Developing and exploring the validity of a patient reported experience measure for adult inpatient diabetes care.

AIM: To develop and explore the validity of a Patient Reported Experience Measure (PREM) for adult inpatient diabetes care. METHOD: 27 in-depth interviews were conducted to inform the development of the 42-item PREM which was cognitively tested with 10 people. A refined 38-item PREM was piloted with 228 respondents completing a paper (n = 198) or online (n = 30) version. The performance of the PREM was evaluated by exploring (i) uptake/number of responses and (ii) survey validity by investigating whether the PREM data were of adequate quality and delivered useful information. RESULTS: The PREM had low drop-out or missing data rates suggesting it was appropriately constructed. Analysis of item frequencies and variances, and problem score calculations concluded that questions provided sufficient score differentiation. CONCLUSIONS: This new PREM allows for experiences of inpatient diabetes care to be measured, understood and reported on to help identify priority areas for improving care quality.

Type 1 diabetes and low carbohydrate diets-Defining the degree of nutritional ketosis.

AIMS: Adopting a low- or very low-carbohydrate (LCD or VLCD) diet in type 1 diabetes mellitus (T1D) is a controversial intervention. The main fear is that these diets may increase the risk of diabetic ketoacidosis. However, there is little data about the ketoacidosis risk and the level of physiological nutritional ketosis in individuals following these diets. We aimed to define the level of ketosis in those with T1D following carbohydrate restricted diets in a real-world observational study. METHODS: Patients with T1D who had self-selected dietary carbohydrate restriction were enrolled from local clinics and were compared to those following an unrestricted regular carbohydrate control diet (RCCD). Participants completed a 3-day diary, documenting food intake, ketones, and blood/interstitial glucose concentrations. RESULTS: Participants were divided into three groups according to mean carbohydrate intake: VLCD (<50 g carbohydrates/day) n = 6, LCD (50-130 g carbohydrates/day) n = 6, and RCCD (>130 g carbohydrates/day) n = 3. Mean beta-hydroxybutyrate (BOHB) concentrations were 1.2 mmol/l (SD 0.14), 0.3 mmol/l (SD 0.12) and 0.1mmol/l (SD 0.05) in the VLCD, LCD and RCCD groups, respectively (p = 0.02). Post hoc Dunn test demonstrated this reached statistical significance between the VLCD and RCCD groups (p = 0.02). CONCLUSION: Carbohydrate restricted diets, in particular VLCDs, are associated with a higher BOHB level. However, the degree of ketosis seen is much lower than we expected, and significantly lower than the level typically associated with diabetic ketoacidosis. This may suggest the risk of ketoacidosis is lower than feared, although safety will need to be evaluated further in large scale randomised trials.

Improved glycaemic control in patients with type 2 diabetes has a beneficial impact on NAFLD, independent of change in BMI or glucose lowering agent.

BACKGROUND AND AIM: The current focus of the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) is lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with type 2 diabetes (T2D) and obesity. In patients with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. METHODS AND RESULTS: In a retrospective analysis of data from 637 people with T2D, we examined the longitudinal impact of optimizing glycaemic control with DPP-IV inhibitors, GLP-1RAs and SGLT2 inhibitors on Fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Multiple linear regression analysis demonstrated a significant correlation between the change in glycated haemoglobin and change in FLI after adjustment for change in BMI, age, sex, and drug class (R = 0.467, p = 0.031). The greatest reduction in FLI was observed in patients with the largest reduction in glycated haemoglobin (p < 0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. CONCLUSIONS: Improvements in glucose control that are independent of weight loss are associated with improvement in NAFLD and should form an integral part of the management patients with co-existent NAFLD and T2D.

Inpatient hypoglycaemia in older people is associated with a doubling in the increased length of stay compared with the younger population.

