Associations Between Physical Activity and Gastrointestinal Transit Times in People with Normal Weight, Overweight, and Obesity.

BACKGROUND: Rapid gastric emptying is associated with obesity and overeating, whereas delayed gastric emptying is associated with anorexia. Acute effects of exercise on gastric emptying have been investigated extensively, but the influence of habitual physical activity on gastric emptying and transit time in other regions of the gastrointestinal tract is poorly understood. OBJECTIVE: The objective was to investigate associations between objectively measured habitual physical activity and gastrointestinal transit times in adults with varying degrees of adiposity. METHODS: 50 adults (58% women) were included in this cross-sectional study. Physical activity was measured by an accelerometer placed on the lower back for 7 d. Gastric emptying time, small bowel transit time, colonic transit time, and whole gut transit time were simultaneously evaluated by a wireless motility capsule, which was ingested together with a standardized mixed meal. Linear regression models were applied to assess the associations of total activity counts and time spent at different intensities-sedentary activity (0-100 counts/min), low light activity (101-759 counts/min), high light activity (760-1951 counts/min); moderate and vigorous activity (≥1952 counts/min)) with gastrointestinal transit times. RESULTS: Median [Q1; Q3] age was 56.5 [46.6-65.5] y, and body mass index (BMI) was 32.1 [28.5-35.1] kg/m2. For every additional hour spent performing high light intensity physical activity, colonic transit time was 25.5 % [95% CI: 3.10, 42.7] more rapid (P = 0.028), and whole gut transit time was 16.2 % [95% CI: 1.84, 28.4] more rapid (P = 0.028) when adjusted for sex, age, and body fat. No other associations were observed. CONCLUSIONS: More time spent on physical activity at high light intensity was associated with more rapid colonic and whole gut transit time, independent of age, sex, and body fat, whereas other intensities of physical activity and gastrointestinal transit times were not associated. TRIAL REGISTRATION: Clinicaltrials.gov IDs (NCT03894670, NCT03854656).

Towards precision medicine in diabetes? A critical review of glucotypes.

In response to a study previously published in PLOS Biology, this Formal Comment thoroughly examines the concept of 'glucotypes' with regard to its generalisability, interpretability and relationship to more traditional measures used to describe data from continuous glucose monitoring.

Development and feasibility testing of a time-restricted eating intervention for women living with overweight/obesity and HIV in a resource-limited setting of South Africa.

BACKGROUND: Human Immunodeficiency Virus (HIV) and type 2 diabetes (T2D) are amongst the leading causes of death in South Africa. The preferred first-line anti-retroviral treatment contains dolutegravir (DTG), shown to increase body weight, may compound the already high rates of obesity and associated risk for T2D. South Africa has widespread food insecurity, making traditional dietary strategies difficult to implement. Time-restricted eating (TRE) may be an appropriate intervention in resource-limited communities. METHODS: This article outlines the development and feasibility testing of a TRE intervention to inform the design of a TRE randomised controlled trial in women (20-45 years old) living with overweight/obesity and HIV, receiving DTG-based treatment from a resource-limited community in Cape Town, South Africa. Factors influencing TRE adoption were identified using the Capability, Opportunity, Motivation - Behaviour model and the Theoretical Domains Framework, combining in-depth interviews (IDIs) and focus group discussions. Participants from the IDIs went on to participate in a single arm 4-week TRE pilot trial where feasibility was explored in terms of reach, acceptability, applicability, and implementation integrity. An iterative, thematic analysis approach was employed to analyse the qualitative data. RESULTS: Participants included 33 isiXhosa-speaking women (mean age 37.1 years, mean BMI 35.9 kg/m2). Thematic analysis identified psychological capability (knowledge of fasting), social influences (cultural preferences, family support), and reflective motivation (awareness of weight, health impact, motivation for TRE) as key factors influencing adoption of TRE for weight management. In a 4-week TRE pilot trial (n = 12), retention was 100%. Positive outcomes perceived included improved energy, appetite control and weight loss. TRE was perceived as acceptable, easy, and enjoyable. Family support facilitated adherence, while habitual and social eating and drinking practices were barriers. Compliance was high, aided by self-selected eating times, reminders, and weekly calls. Recommendations included the incorporation of dietary education sessions and text messages to provide additional support and reminders. CONCLUSIONS: This study indicates that TRE is a feasible weight management strategy in women living with overweight/obesity and HIV, receiving DTG-based treatment in a resource-limited community. These findings will ensure that the forthcoming TRE randomised controlled trial is adapted and optimised to the local South African context.

