-group differences in change in time in range (TIR) 3.9-10.0 mmol/L, assessed at baseline, after 6 and 12 months by blinded CGM. The prespecified secondary outcomes were differences in change in several other glycemic, metabolic, and participant-reported outcomes. RESULTS: The 76 participants had a median baseline HbA1c of 8.3 (7.8, 9.1)% (67 [62-76] mmol/mol), and 61.8% were male. Compared with BGM, CGM usage was associated with significantly greater improvements in TIR (between-group difference 15.2%, 95% CI 4.6; 25.9), HbA1c (-0.9%, -1.4; -0.3 [-9.4 mmol/mol, -15.2; -3.5]), total daily insulin dose (-10.6 units/day, -19.9; -1.3), weight (-3.3 kg, -5.5; -1.1), and BMI (-1.1 kg/m2, -1.8; -0.3) and greater self-rated diabetes-related health, well-being, satisfaction, and health behavior. CONCLUSIONS: In adults with inadequately controlled insulin-treated type 2 diabetes, the 12-month impact of CGM was superior to BGM in improving glucose control and other crucial health parameters. The findings support the use of CGM in the insulin-treated subgroup of type 2 diabetes.

Cardiovascular Autonomic Neuropathy Is Associated With Increased Glucose Variability in People With Type 1 Diabetes.

OBJECTIVE: We investigated the association between the cardiovascular autonomic neuropathy (CAN) diagnosis and glucose variability (GV) in type 1 diabetes (T1D), as autonomic dysfunction previously has been associated with increased GV. RESEARCH DESIGN AND METHODS: CAN was assessed by three recommended cardiovascular reflex tests (CARTs). Glucose metrics were obtained from 10-day blinded continuous glucose monitoring (CGM). Between-group differences in GV indices were assessed by regression analyses in 24 participants with T1D with CAN and 24 matched control subjects without CAN. RESULTS: The CAN diagnosis was associated with 4.9% (95% CI 1.0, 8.7) higher coefficient of variation (CV) (P = 0.014), 0.7 mmol/L (0.3, 1.1) higher SD (P = 0.002) of glucose, and 1.4 mmol/mol (0.0, 2.7) higher mean amplitude of glycemic excursions (P = 0.047). Lower measures of CARTs were associated with higher CV, SD, and time above range values. CONCLUSIONS: The CAN diagnosis associates with a significantly higher GV in T1D, despite a high prevalence of routine CGM use.

Real-time continuous glucose monitoring versus self-monitoring of blood glucose in adults with insulin-treated type 2 diabetes: a protocol for a randomised controlled single-centre trial.

INTRODUCTION: Medical treatment options for type 2 diabetes (T2D) have increased over the last decade and enhance the possibility of individualised treatment strategies where insulin is still one of them. In spite of the advancements in treatment options, less than one-third of the population with T2D obtain their optimal glycaemic goal. In persons with type 1 diabetes, continuous glucose monitoring (CGM) has shown to be the most important driver for improvement in glycaemic control, even more than insulin-pump therapy. The use of technology in T2D has only been investigated in few studies.The overall objective of the research study is to examine the effectiveness of the use of CGM versus self-monitoring of blood glucose (SMBG) in persons with insulin-treated T2D on glycaemic variables and patient-reported outcomes on treatment satisfaction, health behaviour and well-being. The independent effect of peer support will also be studied. METHODS AND ANALYSIS: The study is a single centre, prospective, randomised, open-labelled, three-armed study with the randomisation 2:1:2 in group A with CGM, group B with CGM and peer support, and group C as a control group with SMBG. The participants receive a training course unique for the allocation group. The study runs for 12 months and includes 100 adult participants with insulin-treated T2D, treated at the outpatient clinic at Steno Diabetes Center Copenhagen. Primary outcome is difference in change in time in range. Recruitment begins in August 2020 and ends in July 2021. Final 12-month follow-up is anticipated to be in August 2022. ETHICS AND DISSEMINATION: The study will be carried out in accordance with the Helsinki Declaration and is approved by the Scientific Ethics Committee of the Capital Region (H-20000843). Data collection and handling will be performed in accordance with the General Data Protection Regulation and is approved by the Danish Data Protection Agency (J-2020-100). Dissemination will be in international peer-reviewed journals, conferences and a plain-language summary for participants. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04331444). PROTOCOL VERSION: V.3, 11 December 2020.