BACKGROUND: Hypoglycaemia during hospital admission is associated with poor outcomes including increased length of stay. In this study, we compared the incidence of inpatient hypoglycaemia and length of stays among people of three age groups: ≤65 years, 65-80 years and >80 years old. METHODS: The study was conducted using a 4-year electronic patient record dataset from Oxford University Hospitals NHS Foundation Trust. The dataset contains hospital admission data for people with diabetes. We analysed the blood glucose (BG) measurements and identified all level 1 (BG <4 mmol/l) and level 2 (BG <3 mmol/l) hypoglycaemic episodes. We compared the length of stays between different age groups and with different levels of hypoglycaemia. RESULTS: We analysed data obtained from 17,658 inpatients with diabetes who underwent 32,758 hospital admissions. The length of stays for admissions with no hypoglycaemia were 3[1,6], 3[1,8] and 4[2,11] (median[interquartile range]) days for age groups ≤65 years, 65-80 years and >80 years, respectively. These were statistically significantly lower (P < 0.01 for all pairwise comparisons) than the length of stays for admissions with level 1 hypoglycaemia, which were 6[3,13], 10[5,20] and 12[6,22] days, and level 2 hypoglycaemia, which were 7[3,14], 11[5,24] and 13[6,24] days. CONCLUSIONS: In all age groups, admissions with either level 1 or level 2 hypoglycaemia were associated with an increased length of stay. However, in both the older groups, the length of stay increments were much higher (double) than the younger counterparts. The clinical consequences of hypoglycaemia were more severe in older people compared with the younger population.

Inpatient hypoglycaemia: understanding who is at risk.

AIMS/HYPOTHESIS: We analysed data obtained from the electronic patient records of inpatients with diabetes admitted to a large university hospital to understand the prevalence and distribution of inpatient hypoglycaemia. METHODS: The study was conducted using electronic patient record data from Oxford University Hospitals NHS Foundation Trust. The dataset contains hospital admission data for patients coded for diabetes. We used the recently agreed definition for a level 1 hypoglycaemia episode as any blood glucose measurement <4 mmol/l and a level 2 hypoglycaemia episode as any blood glucose measurement <3 mmol/l. Any two or more consecutive low blood glucose measurements within a 2 h time window were considered as one single hypoglycaemic episode. RESULTS: We analysed data obtained from 17,658 inpatients with diabetes (1696 with type 1 diabetes, 14,006 with type 2 diabetes, and 1956 with other forms of diabetes; 9277 men; mean ± SD age, 66 ± 18 years) who underwent 32,758 hospital admissions between July 2014 and August 2018. The incidence of level 1 hypoglycaemia was 21.5% and the incidence of level 2 hypoglycaemia was 9.6%. Recurrent level 1 and level 2 hypoglycaemia occurred, respectively, in 51% and 39% of hospital admissions in people with type 2 diabetes with at least one hypoglycaemic episode, and in 55% and 45% in those with type 1 diabetes. The incidence of level 2 hypoglycaemia in people with type 2 diabetes, when corrected for the number of people who remained in hospital, remained constant for the first 100 h at approximately 0.15 events per h per admission. With regards to the hypoglycaemia distribution during the day, after correcting for the number of blood glucose tests per h, there were two clear spikes in the rate of hypoglycaemia approximately 3 h after lunch and after dinner. The highest rate of hypoglycaemia per glucose test was seen between 01:00 hours and 05:00 hours. Medication had a significant impact on the incidence of level 2 hypoglycaemia, ranging from 1.5% in people with type 2 diabetes on metformin alone to 33% in people treated with a combination of rapid-acting insulin analogue, long-acting insulin analogue and i.v.-administered insulin. CONCLUSIONS/INTERPRETATION: Retrospective analysis of data from electronic patient records enables clinicians to gain a greater understanding of the incidence and distribution of inpatient hypoglycaemia. This information should be used to drive evidence-based improvements in the glycaemic control of inpatients through targeted medication adjustment for specific populations at high risk of hypoglycaemia.

A food-based, low-energy, low-carbohydrate diet for people with type 2 diabetes in primary care: A randomized controlled feasibility trial.