The prediabetes conundrum: striking the balance between risk and resources.

The current definition of prediabetes is controversial and subject to continuous debate. Nonetheless, prediabetes is a risk factor for type 2 diabetes, is highly prevalent and is associated with diabetic complications and mortality. Thereby, it has the potential to become a huge strain on healthcare systems in the future, necessitating action from legislators and healthcare providers. But how do we best reduce its associated burden on health? As a compromise between differing opinions in the literature and among the authors of this article, we suggest stratifying individuals with prediabetes according to estimated risk and only offering individual-level preventive interventions to those at high risk. At the same time, we argue to identify those with prediabetes and already established diabetes-related complications and treat them as we would treat individuals with established type 2 diabetes.

LEAP2 is associated with cardiometabolic markers but is unchanged by antidiabetic treatment in people with prediabetes.

To examine whether fasting plasma liver-expressed antimicrobial peptide 2 (FP-LEAP2) is associated with markers of cardiometabolic disease susceptibility in a cohort with prediabetes and overweight/obesity and whether antidiabetic interventions affect FP-LEAP2 levels. The analysis included 115 individuals with prediabetes [hemoglobin A1c (HbA1c) 39-47 mmol/mol, 5.7%-6.4%] and overweight/obesity [body mass index (BMI) ≥ 25 kg/m2] from a randomized controlled trial. Changes in FP-LEAP2 levels were assessed in relation to treatment with dapagliflozin (10 mg once daily), metformin (1,700 mg daily), or interval-based exercise (5 days/wk, 30 min/session) compared with control (habitual lifestyle) after 6 and 13 wk of treatment. FP-LEAP2 levels were positively associated with [standardized beta coefficient (95% CI)]: BMI 0.22 (0.03:0.41), P = 0.027; body weight 0.27 (0.06:0.48), P = 0.013; fat mass 0.2 (0.00:0.4), P = 0.048; lean mass 0.47 (0.13:0.8), P = 0.008; HbA1c 0.35 (0.17:0.53), P < 0.001; fasting plasma glucose (FPG) 0.32 (0.12:0.51), P = 0.001; fasting serum insulin 0.28 (0.09:0.47), P = 0.005; total cholesterol 0.19 (0.01:0.38), P = 0.043; triglycerides 0.31 (0.13:0.5), P < 0.001; and transaminases and fatty liver index (standardized beta coefficients 0.23-0.32), all P < 0.020. FP-LEAP2 levels were inversely associated with insulin sensitivity [-0.22 (-0.41: -0.03), P = 0.022] and kidney function [estimated glomerular filtration rate (eGFR) -0.34 (-0.56: -0.12), P = 0.003]. FP-LEAP2 levels were not associated with fat distribution or body fat percentage, fasting glucagon, postload glucose, ß-cell function, or low-density lipoprotein. The interventions were not associated with changes in FP-LEAP2. FP-LEAP2 is associated with body mass, impaired insulin sensitivity, liver-specific enzymes, and kidney function. The findings highlight the importance of studying LEAP2 in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. FP-LEAP2 was not affected by metformin, dapaglifloxin, or exercise in this population.NEW & NOTEWORTHY LEAP2, primarily secreted by the liver, increases with greater body mass, insulin resistance, and liver-specific enzymes in individuals with prediabetes and overweight or obesity. Fasting glucose, body mass, and alanine aminotransferase independently predict LEAP2 levels. LEAP2 is inversely linked to impaired kidney function. Elevated LEAP2 levels might indicate an increased metabolic risk, warranting further investigation into its potential involvement in glucose and body weight control.

Effects of acute exercise and exercise training on plasma GDF15 concentrations and associations with appetite and cardiometabolic health in individuals with overweight or obesity - A secondary analysis of a randomized controlled trial.