Integrated personalized diabetes management goes Europe: A multi-disciplinary approach to innovating type 2 diabetes care in Europe.

Type 2 diabetes mellitus represents a multi-dimensional challenge for European and global societies alike. Building on an iterative six-step disease management process that leverages feedback loops and utilizes commodity digital tools, the PDM-ProValue study program demonstrated that integrated personalized diabetes management, or iPDM, can improve the standard of care for persons living with diabetes in a sustainable way. The novel "iPDM Goes Europe" consortium strives to advance iPDM adoption by (1) implementing the concept in a value-based healthcare setting for the treatment of persons living with type 2 diabetes, (2) providing tools to assess the patient's physical and mental health status, and (3) exploring new avenues to take advantage of emerging big data resources.

A novel spatial Delayed Non-Match to Sample (DNMS) task in the Göttingen minipig.

The pig (Sus scrofus) is a valuable animal for modeling human brain diseases. When evaluating animal models of many human brain disorders cognitive testing is crucial, but the pig's ability to learn the typical types of tasks used in neuropsychological testing of other species is largely unknown. The present study is the first study to evaluate the pig's ability to learn the Delayed Non-Match to Sample (DNMS) task. The pigs were trained in a maze on a spatial version of the DNMS task. Initially, the pigs were trained with a 60s delay interval between sample and test phases, and we found that the pigs required an average of 144 trials to reach criterion for learning the task, which is similar to macaque monkeys. We also found that pigs, in contrast to rats, do not have a natural tendency to alternate in their choices in the task. To evaluate the sensitivity to reduced memory function longer delay intervals (300 s and 900 s) and a scopolamine challenge were introduced. In our test condition we found a significant effect of longer delay intervals (F(2,21)=34.43, P<0.0001) and of scopolamine (F(1,14)=14.28, P=0.002) on the number of correct choices in the task. We conclude that the Göttingen minipig can solve the spatial DNMS task and that the task is sensitive to both increasing delay intervals and to scopolamine.

Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig.

This study investigates 5-hydroxytryptamine 4 (5-HT(4)) receptor binding in the minipig brain with positron emission tomography (PET), tissue homogenate-binding assays, and autoradiography in vitro. The cerebral uptake and binding of the novel 5-HT(4) receptor radioligand [(11)C]SB207145 in vivo was modelled and the outcome compared with postmortem receptor binding. Different models for quantification of [(11)C]SB207145 binding were evaluated: One-tissue and two-tissue compartment kinetic modelling, Logan arterial input, and three different reference tissue models. We report that the pig autoradiographic 5-HT(4) receptor distribution resembles the human 5-HT(4) receptor distribution with the highest binding in the striatum and no detectable binding in the cerebellum. We found that in the minipig brain [(11)C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT(4) receptor concentrations determined in brain homogenates from the same regions, except for hippocampus where PET-measurements significantly underestimate the 5-HT(4) receptor binding, probably because of partial volume effects. This study validates the use of [(11)C]SB207145 as a promising PET radioligand for in vivo brain imaging of the 5-HT(4) receptor in humans.

Effects of dopamine D4 receptor antagonist on spontaneous alternation in rats.

BACKGROUND: The present study was a component of a series of studies scrutinising the neuroreceptor substrate of behavioural flexibility in a rat model. Spontaneous alternation paradigms model the natural tendency of rodents to spontaneously and flexibly shift between alternative spatial responses. In the study it was tested for the first time if the neurochemical substrate mediating spontaneous alternation behaviour includes the dopamine D4 receptor. METHODS: The acute effects of the highly selective dopamine D4 receptor antagonist L-745,870 on rats' performance in a spontaneous alternation paradigm in a T-maze were examined. The paradigm was a food-rewarded continuous trial procedure performed for 20 trials. RESULTS: The spontaneous alternation rate was not affected by the doses of the drug administered (0.02 mg/kg; 0.2 mg/kg; 2 mg/kg), but the position bias of the group receiving the highest L-745,870 dose (2 mg/kg) was significantly increased compared to the group that received the lowest dose (0.02 mg/kg). No significant effects on position bias were found compared to saline. The drug did not increase response perseveration. CONCLUSION: The results show that the neural substrate mediating the spatial distribution of responses in the spontaneous alternation paradigm includes the D4 receptor. However, the statistically significant effect of L-745,870 on position bias was found comparing a high drug dose with a low drug dose, and not comparing the drug doses with saline. For the tested doses of L-745,870 the effect on position bias was not large enough to affect the alternation rate.