AIM: To examine the feasibility of a food-based, low-energy, low-carbohydrate diet with behavioural support delivered by practice nurses for patients with type 2 diabetes. MATERIALS AND METHODS: People with type 2 diabetes and a body mass index (BMI) of ≥30 kg/m2 were randomized 2:1 to intervention or control (usual care) and assessed at 12 weeks. The intervention comprised an 800-1000 kcal/day, food-based, low-carbohydrate (<26% energy) diet for 8 weeks, followed by a 4-week weight maintenance period and four 15-20-minute appointments with a nurse. Primary outcomes were feasibility of recruitment, fidelity of intervention delivery and retention of participants at 12 weeks. Secondary outcomes included change in weight and HbA1c. Focus groups explored the intervention experience. RESULTS: Forty-eight people were screened, 33 enrolled and 32 followed-up. Mean (±SD) weight loss in the intervention group was 9.5 kg (± 5.4 kg) compared with 2 kg (± 2.5 kg) in the control group (adjusted difference - 7.5 kg [-11.0 to -4.0, P < 0.001]). Mean reduction in HbA1c in the intervention group was 16.3 mmol/mol (± 13.3 mmol/mol) compared with 0.7 mmol/mol (±4.5 mmol/mol) in the control group (difference - 15.7 mmol/mol [-24.1 to -7.3, P < 0.001]). CONCLUSIONS: It is feasible to recruit participants to a food-based, low-energy, low-carbohydrate intervention, for practice nurses to deliver the programme in primary care, and to retain participants in both groups. There is evidence of clinically significant short-term improvements in weight and glycaemic control.

The effects of obesity, diabetes and metabolic syndrome on the hydrolytic enzymes of the endocannabinoid system in animal and human adipocytes.

BACKGROUND: Circulating endocannabinoid levels are increased in obesity and diabetes. We have shown that fatty acid amide hydrolase (FAAH, an endocannabinoid hydrolysing enzyme) in subcutaneous adipose tissue positively correlates with BMI in healthy volunteers. The aim of the present study was to investigate whether the hydrolytic enzymes of the endocannabinoid system are affected by diabetes or metabolic syndrome in obesity. METHODS: Using radiolabelled substrates, FAAH and monoacylglycerol lipase (MGL) activities were assessed in adipocytes from various adipose depots in Zucker rats (n = 22, subcutaneous abdominal, visceral and epididymal) and bariatric patients (n = 28, subcutaneous abdominal and omental). RESULTS: FAAH activity was significantly increased in adipocytes of obese (Zucker Fatty) compared to Zucker lean rats (P < 0.05) but was not raised in the Zucker Diabetic Fatty rats (ZDF). MGL activity was raised in both Zucker Fatty (P < 0.001-0.01) and ZDF rats (P < 0.05) and was positively correlated with body weight and plasma glucose levels (P < 0.01). In bariatric patients (BMI range 37-58 kg.m²), there was a trend for MGL activity to correlate positively with BMI, reaching significance when type 2 diabetic patients were removed. FAAH and MGL activities in obese humans were not correlated with blood pressure, skinfold thicknesses, fasting glucose, insulin, HbA1c, triglycerides or cholesterol levels. CONCLUSIONS: FAAH in adipocytes is differentially altered in animal models of obesity and diabetes, while MGL activity is increased by both. However, in obese humans, FAAH or MGL activity in adipocytes is not affected by diabetes, dyslipidaemia or other markers of metabolic dysfunction. This suggests increased circulating levels of endocannabinoids are not a result of altered degradation in adipose tissue.

Prolonged remission followed by low insulin requirements in a patient with type 1 diabetes on a very low-carbohydrate diet.