Growth Differentiation Factor 15 (GDF15) is seemingly involved in appetite control. Acute exercise increases GDF15 concentrations in lean humans, but acute and long-term effects of exercise on GDF15 in individuals with overweight/obesity are unknown. We investigated the effects of acute exercise and exercise training on GDF15 concentrations in individuals with overweight/obesity and associations with appetite and cardiometabolic markers. 90 physically inactive adults (20-45 years) with overweight/obesity were randomized to 6-months habitual lifestyle (CON, n=16), or isocaloric exercise of moderate (MOD, n=37) or vigorous intensity (VIG, n=37), 5 days/week. Testing was performed at baseline, 3, and 6 months. Plasma GDF15 concentrations, other metabolic markers, and subjective appetite were assessed fasted and in response to acute exercise before an ad libitum meal. Cardiorespiratory fitness, body composition, insulin sensitivity, and intraabdominal adipose tissue were measured. At baseline, GDF15 increased 18% (95%CI: 4; 34) immediately after acute exercise and 32% (16; 50) 60 min post-exercise. Fasting GDF15 increased 21% (0; 46) in VIG after 3 months (p=0.045), but this attenuated at 6 months (13% (-11; 43), p=0.316) and was unchanged in MOD (11% (-6; 32), p=0.224, across 3 and 6 months). Post-exercise GDF15 did not change in MOD or VIG. GDF15 was not associated with appetite or energy intake. Higher GDF15 was associated with lower cardiorespiratory fitness, central obesity, dyslipidemia, and poorer glycemic control. In conclusion, GDF15 increased in response to acute exercise but was unaffected by exercise training. Higher GDF15 concentrations were associated with a less favorable cardiometabolic profile but not with markers of appetite. This suggests that GDF15 increases in response to acute exercise independent of training state. Whether this has an impact on free-living energy intake and body weight management needs investigation.

The effect of metformin treatment on volumes of free-living physical activity and sedentary behaviour: A post-hoc analysis of the PRE-D trial.

Perceived physical exertion is increased when exercise is performed on metformin treatment, but the clinical relevance of this is unknown. In this post hoc analysis of a randomized, controlled trial, we investigated whether metformin treatment was associated with lower levels of free-living physical activity. Ninety individuals with overweight/obesity (BMI>25 m2/kg) and HbA1c-defined prediabetes (39-47 mmol/mol) were randomized to treatment with dapagliflozin (SGLT2-inhibitor; 10 mg once daily, n=30), metformin (850 mg twice daily, n=30) or no treatment (control, n=30) for 13 weeks in a parallel-group, open-label trial. Before (baseline), during (6 weeks) and immediately after (13 weeks) cessation of treatment, a 6-day assessment of physical activity and sedentary behaviour was performed using accelerometer-based physical activity monitors. Intention-to-treat analyses revealed no within-group changes or differences in change between the groups for any measures of physical activity or sedentary behaviour at neither 6 nor 13 weeks. Short-term metformin treatment does not reduce free-living physical activity level in individuals with overweight/obesity and HbA1c-defined prediabetes.

Age- and sex-specific effects of a long-term lifestyle intervention on body weight and cardiometabolic health markers in adults with prediabetes: results from the diabetes prevention study PREVIEW.

AIMS/HYPOTHESIS: Lifestyle interventions are the first-line treatment option for body weight and cardiometabolic health management. However, whether age groups or women and men respond differently to lifestyle interventions is under debate. We aimed to examine age- and sex-specific effects of a low-energy diet (LED) followed by a long-term lifestyle intervention on body weight, body composition and cardiometabolic health markers in adults with prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). METHODS: This observational study used longitudinal data from 2223 overweight participants with prediabetes in the multicentre diabetes prevention study PREVIEW. The participants underwent a LED-induced rapid weight loss (WL) period followed by a 3 year lifestyle-based weight maintenance (WM) intervention. Changes in outcomes of interest in prespecified age (younger: 25-45 years; middle-aged: 46-54 years; older: 55-70 years) or sex (women and men) groups were compared. RESULTS: In total, 783 younger, 319 middle-aged and 1121 older adults and 1503 women and 720 men were included in the analysis. In the available case and complete case analyses, multivariable-adjusted linear mixed models showed that younger and older adults had similar weight loss after the LED, whereas older adults had greater sustained weight loss after the WM intervention (adjusted difference for older vs younger adults -1.25% [95% CI -1.92, -0.58], p<0.001). After the WM intervention, older adults lost more fat-free mass and bone mass and had smaller improvements in 2 h plasma glucose (adjusted difference for older vs younger adults 0.65 mmol/l [95% CI 0.50, 0.80], p<0.001) and systolic blood pressure (adjusted difference for older vs younger adults 2.57 mmHg [95% CI 1.37, 3.77], p<0.001) than younger adults. Older adults had smaller decreases in fasting and 2 h glucose, HbA1c and systolic blood pressure after the WM intervention than middle-aged adults. In the complete case analysis, the above-mentioned differences between middle-aged and older adults disappeared, but the direction of the effect size did not change. After the WL period, compared with men, women had less weight loss (adjusted difference for women vs men 1.78% [95% CI 1.12, 2.43], p<0.001) with greater fat-free mass and bone mass loss and smaller improvements in HbA1c, LDL-cholesterol and diastolic blood pressure. After the WM intervention, women had greater fat-free mass and bone mass loss and smaller improvements in HbA1c and LDL-cholesterol, while they had greater improvements in fasting glucose, triacylglycerol (adjusted difference for women vs men -0.08 mmol/l [-0.11, -0.04], p<0.001) and HDL-cholesterol. CONCLUSIONS/INTERPRETATION: Older adults benefited less from a lifestyle intervention in relation to body composition and cardiometabolic health markers than younger adults, despite greater sustained weight loss. Women benefited less from a LED followed by a lifestyle intervention in relation to body weight and body composition than men. Future interventions targeting older adults or women should take prevention of fat-free mass and bone mass loss into consideration. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01777893.

