J.-F. Brun

Low intensity endurance exercise targeted for lipid oxidation improves body composition and insulin sensitivity in patients with the metabolic syndrome

BACKGROUND To investigate the effects of individualized training on the metabolic syndrome. METHODS Twenty-eight patients, suffering from the metabolic syndrome were studied before and after 2 months of training and compared to eleven patients who did not follow any training. All the patients were overweight. Training was individualized at the point where fat oxidation was maximal (LIPOX(max)) as determined by calorimetry. RESULTS The patients exhibited a significant reduction in body weight (- 2.6 +/- 0.7 kg; P=0.002), fat mass (- 1.55 +/- 0.5 kg; P=0.009), waist (- 3.53 +/- 1.3 cm; P<0.05) and hip (- 2.21 +/- 0.9 cm; P<0.05) circumferences, and improved the ability to oxidize lipids at exercise (crossover point: + 31.7 +/- 5.8 W; P<0.0001; LIPOX(max): + 23.5 +/- 5.6 W; P<0.0001; lipid oxidation: + 68.5 +/- 15.4 mg.min(-1); P=0.0001). No clear improvement in either lipid parameters or fibrinogen were observed. The surrogates of insulin sensitivity evidenced a decrease in insulin resistance: HOMA%S (software): + 72.93 +/- 32.64; p<0.05; HOMA-IR (simplified formula): - 2.42 +/- 1.07; P<0.05; QUICKI: + 0.02 +/- 0.004; P<0.01; SI=40/I: + 3.28 +/- 1.5; P<0.05. Significant correlations were found between changes in body weight and HOMA-IR and between changes in LIPOX(max) and QUICKI. CONCLUSIONS Individualized aerobic training improves lipid oxidation, body composition and insulin resistance.

Effects of a two-month rehabilitation program on substrate utilization during exercise in obese adolescents

BACKGROUND We assessed the impact of an exercise and diet program for two weeks in a specialized institute and six weeks at home on body composition and exercise metabolism in obese adolescents. METHODS Fourteen obese adolescents took part in the two-week training course and seven continued exercise and diet at home. The substrate crossover point and the maximal fat oxidation point (Lipox max) were determined before and after the program, using indirect calorimetry. Individualized exercise training at Lipox max was programmed over the two months. RESULTS At the end of the two-week program, all adolescents showed a decrease in weight (p<0.001). Only the seven subjects who continued exercise training at home showed improved exercise fat use (increased crossover point of 17% +/- 3 (p<0.005) and Lipox max of 12.5% +/- 1.5 (p<0.005)). CONCLUSION The teenagers who had performed this targeted regular training for two months exhibit an increase in their ability to oxidize lipids at exercise. This increase is no longer found in those treated by diet alone. The efficiency of this targeted training protocol based on calorimetry for the treatment of teenager obesity will require longer studies on greater samples of subjects.

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Aims/hypothesisIntramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied.MethodsMuscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were measured in muscle tissue. Lipid accumulation in muscle and primary myotubes was estimated by Oil Red O staining and fatty acid translocase (FAT)/CD36 localisation by immunofluorescence.ResultsObesity and type 2 diabetes are independently characterised by skeletal muscle IMCL accumulation and permanent FAT/CD36 relocation. Mitochondrial function is not reduced in type 2 diabetes. IMCL accumulation was independent of type 2 diabetes in cultured myotubes and was correlated with obesity markers of the donor. In obese participants, membrane relocation of FAT/CD36 is a determinant of IMCL accumulation.Conclusions/interpretationIn skeletal muscle, mitochondrial function is normal in type 2 diabetes, while IMCL accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

Grape Polyphenols Prevent Fructose- Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients

OBJECTIVE To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk. RESEARCH DESIGN AND METHODS Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR. RESULTS In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs. CONCLUSIONS A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.

Training-induced improvement in lipid oxidation in type 2 diabetes mellitus is related to alterations in muscle mitochondrial activity. Effect of endurance training in type 2 diabetes

AIM We investigated whether or not, in type 2 diabetic (T2D) patients, an individualized training effect on whole-body lipid oxidation would be associated with changes in muscle oxidative capacity. METHODS Eleven T2D patients participated in the study. Whole-body lipid oxidation during exercise was assessed by indirect calorimetry during graded exercise. Blood samples for measuring blood glucose and free fatty acids during exercise, and muscle oxidative capacity measured from skeletal muscle biopsy (mitochondrial respiration and citrate synthase activity), were investigated in the patients before and after a 10-week individualized training program targeted at LIPOXmax, corresponding to the power at which the highest rate of lipids is oxidized (lipid oxidation at LIPOXmax). RESULTS Training induced both a shift to a higher-power intensity of LIPOXmax (+9.1+/-4.2W; P<0.05) and an improvement of lipid oxidation at LIPOXmax (+51.27+/-17.93 mg min(-1); P<0.05). The improvement in lipid oxidation was correlated with training-induced improvement in mitochondrial respiration (r=0.78; P<0.01) and citrate synthase activity (r=0.63; P<0.05). CONCLUSION This study shows that a moderate training protocol targeted at the LIPOXmax in T2D patients improves their ability to oxidize lipids during exercise, and that this improvement is associated with enhanced muscle oxidative capacity.