Validation of in vitro probabilistic tractography.

Diffusion weighted imaging (DWI) and tractography allow the non-invasive study of anatomical brain connectivity. However, a gold standard for validating tractography of complex connections is lacking. Using the porcine brain as a highly gyrated brain model, we quantitatively and qualitatively assessed the anatomical validity and reproducibility of in vitro multi-fiber probabilistic tractography against two invasive tracers: the histochemically detectable biotinylated dextran amine and manganese enhanced magnetic resonance imaging. Post mortem DWI was used to ensure that most of the sources known to degrade the anatomical accuracy of in vivo DWI did not influence the tracking results. We demonstrate that probabilistic tractography reliably detected specific pathways. Moreover, the applied model allowed identification of the limitations that are likely to appear in many of the current tractography methods. Nevertheless, we conclude that DWI tractography can be a precise tool in studying anatomical brain connectivity.

The effect of the inter-phase delay interval in the spontaneous object recognition test for pigs.

In the neuroscience community interest for using the pig is growing. Several disease models have been developed creating a need for validation of behavioural paradigms in these animals. Here, we report the effect of different inter-phase delay intervals on the performance of Göttingen minipigs in the spontaneous object recognition test. The test consisted of a sample and a test phase. First, the pigs explored two similar objects. After a 10-min, 1-h, or 24-h delay two different objects were presented; one familiar from the sample phase and one novel. An exploration-time difference between the novel and the familiar object was interpreted as recognition of the familiar object. We scored the exploration times both manually and automatically, and compared the methods. A strong discrimination between novel and familiar objects after a 10-min inter-phase delay interval and no discrimination after 24h were found in our set-up of the spontaneous object recognition test. After a 1-h delay, the pigs still showed a significant habituation to the familiar object, but no discrimination was observed. Discrimination between the two objects was mainly confined to the first half of the test phase, and we observed a high between-subject variation. Furthermore, automatic tracking was valid for determination of habituation and discrimination parameters but lead to an overestimation of individual measurements. We conclude that the spontaneous object recognition test for pigs is sensitive to increasing inter-phase delay intervals, and that automatic data acquisition can be applied.

The use of pigs in neuroscience: modeling brain disorders.

The use of pigs in neuroscience research has increased in the past decade, which has seen broader recognition of the potential of pigs as an animal for experimental modeling of human brain disorders. The volume of available background data concerning pig brain anatomy and neurochemistry has increased considerably in recent years. The pig brain, which is gyrencephalic, resembles the human brain more in anatomy, growth and development than do the brains of commonly used small laboratory animals. The size of the pig brain permits the identification of cortical and subcortical structures by imaging techniques. Furthermore, the pig is an increasingly popular laboratory animal for transgenic manipulations of neural genes. The present paper focuses on evaluating the potential for modeling symptoms, phenomena or constructs of human brain diseases in pigs, the neuropsychiatric disorders in particular. Important practical and ethical aspects of the use of pigs as an experimental animal as pertaining to relevant in vivo experimental brain techniques are reviewed. Finally, current knowledge of aspects of behavioral processes including learning and memory are reviewed so as to complete the summary of the status of pigs as a species suitable for experimental models of diverse human brain disorders.

Behavioral response to novelty correlates with dopamine receptor availability in striatum of Göttingen minipigs.

Behavioral response to novelty in rats has been linked both to dopamine transmission in the ventral striatum, and to propensity to self-administer psychostimulant drugs. In order to probe the relationship between behavioral response to novelty and dopamine systems we have developed a behavioral model for correlation with positron emission tomography (PET) of dopamine transmission in brain of Göttingen minipigs. In the present study, we measured exploration of a novel object by recording the number of contacts, and duration of contact with a novel object, in groups of six male and six female adult minipigs. We hypothesized that these novelty scores would correlate with the amphetamine-evoked dopamine release in ventral striatum, measured 2 weeks later in a PET study of the availability of binding sites for the dopamine D2/3 antagonist [11C]raclopride. There were significant correlations between duration of contact with a novel object and the amphetamine-evoked reductions in binding potential (DeltapB) in the left ventral striatum of the 12 animals; Comparison of results by gender revealed that the correlation was driven mainly by the male group, and was not present in the female group. We interpret these results to show that propensity to explore an unfamiliar object is relatively elevated in pigs with low basal occupancy of dopamine D2/3 receptors by endogenous dopamine, and with high amphetamine-induced occupancy of released dopamine in the male pigs.