Human Gastrointestinal Transit and Hormonal Response to Different Meal Types: A Randomized Crossover Study.

BACKGROUND: The wireless motility capsule (WMC) technique is a noninvasive and radiation-free method for measuring regional and whole gut transit in response to ingestion of a granola bar (SmartBar) or an eggbeater meal. The WMC has the potential to measure gastrointestinal transit in metabolic research as part of a standardized mixed meal tolerance test. OBJECTIVES: To evaluate gastrointestinal transit with the WMC and postprandial plasma/serum concentrations of metabolites and gastrointestinal hormones as well as subjective appetite following ingestion of a SmartBar compared with a standardized mixed meal. METHODS: Fourteen healthy participants [3 men, median (IQR) age 53.8 (45.8; 64.50) y, body weight 63.9 (59.9; 69.7) kg, BMI 23.1 (21.8; 23.9) kg/m2] completed a 2-d crossover study. Following ingestion of either a SmartBar (260 kcal, 7 energy percent (E%) fat, 74E% carbohydrate, and 19E% protein) or a standardized mixed meal (498 kcal, 34E% fat, 49E% carbohydrate, and 17E% protein), participants swallowed the WMC. Blood samples were drawn in the fasted state and postprandially for analyses of gastrointestinal hormones and metabolites. The primary outcome was difference in gastric emptying time between the 2 test days. Wilcoxon signed rank tests were used to test differences between test days. RESULTS: Median (IQR) gastric emptying time was 98.0 (70.0; 113.0) min longer (P = 0.001) and incremental area under the curve of triglyceride, glucose-dependent insulinotropic polypeptide, and peptide YY were 40 mmol/L × min, 45.7%, and 63.7% greater after the standardized mixed meal compared with the SmartBar (all P < 0.001). CONCLUSIONS: The WMC can be used in combination with a standardized mixed meal for evaluation of gastrointestinal transit in healthy men and women. Gastric emptying time was prolonged in response to the standardized mixed meal whereas transit times of the small bowel, colon, and whole gut did not differ between the test meals.

Predicting Food Intake from Food Reward and Biometric Responses to Food Cues in Adults with Normal Weight Using Machine Learning.

BACKGROUND: Eating behaviors are determined by a complex interplay between behavioral and physiologic signaling occurring before, during, and after eating. OBJECTIVES: The aim was to explore how selected behavioral and physiologic variables separately and grouped together predicted intake of 8 different foods. METHODS: One hundred adults with normal weight performed a food preference task combined with biometric measurements (the Steno Biometric Food Preference Task) in the fasting state. The task measured food reward as well as biometric (eye tracking, electrodermal activity, and facial expressions) responses to images of foods varying in fat content and taste. Energy intake from an ad libitum buffet of the same 8 foods as assessed in the preference task was subsequently assessed. A mixed-effects random forest approach was applied to explore how individual and combined measures of food reward and biometric responses predicted energy intake of the 8 single foods. The performance of the different prediction models was compared with the predictions from a linear model including only an intercept (naïve model) using bootstrap cross-validation. RESULTS: Participants had a median [IQR] intake of 369 kJ [126-472 kJ] per food. Combined or separate measures of food reward or biometric responses did not predict energy intake better than the naïve model. CONCLUSIONS: We did not find that the reward or biometric responses to food cues assessed in a clinical setting were useful in predicting energy intake of single foods. However, this study provides a framework in the field of behavioral nutrition for applying machine learning with a focus on individual predictions. This is necessary on the road toward personalized nutrition and provides great potential for handling complex data with multiple variables.This trial was registered at clinicaltrials.gov as NCT03986619.