Summary: The use of a low-carbohydrate diet (LCD) reduces insulin requirements in insulinopenic states such as type 1 diabetes mellitus (T1DM). However, the use of potentially ketogenic diets in this clinical setting is contentious and the mechanisms underlying their impact on glycaemic control are poorly understood. We report a case of a patient with a late-onset classic presentation of T1DM who adopted a very low-carbohydrate diet and completely avoided insulin therapy for 18 months, followed by tight glycaemic control on minimal insulin doses. The observations suggest that adherence to an LCD in T1DM, implemented soon after diagnosis, can facilitate an improved and less variable glycaemic profile in conjunction with temporary remission in some individuals. Importantly, these changes occurred in a manner that did not lead to a significant increase in blood ketone (beta-hydroxybutyrate) concentrations. This case highlights the need for further research in the form of randomised controlled trials to assess the long-term safety and sustainability of carbohydrate-reduced diets in T1DM. Learning points: This case highlights the potential of low-carbohydrate diets (LCDs) in type 1 diabetes mellitus (T1DM) to mediate improved diabetes control and possible remission soon after diagnosis. Could carbohydrate-reduced diets implemented early in the course of T1DM delay the decline in endogenous insulin production? Adherence to an LCD in T1DM can facilitate an improved and less variable glycaemic profile. This case suggests that LCDs in T1DM may not be associated with a concerning supraphysiological ketonaemia.

Dietary Approaches to the Management Of type 2 Diabetes (DIAMOND) in primary care: A protocol for a cluster randomised trial.

INTRODUCTION: There is strong evidence that type 2 diabetes (T2D) remission can be achieved by adopting a low-energy diet achieved through total dietary replacement products. There is promising evidence that low-carbohydrate diets can achieve remission of T2D. The Dietary Approaches to the Management of type 2 Diabetes (DIAMOND) programme combines both approaches in a behaviourally informed low-energy, low-carbohydrate diet for people with T2D, delivered by nurses in primary care. This trial compares the effectiveness of the DIAMOND programme to usual care in inducing remission of T2D and in reducing risk of cardiovascular disease. METHODS AND ANALYSIS: We aim to recruit 508 people in 56 practices with T2D diagnosed within 6 years, who are demographically representative of the UK population. We will allocate general practices, based on ethnicity and socioeconomic status, to provide usual care for diabetes or offer the DIAMOND programme. Participants in practices offering DIAMOND will see the nurse seven times over 6 months. At baseline, 6 months, and 1 year we will measure weight, blood pressure, HbA1c, lipid profile and risk of fatty liver disease. The primary outcome is diabetes remission at 1 year, defined as HbA1c < 48 mmol/mol and off glucose-lowering medication for at least 6 months. Thereafter, we will assess whether people resume treatment for diabetes and the incidence of microvascular and macrovascular disease through the National Diabetes Audit. Data will be analysed using mixed-effects generalised linear models. This study has been approved by the National Health Service Health Research Authority Research Ethics Committee (Ref: 22/EM/0074). TRIAL REGISTRATION NUMBER: ISRCTN46961767.

The activity of the endocannabinoid metabolising enzyme fatty acid amide hydrolase in subcutaneous adipocytes correlates with BMI in metabolically healthy humans.

BACKGROUND: The endocannabinoid system (ECS) is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoylglcyerol (2-AG), and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI), or other markers of adiposity and metabolism. METHODS: Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs. RESULTS: MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose) or serum adipokine levels (adiponectin, leptin or resistin). In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels. CONCLUSIONS: In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently.

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink.

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m2 between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34-5.75) and 3.78 (95% CI, 1.42-10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08-2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Predicting the Risk of Inpatient Hypoglycemia With Machine Learning Using Electronic Health Records.

