Behavioural interventions to promote physical activity in a multiethnic population at high risk of diabetes: PROPELS three-arm RCT

Background Type 2 diabetes is a leading cause of mortality globally and accounts for significant health resource expenditure. Increased physical activity can reduce the risk of diabetes. However, the longer-term clinical effectiveness and cost-effectiveness of physical activity interventions in those at high risk of type 2 diabetes is unknown. Objectives To investigate whether or not Walking Away from Diabetes (Walking Away) – a low-resource, 3-hour group-based behavioural intervention designed to promote physical activity through pedometer use in those with prediabetes – leads to sustained increases in physical activity when delivered with and without an integrated mobile health intervention compared with control. Design Three-arm, parallel-group, pragmatic, superiority randomised controlled trial with follow-up conducted at 12 and 48 months. Setting Primary care and the community. Participants Adults whose primary care record included a prediabetic blood glucose measurement recorded within the past 5 years [HbA1c ≥ 42 mmol/mol (6.0%), < 48 mmol/mol (6.5%) mmol/mol; fasting glucose ≥ 5.5 mmol/l, < 7.0 mmol/l; or 2-hour post-challenge glucose ≥ 7.8 mmol/l, < 11.1 mmol/l] were recruited between December 2013 and February 2015. Data collection was completed in July 2019. Interventions Participants were randomised (1 : 1 : 1) using a web-based tool to (1) control (information leaflet), (2) Walking Away with annual group-based support or (3) Walking Away Plus (comprising Walking Away, annual group-based support and a mobile health intervention that provided automated, individually tailored text messages to prompt pedometer use and goal-setting and provide feedback, in addition to biannual telephone calls). Participants and data collectors were not blinded; however, the staff who processed the accelerometer data were blinded to allocation. Main outcome measures The primary outcome was accelerometer-measured ambulatory activity (steps per day) at 48 months. Other objective and self-reported measures of physical activity were also assessed. Results A total of 1366 individuals were randomised (median age 61 years, median body mass index 28.4 kg/m2, median ambulatory activity 6638 steps per day, women 49%, black and minority ethnicity 28%). Accelerometer data were available for 1017 (74%) and 993 (73%) individuals at 12 and 48 months, respectively. The primary outcome assessment at 48 months found no differences in ambulatory activity compared with control in either group (Walking Away Plus: 121 steps per day, 97.5% confidence interval –290 to 532 steps per day; Walking Away: 91 steps per day, 97.5% confidence interval –282 to 463). This was consistent across ethnic groups. At the intermediate 12-month assessment, the Walking Away Plus group had increased their ambulatory activity by 547 (97.5% confidence interval 211 to 882) steps per day compared with control and were 1.61 (97.5% confidence interval 1.05 to 2.45) times more likely to achieve 150 minutes per week of objectively assessed unbouted moderate to vigorous physical activity. In the Walking Away group, there were no differences compared with control at 12 months. Secondary anthropometric, biomechanical and mental health outcomes were unaltered in either intervention study arm compared with control at 12 or 48 months, with the exception of small, but sustained, reductions in body weight in the Walking Away study arm (≈ 1 kg) at the 12- and 48-month follow-ups. Lifetime cost-effectiveness modelling suggested that usual care had the highest probability of being cost-effective at a threshold of £20,000 per quality-adjusted life-year. Of 50 serious adverse events, only one (myocardial infarction) was deemed possibly related to the intervention and led to the withdrawal of the participant from the study. Limitations Loss to follow-up, although the results were unaltered when missing data were replaced using multiple imputation. Conclusions Combining a physical activity intervention with text messaging and telephone support resulted in modest, but clinically meaningful, changes in physical activity at 12 months, but the changes were not sustained at 48 months. Future work Future research is needed to investigate which intervention types, components and features can help to maintain physical activity behaviour change over the longer term. Trial registration Current Controlled Trials ISRCTN83465245. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 77. See the NIHR Journals Library website for further project information.

l-Menthol increases extracellular dopamine and c-Fos-like immunoreactivity in the dorsal striatum, and promotes ambulatory activity in mice

Similar to psychostimulants, the peripheral administration of menthol promotes mouse motor activity, and the neurotransmitter dopamine has been suggested to be involved in this effect. The present study aimed to elucidate the effects of l-menthol on parts of the central nervous system that are involved in motor effects. The subcutaneous administration of l-menthol significantly increased the number of c-Fos-like immunoreactive nuclei in the dorsal striatum of the mice, and motor activity was promoted. It also increased the extracellular dopamine level in the dorsal striatum of the mice. These observations indicated that after subcutaneous administration, l-menthol enhances dopamine-mediated neurotransmission, and activates neuronal activity in the dorsal striatum, thereby promoting motor activity in mice.