The process of health behaviour change following participation in a randomised controlled trial targeting prediabetes: A qualitative study.

AIM: To explore how participating in a randomised controlled trial affected motivation, barriers and strategies in the process of health behaviour change among individuals with prediabetes. METHODS: An extension to the PRE-D trial, a qualitative study investigated the efficacy of glucose-lowering interventions (metformin, dapagliflozin or exercise) compared with a control group among individuals with prediabetes and overweight/obesity. Data were collected through separate focus group interviews with participants using semi-structured interview guides inspired by health behaviour change theories. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis with an inductive-deductive approach. RESULTS: Four interrelated themes were generated from interviews: (1) 'self-construction of prediabetes', on how participants understood the term 'prediabetes', (2) 'altered health image', on how participants' health perceptions were affected, (3) 'personal strategies for health behaviour change', on different ways to attempt to implement behaviour changes and (4) 'the process of health behaviour change', on how participants progressed and relapsed while trying to change behaviour. Themes relate to the health belief model, self-determination theory, self-efficacy and the trans-theoretical model of change. Participants shared their experiences and thoughts during interviews and inspired each other, which led some participants to develop a new perspective on prediabetes severity and increased their motivation for behaviour change. CONCLUSIONS: How participants perceived and accepted, rejected or neglected prediabetes appeared to affect their health images and whether they realised a need for behaviour change. Their achievements during interventions, health literacy, self-efficacy and perceived support from their social networks, professionals and technological aids influenced the maintenance of health behaviour changes.

Is time-restricted eating a robust eating regimen during periods of disruptions in daily life? A qualitative study of perspectives of people with overweight during COVID-19.

BACKGROUND: Time-restricted eating (TRE) has been suggested as a feasible dietary strategy in individuals with overweight. Disruptions in daily life e.g., severe illness can affect engagement in lifestyle interventions to obtain healthier body weight. This study examined if and how the engagement with TRE among people with overweight was affected by the Danish COVID-19 lockdowns as an example of disruptions in daily life. METHODS: Fifteen participants with overweight enrolled in a TRE intervention, i.e. restricting all eating and drinking except water to the same daily ten-hour window, were interviewed about their experiences and engagement with TRE during COVID-19 lockdowns. Interviews were semi-structured and conducted by phone or face-to-face with safe social distancing. Data analysis was grounded in a reflexive thematic analysis approach. RESULTS: Daily life rhythms were disrupted by lockdowns by preventing participants from performing ordinary daily activities such as going to work, socialising, eating out or exercising. For some, this challenged their TRE engagement, while most were able to undertake the TRE eating window but reported increased snacking and consumption of take-away food within their eating window. For all, exercise habits became unhealthier. The negative impact on TRE engagement primarily occurred during daytime, as social distancing made it easier to engage with TRE during evenings. CONCLUSIONS: This study showed that even people highly motivated to obtain healthier lifestyles practices struggled to maintain engagement with healthy behaviours, whereas sticking to the TRE window was manageable during COVID-19. TRE as a weight loss strategy was challenged which calls for more attention to supporting people in daily life to obtain healthier practices, also in case of periods of other disruptions such as divorce, serious illness etc.

What happens after a weight loss intervention? A qualitative study of drivers and challenges of maintaining time-restricted eating among people with overweight at high risk of type 2 diabetes.