Validation of a digital video tracking system for recording pig locomotor behaviour.

We are introducing a system for automatically tracking pig locomotor behaviour. Transposing methods for the video-based tracking of rodent behaviour engenders several problems. We have therefore improved existing methods, based on image-subtraction, to offer increased flexibility and accuracy in tracking large-sized animals in situations with a constantly changing background. The improved tracking algorithms introduce a reference frame, which does not include the animal and is automatically updated, and implementation of an automatic threshold detection algorithm. This makes the system more robust to the tracking environment, which could even be of the same colour as the animal, and allows the tracking environment to change during recording. We validated the system by estimating the repeatability, accuracy, and basic noise level, and tested the system in different levels of animal activity evoked by administration of apomorphine (APO) to minipigs in an open field test. Seven pigs each received the vehicle and three doses of APO (0.05, 0.1, and 0.3 mg/kg i.m.), and the locomotor behaviour of each session was recorded for 60-min. The calculated coefficient of repeatability was 0.6%, indicating high repeatability and the basic noise level of the tracking system was estimated to be 2%. Administration of the two lowest doses of APO was accompanied by increased locomotor activity of the pigs. Thus, this digital video-based tracking system for automatically tracking the spontaneous locomotor behaviour of pigs is highly reliable and accurate, and was able to detect well-known effects of APO in pig locomotor activity.

Mapping the amphetamine-evoked dopamine release in the brain of the Göttingen minipig.

The availability of dopamine D(2/3) binding sites in brain of six male and six female Göttingen minipigs was measured in a baseline condition and after challenge with amphetamine sulfate (1mg/kg, i.v.) in PET studies with [(11)C]raclopride. Maps of the binding potential (pB; B(max)/K(d)) of [(11)C]raclopride were spatially normalized and co-registered to a common stereotaxic coordinate system for pig brain. The pB maps were then analyzed by volume of interest and voxel-wise comparisons of gender and condition. The mean baseline pB tended to be 10-20% higher in striatum of the female group, but this gender difference was not significant. Variance of the mean baseline pB was higher in the males (44%) than in females (30%), but there was no correlation between pB and individual plasma cortisol or testosterone concentrations. Using statistical parametric mapping, we detected a focus in the right posterior putamen where the magnitude of the amphetamine-evoked decrease in pB was greater in the male than in the female group. Thus, the spatial pattern of reactivity of dopamine D(2/3) receptor availability to amphetamine challenge is not identical in male and female pigs. Within the entire population, the decline in pB evoked by amphetamine (Delta pB) was greater in the ventral striatum (-28%) than in the caudate nucleus (-17%), consistent with earlier reports in monkeys and humans. The magnitude of Delta pB correlated highly with the baseline pB values in all divisions of the striatum. Based upon the principles of competitive binding, the slope of this empirical relationship, f(i), is equal to the fraction of [(11)C]raclopride binding sites sensitive to endogenous dopamine; the magnitude of this fraction ranged from 0.29 in the caudate to 0.36 in the ventral striatum.

Acquisition of visually guided conditional associative tasks in Göttingen minipigs.

Fourteen Göttingen minipigs were trained on two different visually guided conditional associative tasks. In a spatial conditional task, a black stimulus signalled that a response to the left was correct, and a white stimulus signalled that a response to the right was correct. In a conditional go/no-go task, a blue stimulus signalled go, and a red stimulus signalled no-go. The pigs were trained until a behavioural criterion of 90% correct for each of two consecutive sessions. For the spatial conditional task, all pigs reached this criterion in 520 trials or less. For the conditional go/no-go task, all pigs, except three, reached this criterion in 1600 trials or less. Sows and boars learned equally fast. The tasks can be useful for the testing of cognitive function in pig models of human brain disorders.

Response to novelty correlates with learning rate in a Go/No-go task in Göttingen minipigs.

