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.

Predicting the HbA1c level following glucose-lowering interventions in individuals with HbA1c-defined prediabetes: a post-hoc analysis from the randomized controlled PRE-D trial.

PURPOSE: To investigate whether the prediction of post-treatment HbA1c levels can be improved by adding an additional biomarker of the glucose metabolism in addition to baseline HbA1c. METHODS: We performed an exploratory analysis based on data from 112 individuals with prediabetes (HbA1c 39-47 mmol) and overweight/obesity (BMI ≥ 25 kg/m2), who completed 13 weeks of glucose-lowering interventions (exercise, dapagliflozin, or metformin) or control (habitual living) in the PRE-D trial. Seven prediction models were tested; one basic model with baseline HbA1c as the sole glucometabolic marker and six models each containing one additional glucometabolic biomarker in addition to baseline HbA1c. The additional glucometabolic biomarkers included: 1) plasma fructosamine, 2) fasting plasma glucose, 3) fasting plasma glucose × fasting serum insulin, 4) mean glucose during a 6-day free-living period measured by a continuous glucose monitor 5) mean glucose during an oral glucose tolerance test, and 6) mean plasma glucose × mean serum insulin during the oral glucose tolerance test. The primary outcome was overall goodness of fit (R2) from the internal validation step in bootstrap-based analysis using general linear models. RESULTS: The prediction models explained 46-50% of the variation (R2) in post-treatment HbA1c with standard deviations of the estimates of ~2 mmol/mol. R2 was not statistically significantly different in the models containing an additional glucometabolic biomarker when compared to the basic model. CONCLUSION: Adding an additional biomarker of the glucose metabolism did not improve the prediction of post-treatment HbA1c in individuals with HbA1c-defined prediabetes.

Discordance Between Glucose Levels Measured in Interstitial Fluid vs in Venous Plasma After Oral Glucose Administration: A Post-Hoc Analysis From the Randomised Controlled PRE-D Trial.

Aims: The oral glucose tolerance test (OGTT) is together with haemoglobin A1c (HbA1c) gold standard for diagnosing prediabetes and diabetes. The objective of this study was to assess the concordance between glucose values obtained from venous plasma versus interstitial fluid after oral glucose administration in 120 individuals with prediabetes and overweight/obesity. Methods: 120 adults with prediabetes defined by HbA1c 39-47 mmol/mol and overweight or obesity who participated in the randomised controlled PRE-D trial were included in the study. Venous plasma glucose concentrations were measured at 0, 30, 60 and 120 minutes during a 75 g oral glucose tolerance test (OGTT) performed on three different occasions within a 26 weeks period. During the OGTT, the participants wore a CGM device (IPro2, Medtronic), which assessed glucose concentrations every five minutes. Results: A total of 306 OGTTs with simultaneous CGM measurements were obtained. Except in fasting, the CGM glucose values were below the OGTT values throughout the OGTT period with mean (SD) differences of 0.2 (0.7) mmol/L at time 0 min, -1.1 (1.3) at 30 min, -1.4 (1.8) at 60 min, and -0.5 (1.1) at 120 min). For measurements at 0 and 120 min, there was a proportional bias with an increasing mean difference between CGM and OGTT values with increasing mean of the two measurements. Conclusions: Due to poor agreement between the OGTT and CGM with wide 95% limits of agreement and proportional bias at 0 and 120 min, the potential for assessing glucose tolerance in prediabetes using CGM is questionable.

Effect of exercise training on skeletal muscle protein expression in relation to insulin sensitivity: Per-protocol analysis of a randomized controlled trial (GO-ACTIWE).

Exercise training improves peripheral insulin sensitivity and leads to molecular adaptations in the skeletal muscle. We investigated changes in the expression of key muscle proteins in the glucose metabolic pathway following active commuting by bike or leisure-time exercise at two different intensities. In addition, potential associations between insulin sensitivity and muscle protein expression were examined. This per-protocol analysis included 72 out of 130 physically inactive, healthy women and men (20-45 years) with overweight/obesity (BMI: 25-35 kg/m2 ) who completed 6 months of no intervention (CON, n = 12), active commuting by bike (BIKE, n = 14), or leisure-time exercise of moderate (MOD, n = 28) or vigorous (VIG, n = 18) intensity. Exercise was prescribed 5 days/week with a weekly exercise energy expenditure of 1,600 kcal for women and 2,100 kcal for men. Insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp and skeletal muscle biopsies were obtained from m. vastus lateralis and analyzed for protein expression at baseline and after 3 and 6 months of intervention. We found an increased expression of pyruvate dehydrogenase (PDH) in the exercise groups compared with the control group following 6 months of training. No differential effects were observed on the protein expression following moderate versus vigorous intensity exercise. In addition, we found a positive association between insulin sensitivity and the expression of glucose transporter type 4 as well as PDH. The positive association and the increase in expression of PDH after exercise training points toward a role for PDH in the training-induced enhancement of insulin sensitivity.