Time-restricted eating (TRE)1 has been conceptualised as a strategy for achieving weight loss and improving metabolic health, but limited knowledge exists about how people can maintain TRE in daily life. This study examined how TRE was maintainable in daily life after a three-month intervention (the RESET study) in which participants were encouraged to consume all food and beverages except water within a 10-h daily window. Specifically, we examined TRE maintenance patterns across participants, including drivers and challenges for maintenance success. A qualitative longitudinal study was conducted, and twenty participants with overweight at high risk of type 2 diabetes were interviewed using a semi-structured interview guide at the end of the intervention and after a three-month follow-up period. Data were analysed longitudinally in two steps inspired by a pattern-oriented longitudinal analysis approach. Seven participants maintained a strict 10-h window, ten maintained an adjusted TRE regimen (e.g., taking days off), and three did not attempt maintenance. Maintenance drivers included consistent daily rhythms and regular meal patterns, subjective experiences (e.g., feeling healthier), making flexible adjustments to the TRE regimen, family support and avoiding feelings of guilt. Maintenance challenges included social evening events, inconsistent daily rhythms and eating patterns, preoccupation with losing weight, lack of family support and self-blame. TRE was manageable for most participants; however, personalised support for adjusting TRE to daily life is needed to ensure long-term maintenance. Future studies should explore the effectiveness of a personalised TRE concept to determine the usefulness of TRE in real-life settings.

The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial.

AIMS/HYPOTHESIS: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. METHODS: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30-70 years of age, and prediabetes (HbA1c 39-47 mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). RESULTS: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). CONCLUSIONS/INTERPRETATION: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. TRIAL REGISTRATION: ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

No effects of dapagliflozin, metformin or exercise on plasma glucagon concentrations in individuals with prediabetes: A post hoc analysis from the randomized controlled PRE-D trial.

AIM: To assess the effects of dapagliflozin, metformin and exercise treatment on changes in plasma glucagon concentrations in individuals with overweight and HbA1c-defined prediabetes. MATERIALS AND METHODS: One-hundred and twenty individuals with overweight (body mass index ≥ 25 kg/m2 ) and prediabetes (HbA1c of 39-47 mmol/mol) were randomized to a 13-week intervention with dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 minutes of interval training 5 days per week) or control (habitual living). A 75-g oral glucose tolerance test (OGTT) (0, 30, 60 and 120 minutes) was administered at baseline, at 13 weeks (end of intervention) and at 26 weeks (end of follow-up). Linear mixed effects models with participant-specific random intercepts were used to investigate associations of the interventions with fasting plasma glucagon concentration, insulin/glucagon ratio and glucagon suppression during the OGTT. RESULTS: At baseline, the median (Q1; Q3) age was 62 (54; 68) years, median fasting plasma glucagon concentration was 11 (7; 15) pmol/L, mean (SD) HbA1c was 40.9 (2.3) mmol/mol and 56% were women. Compared with the control group, fasting glucagon did not change in any of the groups from baseline to the end of the intervention (dapagliflozin group: -5% [95% CI: -29; 26]; exercise group: -8% [95% CI: -31; 24]; metformin group: -2% [95% CI: -27; 30]). Likewise, there were no differences in insulin/glucagon ratio and glucagon suppression during the OGTT between the groups. CONCLUSIONS: In individuals with prediabetes, 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in fasting or post-OGTT glucagon concentrations.

Watching, keeping and squeezing time to lose weight: Implications of time-restricted eating in daily life.

Time-restricted eating (TRE) is a novel intervention that allows eating and drinking within a certain time window and has shown positive effects on body weight in few studies. Weight loss strategies that easily can be integrated into daily life are needed, but knowledge about how TRE affects daily life is lacking. This study examined how individuals having overweight or obesity at high risk of type 2 diabetes performed TRE in daily life, with a focus on how the timing of eating changed the organisation and rhythms of daily activities. Semi-structured interviews were conducted with participants enrolled in a randomised controlled trial studying the effect of a 12-week TRE intervention focusing on a self-selected daily 10-h window between 6 AM and 8 PM. Seventeen participants from the intervention group were interviewed at baseline and end of intervention, and data were analysed using a thematic analysis approach. Participants found TRE simple and appealing due to the unrestricted dietary intake. In general, participants did not change their food preferences and continued to eat three main daily meals. However, participants had to increase their awareness of the time of day, reshuffle ordinary daily activities and plan their intake more carefully. Two participants reported fully adherence every day, whereas all other participants reported one to several episodes of intake outside their window during the 12 weeks. Social evening activities and collective rhythms were largest barriers. Our findings suggest that TRE interventions would benefit from a broader perspective on daily life and an expanded view on families and friends as joint units of intervention. TRE interventions should consider individuals' daily rhythms and help them develop practical solutions to integrating new eating practices.

Reversion from prediabetes to normoglycaemia and risk of cardiovascular disease and mortality: the Whitehall II cohort study.