Effectiveness of at-home skin temperature monitoring in reducing the incidence of foot ulcer recurrence in people with diabetes: a multicenter randomized controlled trial (DIATEMP)

IntroductionThe skin of people with diabetic foot disease is thought to heat up from ambulatory activity before it breaks down into ulceration. This allows for early recognition of imminent ulcers. We assessed whether at-home monitoring of plantar foot skin temperature can help prevent ulcer recurrence in diabetes.Research design and methodsIn this parallel-group outcome-assessor-blinded multicenter randomized controlled trial (7 hospitals, 4 podiatry practices), we randomly assigned people with diabetes, neuropathy, foot ulcer history (<4 years, n=295), or Charcot’s neuro-arthropathy (n=9) to usual care (ie, podiatric treatment, education, and therapeutic footwear) or usual care plus measuring skin temperatures at 6–8 plantar sites per foot each day (enhanced therapy). If ∆T>2.2°C between corresponding sites on the left and right foot for two consecutive days, participants were instructed to reduce ambulatory activity until this hotspot disappeared and contact their podiatrist. Primary outcome was ulcer recurrence in 18 months on the plantar foot, interdigital, or medial/lateral/anterior forefoot surfaces; secondary outcome was ulcer recurrence at any foot site.ResultsOn the basis of intention-to-treat, 44 of 151 (29.1%) participants in enhanced therapy and 57 of 153 (37.3%) in usual care had ulcer recurrence at a primary outcome site (RR: 0.782 (95%CI 0.566 to 1.080), p=0.133). Of the 83 participants in enhanced therapy who measured a hotspot, the 24 subsequently reducing their ambulatory activity had significantly fewer ulcer recurrences (n=3) than those in usual care (RR: 0.336 (95% CI 0.114 to 0.986), p=0.017). Enhanced therapy was effective over usual care for ulcer recurrence at any foot site (RR: 0.760 (95% CI 0.579 to 0.997), p=0.046).ConclusionsAt-home foot temperature monitoring does not significantly reduce incidence of diabetic foot ulcer recurrence at or adjacent to measurement sites over usual care, unless participants reduce ambulatory activity when hotspots are found, or when aiming to prevent ulcers at any foot site.Trial registration numberNTR5403.

Leptin Receptor Expression in GABAergic Cells is Not Sufficient to Normalize Metabolism and Reproduction in Mice

Previous studies indicate that leptin receptor (LepR) expression in GABAergic neurons is necessary for the biological effects of leptin. However, it is not clear whether LepR expression only in GABAergic neurons is sufficient to prevent the metabolic and neuroendocrine imbalances caused by LepR deficiency. In the present study, we produced mice that express the LepR exclusively in GABAergic cells (LepRVGAT mice) and compared them with wild-type (LepR+/+) and LepR-deficient (LepRNull/Null) mice. Although LepRVGAT mice showed a pronounced reduction in body weight and fat mass, as compared with LepRNull/Null mice, male and female LepRVGAT mice exhibited an obese phenotype relative to LepR+/+ mice. Food intake was normalized in LepRVGAT mice; however, LepRVGAT mice still exhibited lower energy expenditure in both sexes and reduced ambulatory activity in the females, compared with LepR+/+ mice. The acute anorexigenic effect of leptin and hedonic feeding were normalized in LepRVGAT mice despite the hyperleptinemia they present. Although LepRVGAT mice showed improved glucose homeostasis compared with LepRNull/Null mice, both male and female LepRVGAT mice exhibited insulin resistance. In contrast, LepR expression only in GABAergic cells was sufficient to normalize the density of agouti-related peptide (AgRP) and α-MSH immunoreactive fibers in the paraventricular nucleus of the hypothalamus. However, LepRVGAT mice exhibited reproductive dysfunctions, including subfertility in males and alterations in the estrous cycle of females. Taken together, our findings indicate that LepR expression in GABAergic cells, although critical to the physiology of leptin, is insufficient to normalize several metabolic aspects and the reproductive function in mice.