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.

Timing and Frequency of Daily Energy Intake in Adults with Prediabetes and Overweight or Obesity and Their Associations with Body Fat.

Knowledge on how energy intake and macronutrients are distributed during the day and the role of daily eating patterns in body composition among adults with overweight/obesity and prediabetes is lacking. Therefore, we evaluated the diurnal dietary intake and studied the associations of daily eating patterns with body fat percentage. A total of 119 adults with prediabetes were included (mean (SD) HbA1c 41 (2.3) mmol/mol, BMI 31.5 (5.0) kg/m2, age 57.8 (9.3) years, 44% men). Information on dietary intake was obtained from self-reported food records for three consecutive days. All foods and beverages (except water) were registered with information on time of ingestion. Body fat was measured by dual-energy X-ray absorptiometry. A total of 60.5% of the participants reported a daily eating window of 12 or more hours/day, and almost half of the daily total energy intake was reported in the evening. In analyses adjusted for age, gender, and total daily energy intake, having the first daily energy intake one hour later was associated with slightly higher body fat percentage (0.64% per hour, 95% CI: 0.28; 1.01; p < 0.001), whereas higher meal frequency was associated with slightly lower body fat percentage (0.49% per extra daily meal, 95% CI: -0.81; -0.18; p = 0.002). Prospective studies are warranted to address the clinical implications of daily eating patterns on body fat and cardiometabolic health.

Physiological factors contributing to HbA1c in the normal and pre-diabetic range: a cross-sectional analysis.

PURPOSE: Little is known about the underlying physiology that contributes to Haemoglobin A1c (HbA1c) in the normal and pre-diabetic range. We determined the contribution of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), insulin secretion, insulin sensitivity and endogenous glucose production to HbA1c levels in the normal and pre-diabetic range. METHODS: A total of 62 Danish men and women with normal or impaired glucose regulation were studied. HbA1c levels were measured and participants underwent an oral glucose tolerance test with measurements of FPG and 2hPG, an intravenous glucose tolerance test for determination of first-phase insulin release, and a hyperinsulinaemic euglycaemic clamp for estimation of peripheral and hepatic insulin sensitivity. Associations of HbA1c with the different measures of glucose metabolism were analysed by linear regression analysis. RESULTS: HbA1c levels ranged from 28 to 45 mmol/mol (4.7-6.3%) in the study population. 1 SD higher (log) FPG concentration (~1 mmol/L) was associated with 2 mmol/mol higher HbA1c concentration (P < 0.001). In comparison, 1 SD higher levels of (log) first-phase insulin secretion or (log) disposition index were associated with 1.5 mmol/mol lower HbA1c levels (P < 0.05). HbA1c was not associated with peripheral or hepatic insulin sensitivity, endogenous glucose production or 2hPG levels. CONCLUSION: HbA1c levels within the normal and pre-diabetic range seem to reflect decreased insulin secretion to a higher extent than insulin resistance. Therefore, early prevention strategies for high-risk individuals identified by HbA1c are not straightforward. More research on how to improve the health of beta cells either directly or indirectly in high-risk individuals is needed.

Exercise-induced molecular mechanisms promoting glycogen supercompensation in human skeletal muscle.

OBJECTIVE: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man. METHODS: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control. Euglycemic hyperinsulinemic clamps in combination with leg balance technique allowed for investigating insulin-stimulated leg glucose uptake under these 3 experimental conditions. Cellular signaling in muscle biopsies was investigated by global proteomic analyses and immunoblotting. We strengthened the validity of proposed molecular effectors by follow-up studies in muscle of transgenic mice. RESULTS: Sustained activation of glycogen synthase (GS) and AMPK in combination with elevated expression of proteins determining glucose uptake capacity were evident in the prior exercised muscle. We hypothesize that these alterations offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen. In line with key roles of AMPK and GS seen in the human experiments we observed abrogated ability for glycogen supercompensation in muscle with inducible AMPK deletion and in muscle carrying a G6P-insensitive form of GS in muscle. CONCLUSION: Our study demonstrates that both AMPK and GS are key regulators of glycogen supercompensation following a single bout of glycogen-depleting exercise in skeletal muscle of both man and mouse.