AIMS/HYPOTHESIS: Reversion from prediabetes to normoglycaemia is accompanied by an improvement in cardiovascular risk factors, but it is unclear whether this translates into a reduction in risk of cardiovascular disease (CVD) events or death. Hence, we studied the probability of reversion from prediabetes to normoglycaemia and the associated risk of future CVD and death using data from the Whitehall II observational cohort study. METHODS: Three glycaemic criteria for prediabetes (fasting plasma glucose [FPG] 5.6-6.9 mmol/l, 2 h plasma glucose [2hPG] 7.8-11.0 mmol/l, and HbA1c 39-47 mmol/mol [5.7-6.4%]) were assessed in 2002-2004 and 2007-2009 for 5193 participants free of known diabetes at enrolment. Among participants with prediabetes in the first examination, we calculated the probability of reversion to normoglycaemia by re-examination according to each glycaemic criterion. Poisson regression analysis was used to estimate and compare incidence rates of a composite endpoint of a CVD event or death in participants with prediabetes who did vs did not revert to normoglycaemia. Analyses were adjusted for age, sex, ethnicity and previous CVD. RESULTS: Based on the FPG criterion, 820 participants had prediabetes and 365 (45%) of them had reverted to normoglycaemia in 5 years. The corresponding numbers were 324 and 120 (37%) for the 2hPG criterion and 1709 and 297 (17%) for the HbA1c criterion. During a median follow-up of 6.7 (interquartile range 6.3-7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Reverting from 2hPG-defined prediabetes to normoglycaemia vs remaining prediabetic or progressing to diabetes was associated with a halving in event rate (12.7 vs 29.1 per 1000 person-years, p = 0.020). No association with event rate was observed for reverting from FPG-defined (18.6 vs 18.2 per 1000 person-years, p = 0.910) or HbA1c-defined prediabetes to normoglycaemia (24.5 vs 22.9 per 1000 person-years, p = 0.962). CONCLUSIONS/INTERPRETATION: Most people with HbA1c-defined prediabetes remained prediabetic or progressed to diabetes during 5 years of follow-up. In contrast, reversion to normoglycaemia was frequent among people with FPG- or 2hPG-defined prediabetes. Only reversion from 2hPG-defined prediabetes to normoglycaemia was associated with a reduction in future risk of CVD and death.

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures.

BACKGROUND AND AIM: Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. METHODS: This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. RESULTS: A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg). CONCLUSION: Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.

Glucose patterns during an oral glucose tolerance test and associations with future diabetes, cardiovascular disease and all-cause mortality rate.

AIMS/HYPOTHESIS: In addition to blood glucose concentrations measured in the fasting state and 2 h after an OGTT, intermediate measures during an OGTT may provide additional information regarding a person's risk of future diabetes and cardiovascular disease (CVD). First, we aimed to characterise heterogeneity of glycaemic patterns based on three time points during an OGTT. Second, we compared the incidences of diabetes and CVD and all-cause mortality rates among those with different patterns. METHODS: Our cohort study included 5861 participants without diabetes at baseline from the Danish Inter99 study. At baseline, all participants underwent an OGTT with measurements of plasma glucose levels at 0, 30 and 120 min. Latent class mixed-effects models were fitted to identify distinct patterns of glycaemic response during the OGTT. Information regarding incident diabetes, CVD and all-cause mortality rates during a median follow-up time of 11, 12 and 13 years, respectively, was extracted from national registers. Cox proportional hazard models with adjustment for several cardiometabolic risk factors were used to compare the risk of diabetes, CVD and all-cause mortality among individuals in the different latent classes. RESULTS: Four distinct glucose patterns during the OGTT were identified. One pattern was characterised by high 30 min but low 2 h glucose values. Participants with this pattern had an increased risk of developing diabetes compared with participants with lower 30 min and 2 h glucose levels (HR 4.1 [95% CI 2.2, 7.6]) and participants with higher 2 h but lower 30 min glucose levels (HR 1.5 [95% CI 1.0, 2.2]). Furthermore, the all-cause mortality rate differed between the groups with significantly higher rates in the two groups with elevated 30 min glucose. Only small non-significant differences in risk of future CVD were observed across latent classes after confounder adjustment. CONCLUSIONS/INTERPRETATION: Elevated 30 min glucose is associated with increased risk of diabetes and all-cause mortality rate independent of fasting and 2 h glucose levels. Therefore, subgroups at high risk may not be revealed when considering only fasting and 2 h glucose levels during an OGTT.