Novelty-seeking and harm-avoidance personality traits influence Go/No-go (GNG) learning in humans. Animal studies have also indicated a link between response to novelty and spatial discrimination learning. In the present study, we test the hypothesis that learning rate in a GNG task correlates with the behavioral response of Göttingen minipigs to novelty. In a group of 12 minipigs of mixed genders, response to novelty was measured by numbers of contacts with a novel object, and the total duration of exploration of the novel object. These parameters were correlated to individual learning rate in a GNG task. The number of sessions to reach criterion in the GNG task correlated significantly with the number of contacts to a novel object (r = 0.70, p = 0.03), but not with the duration of object exploration (r = 0.29, p = 0.41). Thus, pigs with a low behavioral response to novelty learned the GNG task faster than did pigs with a strong behavioral response to novelty, indicated by the tendency to approach novel objects. We hypothesize that the critical factor in this relation is difference in emotional reactivity rather than difference in motivation for exploration. In conclusion, in addition to 'cognitive' ability, 'temperamental' factors are likely to influence learning in individual pigs.

Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by d-amphetamine.

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for validation of a pig model of psychosis, we wished to verify the existence of PPI in landrace pigs and investigate the potential disruption of PPI by d-amphetamine (AMPH) in these animals. PPI of the acoustic startle reflex and its potential disruption by AMPH were investigated using three doses 0.5-1.5mg/kg with a paradigm including two levels of prepulses (82 and 88dB) and a prepulse (PP) interval of 60 and 120ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI and, in spite of only the 0.5mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace pigs and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable additional tool in assessing pig models of neuropsychiatric disorders.

Discriminations, reversals, and extra-dimensional shifts in the Göttingen minipig.

Göttingen minipigs were trained on a set-shifting procedure involving discriminations, reversals, and extra-dimensional shifts. The discriminations used were black-white discriminations and right-left discriminations. The initial visual and spatial discrimination seemed equally difficult, and only for the visual modality was reversal found to be more difficult than the initial discrimination. Visual reversal was more difficult than spatial reversal, and a larger number of perseverative sessions were found for visual reversal compared to spatial reversal. The acquisition of the extra-dimensional shift from the visual to the spatial dimension was not inferior to the learning of spatial reversal. Neither was the acquisition of the extra-dimensional shift from the spatial to the visual dimension inferior to the learning of visual reversal. Thus, no evidence was found for attention to stimulus dimensions in discrimination learning of the pigs.

Pre-pulse inhibition of the acoustic startle eye-blink in the Göttingen minipig.

Pre-pulse inhibition (PPI) of the startle response is a measure of sensorimotor gating which has been frequently shown to be deficient in schizophrenic patients. In humans it is typically measured as the attenuation of the startle eye-blink reflex EMG when a startle eliciting noise is preceded by a weak white noise pre-pulse (PP), the interval between the PP and the startle noise stimulus (SNS) determining the degree of inhibition. Aiming at developing a new animal model of schizophrenia, we have investigated the acoustic startle eye-blink and PPI in 10 Göttingen minipigs. The stimuli and the block design of the stimulation were similar to paradigms used in human research. Initially the startle habituation across trials and blocks, secondarily the PPI at PP to SNS intervals of 30, 60, 120, 220, 520, 1020 and 2020 ms was investigated. One pig out of ten did not have a startle response, and three other pigs did not have a startle response of a sufficient magnitude to demonstrate the PPI seen in the other six pigs at the expected PP intervals of 60, 120, and 220 ms. Maximal inhibition was seen at the 220 ms interval (mean PPI 58.6%, range -18.4 to 94.6%, N = 9). Most of the results in the pigs are in accordance with findings in studies of the human startle eye-blink EMG and this initial study promotes further studies and the use of the PPI measure in the validation of minipig models of psychiatric disorders.

Minipig negative slow wave demonstrates target/nontarget differences in P300 paradigm.

The negative slow wave (NSW) is a late component of the event-related potential (ERP) in man modulated like the P300 by the stimulus, the task, and the response demand. Aiming at the development of a minipig model of schizophrenia, we investigated scalp ERPs in an auditory P300 paradigm in six Göttingen minipigs. Before training, we observed no difference between target and nontarget NSW. After training, target NSW amplitude was increased 50% compared to nontarget. A P350 was recognized, but the finding of a lack of target/nontarget difference is not conclusive.