Promoting physical activity in a multi-ethnic population at high risk of diabetes: the 48-month PROPELS randomised controlled trial

Background Physical activity is associated with a reduced risk of type 2 diabetes and cardiovascular disease but limited evidence exists for the sustained promotion of increased physical activity within diabetes prevention trials. The aim of the study was to investigate the long-term effectiveness of the Walking Away programme, an established group-based behavioural physical activity intervention with pedometer use, when delivered alone or with a supporting mHealth intervention. Methods Those at risk of diabetes (nondiabetic hyperglycaemia) were recruited from primary care, 2013–2015, and randomised to (1) Control (information leaflet); (2) Walking Away (WA), a structured group education session followed by annual group-based support; or (3) Walking Away Plus (WAP), comprising WA annual group-based support and an mHealth intervention delivering tailored text messages supported by telephone calls. Follow-up was conducted at 12 and 48 months. The primary outcome was accelerometer measured ambulatory activity (steps/day). Change in primary outcome was analysed using analysis of covariance with adjustment for baseline, randomisation and stratification variables. Results One thousand three hundred sixty-six individuals were randomised (median age = 61 years, ambulatory activity = 6638 steps/day, women = 49%, ethnic minorities = 28%). Accelerometer data were available for 1017 (74%) individuals at 12 months and 993 (73%) at 48 months. At 12 months, WAP increased their ambulatory activity by 547 (97.5% CI 211, 882) steps/day compared to control and were 1.61 (97.5% CI 1.05, 2.45) times more likely to achieve 150 min/week of moderate-to-vigorous physical activity. Differences were not maintained at 48 months. WA was no different to control at 12 or 48 months. Secondary anthropometric and health outcomes were largely unaltered in both intervention groups apart from small reductions in body weight in WA (~ 1 kg) at 12- and 48-month follow-up. Conclusions Combining a pragmatic group-based intervention with text messaging and telephone support resulted in modest changes to physical activity at 12 months, but changes were not maintained at 48 months. Trial registration ISRCTN 83465245 (registered on 14 June 2012).

Adaptive Accumulation of Plantar Pressure for Ambulatory Activity Recognition and Pedestrian Identification

In this paper, we propose a novel method for ambulatory activity recognition and pedestrian identification based on temporally adaptive weighting accumulation-based features extracted from categorical plantar pressure. The method relies on three pressure-related features, which are calculated by accumulating the pressure of the standing foot in each step over three different temporal weighting forms. In addition, we consider a feature reflecting the pressure variation. These four features characterize the standing posture in a step by differently weighting step pressure data over time. We use these features to analyze the standing foot during walking and then recognize ambulatory activities and identify pedestrians based on multilayer multiclass support vector machine classifiers. Experimental results show that the proposed method achieves 97% accuracy for the two tasks when analyzing eight consecutive steps. For faster processing, the method reaches 89.9% and 91.3% accuracy for ambulatory activity recognition and pedestrian identification considering two consecutive steps, respectively, whereas the accuracy drops to 83.3% and 82.3% when considering one step for the respective tasks. Comparative results demonstrated the high performance of the proposed method regarding accuracy and temporal sensitivity.

MO183TELEMEDICINE AS A MODALITY OF HEALTH CARE DELIVERY FOR PATIENTS WITH SEVERE CHRONIC KIDNEY DISEASE DURING COVID-19 PANDEMIC