OBJECTIVE: We analyzed data from inpatients with diabetes admitted to a large university hospital to predict the risk of hypoglycemia through the use of machine learning algorithms. RESEARCH DESIGN AND METHODS: Four years of data were extracted from a hospital electronic health record system. This included laboratory and point-of-care blood glucose (BG) values to identify biochemical and clinically significant hypoglycemic episodes (BG ≤3.9 and ≤2.9 mmol/L, respectively). We used patient demographics, administered medications, vital signs, laboratory results, and procedures performed during the hospital stays to inform the model. Two iterations of the data set included the doses of insulin administered and the past history of inpatient hypoglycemia. Eighteen different prediction models were compared using the area under the receiver operating characteristic curve (AUROC) through a 10-fold cross validation. RESULTS: We analyzed data obtained from 17,658 inpatients with diabetes who underwent 32,758 admissions between July 2014 and August 2018. The predictive factors from the logistic regression model included people undergoing procedures, weight, type of diabetes, oxygen saturation level, use of medications (insulin, sulfonylurea, and metformin), and albumin levels. The machine learning model with the best performance was the XGBoost model (AUROC 0.96). This outperformed the logistic regression model, which had an AUROC of 0.75 for the estimation of the risk of clinically significant hypoglycemia. CONCLUSIONS: Advanced machine learning models are superior to logistic regression models in predicting the risk of hypoglycemia in inpatients with diabetes. Trials of such models should be conducted in real time to evaluate their utility to reduce inpatient hypoglycemia.

Dietary Approaches to the Management Of type 2 Diabetes (DIAMOND): protocol for a randomised feasibility trial.

INTRODUCTION: Some clinicians have observed that low-carbohydrate, low-energy diets can improve blood glucose control, with reports of remission from type 2 diabetes in some patients. In clinical trials, support for low-carbohydrate, low-energy diets has been provided by specialist staff and these programmes are unsuitable for widespread deployment in routine primary care. The aim of this trial is to test whether a newly developed behavioural support programme can effectively deliver a low-energy, low-carbohydrate diet in a primary care setting. METHODS AND ANALYSIS: This is a feasibility randomised controlled trial (RCT) with embedded qualitative study. Thirty adult patients with type 2 diabetes and body mass index ≥30 kg/m2 in 2-4 general practices will be randomised 2:1 intervention or control and followed up over 12 weeks. The intervention diet comprises 8 weeks of a low-carbohydrate food-based diet providing around 800 kcal/day, followed by 4 weeks of weight maintenance. This programme will be delivered by practice nurses, who will also support patients through goal-setting, motivation and self-monitoring across four appointments, and provide a self-help booklet with recipes, shopping lists and other behavioural support. Primary outcome measures of feasibility will be met if CIs do not cross the following proportions: that 60% of intervention group participants attempt the dietary intervention, healthcare professionals conduct the intervention delivery session with at least 60% of essential elements present and 60% of participants attend the final follow-up session. Secondary outcome measures will assess process and qualitative measures, as well as exploratory outcomes including change in haemoglobin A1c and change in weight. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the National Research Ethics Service, South Central Oxford B Research Ethics Committee (ref: 18/SC/0071). The study results will inform whether to progress to a full-scale RCT to test the efficacy of offering this programme for patients with type 2 diabetes in primary care. TRIAL REGISTRATION NUMBER: ISRCTN62452621; Pre-results.

Fatty acid metabolism in patients with PPARgamma mutations.

CONTEXT: PPARG mutations may cause insulin resistance and dyslipidemia, but little is known about the mechanisms of the abnormalities of lipid metabolism. OBJECTIVE: We hypothesized that in PPARG mutations, abnormal adipose tissue triglyceride storage causes insulin resistance. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: Whole-body and adipose tissue-specific metabolic phenotyping through arteriovenous blood sampling was made before and after a mixed meal including 13C-palmitic acid. Studies were performed in a 32-yr-old male with partial lipodystrophy and type 2 diabetes, heterozygous for the PPARG P467L mutation and in an apparently phenotypically normal 32-yr-old male heterozygous for the PPARG n.AAA553T mutation. Comparator groups were age- and sex-matched healthy participants (n=10) and type 2 diabetes sex-matched participants (n=6). RESULTS: The P467L patient had elevated unmodulated fasting and postprandial plasma nonesterified fatty acid (NEFA) concentrations, despite a low adipose tissue NEFA output. Instead, NEFA appeared to originate directly from triglyceride-rich lipoproteins: 13C-palmitic acid accumulated rapidly in the NEFA fraction, as a sign of impaired fatty acid trapping in tissues. In contrast to the Pparg haploinsufficient mouse, the patient with n.AAA553T mutation did not exhibit paradoxically insulin sensitive and showed a mostly normal metabolic pattern. CONCLUSIONS: The lipodystrophic PPARG P467L phenotype include excessive and uncontrolled generation of NEFA directly from triglyceride-rich lipoproteins, explaining high systemic NEFA concentrations, whereas the human PPARG haploinsufficiency is metabolically almost normal.