Background and Aims Telemedicine is a new modality of care delivery. Over the last months, it has been used to deliver health care to outpatients with chronic kidney disease (CKD) during COVID-19 pandemic. However, experience of telemedicine in patients with severe CKD is scarce and there are not reassuring data about its efficacy in improving patients’ outcome. To evaluate the efficacy and the outcome profile of telemedicine in people with severe CKD, we reviewed all data of outpatients with severe kidney impairment who underwent nephrological evaluation during the first wave of this pandemic. In particular, outcomes of the ambulatory activity (urgent-start dialysis, late referral and modalities of dialysis initiation) were compared to 2019 ambulatory activity. Method Outpatients with severe chronic kidney disease included in the ambulatory program called “Pre-Dialysis Program were enrolled in a retrospective study. We reviewed all electronic charts of patients who underwent nephrological follow-up from 9th March to June 21st, 2020 (15 weeks in total) at the University Hospital of Modena, Italy. Extension of the observation period to 30th September 2020 allowed us to determine the long-term effects of telemedicine on the rate of urgent-star dialysis, late referral, and modalities of dialysis initiation. Results During 15 weeks of follow-up, 186 nephrological visits were performed (Table) They were subdivided into telemedicine visits (56.5%) and in-person visits (43.5%). Overall, mean age of patients was 71.7±13.1 years with a prevalence of male (60.2%). Patients who received telemedicine visits had a statistically significant lower sCr (3.7±1.2 vs 4.5±1.5 mg/dl; P=0.0001) and higher eGFR level (14.7±6.02 vs 12.16±5.8 ml/min; P=0.002) than patients followed in the ambulatory setting. A high prevalence of patients with CKD stage 5 was monitored by in-person visits (P=0.0001). Patients followed by telemedicine had a clinical profile including a lower weight (P=0.007) and better control of metabolic acidosis (P=0.039) than the counterpart. Changes in domiciliary therapy occurred more frequently in patients monitored in the ambulatory setting (P=0.036). Statistically significant differences were encountered in the prescription of diuretics (P=0.002), sodium bicarbonate (P=0.043), antihypertensive drugs (P=0.001) and uric acid-lowering agents (P=0.046). During the 15-week period in 2019, 214 visits were performed (+13% compared to 2020). The vast majority of these visits were conducted in the hospital setting (210 out of 214; 98.2%). The severity of CKD was similar between patients, without statistically significant difference in the rate of patients in CKD stage III (P=0.7), stage IV (0.388) and stage V (P=0.593). Implementation of telemedicine to in-person visits during COVID-19 pandemic did not change the outcomes of patients. Short-term follow-up showed a similar rate in urgent-start dialysis (P=0.361), late referral (P=1), and HD (P=0.875) or PD initiation (P=0.661). Similar results were seen also at the end of the extended follow-up. Conclusion Implementation of telemedicine has been fundamental to maintain a high level of care in CKD patients during the COVID-19 pandemic. Telemedicine services in combination with in-person visits have contributed to the delivery of clinical monitoring in a group of patients with severe and progressive CKD. No differences have been identified in terms of rate of unplanned dialysis, late referral, and modality of dialysis initiation.

Liver-Specific Kisspeptin Deletion Impairs Energy Metabolism in Mice

Kisspeptin, a neuroendocrine protein critical for the control of pubertal development and fertility has been shown to be modulated by nutritional signals. While the secretion of kisspeptin from specific hypothalamic nuclei is well-known to regulate GnRH-mediated pubertal maturation and reproduction, it remains unclear what role peripheral kisspeptin, specifically of hepatic origin, plays in regulating metabolism and glucose homeostasis. To define the role of kisspeptin in the liver, we developed a novel Kiss1f/f mouse line and targeted liver-specific Kiss1 ablation by injecting a AAV8-TBG-iCre virus via the tail vein (LKiss1KO). Control mice included Kiss1f/f male and female mice injected with AAV-GFP (LKiss1WT). We previously showed that deletion of hepatic kisspeptin did not affect body weight, but resulted in decreased insulin secretion and glucose intolerance in both sexes. To clarify the effects of liver-specific Kiss1 knockout on insulin action and glucose homeostasis in vivo, we conducted hyperinsulinemic-euglycemic clamp studies three weeks after tail injections. We noted a sexual dimorphism in the glucose infusion rate (GIR), female mice have a higher GIR to maintain euglycemia associated with an elevated glucose consumption rate, suggesting that female mice are more insulin sensitive than male mice. However, the deletion of liver kisspeptin had no effect on the glucose production rate in either sex. Indirect calorimetry assessment was conducted 4 weeks post-injection. Both male and female LKiss1KO mice showed significantly higher oxygen consumption, carbon dioxide production, and increased energy expenditure as compared to the LKiss1WT groups. However, there were no differences in either the respiratory exchange ratio or total ambulatory activity among treatments. These findings clearly define a pivotal role for hepatic Kiss1 in the modulation of insulin secretion to maintain glucose homeostasis without modulating glucose production as well as in maintaining energy homeostasis in both male or female mice.

Testosterone reduces body fat in male mice by stimulation of physical activity via extrahypothalamic ERα signaling

Testosterone (T) reduces male fat mass but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high fat diet-induced adult obese male mice to supplementation with T or the non-aromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. Stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.