Barriers and facilitators to integrating primary and specialist healthcare in the United Kingdom: a narrative literature review.

Many national policies propose integration between primary and specialist care to improve the care of people with long-term conditions. There is an increasing need to understand how to practically implement such service redesign. This paper reviews the literature on the barriers to, and facilitators of, integrating primary and specialist healthcare for people with long-term conditions in the UK, with the aim of informing the development and implementation of similar initiatives in integration. MEDLINE and CINAHL databases were searched and 14 articles discussing factors hindering or enabling integration were identified. The factors were extracted and synthesised and key lessons were tabulated. Successful integration of care requires synchronised changes on different levels, a well-resourced team, a well-defined and evidence-based service, agreed and articulated new roles and responsibilities, and a willingness among healthcare professionals to co-work and co-learn. Barriers to successful implementation of integrated care include a lack of commitment across organisations, limited resources, poorly functioning information technology (IT), poor coordination of finances and care pathways, conflicting objectives, and conflict within teams. The examples of integrated working provide insights into problems and solutions around interorganisational and interprofessional working that will guide those planning integration in the future.

Single Sensor Gait Analysis to Detect Diabetic Peripheral Neuropathy: A Proof of Principle Study.

This study explored the potential utility of gait analysis using a single sensor unit (inertial measurement unit [IMU]) as a simple tool to detect peripheral neuropathy in people with diabetes. Seventeen people (14 men) aged 63±9 years (mean±SD) with diabetic peripheral neuropathy performed a 10-m walk test instrumented with an IMU on the lower back. Compared to a reference healthy control data set (matched by gender, age, and body mass index) both spatiotemporal and gait control variables were different between groups, with walking speed, step time, and SDa (gait control parameter) demonstrating good discriminatory power (receiver operating characteristic area under the curve >0.8). These results provide a proof of principle of this relatively simple approach which, when applied in clinical practice, can detect a signal from those with known diabetes peripheral neuropathy. The technology has the potential to be used both routinely in the clinic and for tele-health applications. Further research should focus on investigating its efficacy as an early indicator of or effectiveness of the management of peripheral neuropathy. This could support the development of interventions to prevent complications such as foot ulceration or Charcot's foot.

Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.

CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. OBJECTIVE: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. DESIGN AND SETTING: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. PATIENTS AND PARTICIPANTS: Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. CONCLUSIONS: Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.

A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study.

BACKGROUND: Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans. METHODS: Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler. RESULTS: CBD reduced resting systolic BP (-6 mmHg; P < 0.05) and stroke volume (-8 ml; P < 0.05), with increased heart rate (HR) and maintained cardiac output. Subjects who had taken CBD had lower BP (-5 mmHg; P < 0.05, especially before and after stress), increased HR (+10 bpm; P < 0.01), decreased stroke volume (-13 ml; P < 0.01), and a blunted forearm skin blood flow response to isometric exercise. In response to cold stress, subjects who had taken CBD had blunted BP (-6 mmHg; P < 0.01) and increased HR (+7 bpm; P < 0.05), with lower total peripheral resistance. CONCLUSIONS: This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.

Rosiglitazone increases indexes of stearoyl-CoA desaturase activity in humans: link to insulin sensitization and the role of dominant-negative mutation in peroxisome proliferator-activated receptor-gamma.

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and delta6- and delta5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and delta5-desaturase but not delta6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARgamma carrier, SCD and delta5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARgamma mutation supports a pivotal role of PPARgamma function in SCD regulation.