Substrate oxidation during exercise: type 2 diabetes is associated with a decrease in lipid oxidation and an earlier shift towards carbohydrate utilization

OBJECTIVES Exercise is a recommended treatment for type 2 diabetes but the actual pattern of metabolic adaptation to exercise in this disease is poorly known and not taken in account in the protocols used. Metabolic defects involved in the pathways of substrate oxidation were described in type 2 diabetes. We hypothesized that type 2 diabetes, regardless of age, gender, training status and weight, could influence by its own the balance of substrates at exercise. METHODS 30 sedentary type 2 diabetic subjects and 38 sedentary matched control subjects were recruited. We used exercise calorimetry to determine lipid and carbohydrate oxidation rates. We calculated two parameters quantifying the balance of substrates induced by increasing exercise intensity: the maximal lipid oxidation point (PLipoxMax) and the Crossover point (COP), intensity from which the part of carbohydrate utilization providing energy becomes predominant on lipid oxidation. RESULTS Lipid oxidation was lower in the diabetic group, independent of exercise intensity. PLipoxMax and COP were lower in the diabetic group [PLipoxMax=25.3+/-1.4% vs. 36.6+/-1.7% %Wmax (P<0.0001)] - COP =24.2+/-2.2% vs. 38.8+/-1.9% %Wmax (P<0.0001). CONCLUSIONS Type 2 diabetes is associated with a decrease in lipid oxidation at exercise and a shift towards a predominance of carbohydrate oxidation for exercise intensities lower than in control subjects. Taking into account these alterations could provide a basis for personalizing training intensity.

Cost-sparing effect of twice-weekly targeted endurance training in type 2 diabetics: A one-year controlled randomized trial

OBJECTIVE We evaluated the effects of targeted, moderate endurance training on healthcare cost, body composition and fitness in type 2 diabetes patients routinely followed within the French healthcare system. DESIGN AND METHODS A total of 25 type 2 diabetic patients was randomly assigned to one of two groups: 13 underwent a training programme (eight sessions, followed by training twice a week for 30-45 minutes at home at the level of the ventilatory threshold [V(T)]); and 12 received their usual routine treatment. Both groups were followed for one year to evaluate healthcare costs, exercise effectiveness and a six-minute walking test. RESULTS The training prevented loss of maximum aerobic capacity, which decreased slightly in the untrained group (P=0.014), and resulted in a higher maximum power output (P=0.041) and six-minute walking distance (P=0.020). The Voorrips activity score correlated with both V(O2max) (r=0.422, P<0.05) and six-minute walking distance (r=0.446, P<0.05). Changes in V(O2max) were negatively correlated with changes in body weight (r=0.608, P<0.01). Training decreased the insulin-resistance index (HOMA-IR) by 26% (P<0.05). Changes in percentages of fat were correlated to changes in waist circumference (r=0.436, P<0.05). The total healthcare cost was reduced by 50% in the trained group (euro 1.65+/-1 per day versus euro 3.00+/-1.47 per day in the untrained group; P<0.02) due to fewer hospitalizations (P=0.05) and less use of sulphonylureas (P<0.05). CONCLUSION Endurance training at V(T) level prevented the decline in aerobic working capacity seen in untrained diabetics over the study period, and resulted in a marked reduction in healthcare costs due to less treatments and fewer hospitalizations.

Lower limb vein enlargement and spontaneous blood flow echogenicity are normal sonographic findings during pregnancy.

We studied pregnancy‐induced changes in lower limb venous function.

Accuracy of continuous subcutaneous glucose monitoring with the GlucoDay® in type 1 diabetic patients treated by subcutaneous insulin infusion during exercise of low versus high intensity

AIM The GlucoDay allows continuous glucose monitoring by subcutaneous microdialysis in sedentary conditions. To validate it when glycaemia may undergo rapid and dramatic changes, we investigated its accuracy during two exercise sessions with markedly different glucose disposal rates. METHODS Nine male diabetic patients, aged 32-61, treated by insulin pumps, first underwent a standard maximal exercise-test designed for determining the maximal oxygen consumption and the first ventilatory threshold (Vt1). Then two 30 min steady-state workloads at 15% below and 15% above the Vt1 were performed in random order with the GlucoDay, and measurement of CHO oxidation rates was made by indirect calorimetry. RESULTS CHO oxidation during exercise at +15% Vt1 was higher (+943.5 mg/min, ie +45.5%, P<0.01) than during exercise at -15% Vt1 No hypoglycaemia occurred. Due to breakages of 39% of subcutaneous probes, eleven steady-state sessions in 7 subjects allowed to compare 141 paired glucose (sensor vs. venous) determinations. The Clarke error grid situates 92.9% of glucose values within the A zone and 6.4% within the B zone, while only one pair of values (0.7%) falls in the D zone. Venous glucose tended to decrease more rapidly than sensor glucose during exercise. Bland-Altman plots evidence for a few cases of underestimation of venous glucose at high intensity. CONCLUSIONS This study showed satisfactory accuracy of the GlucoDay during exercise. A slight lag time in sensor values likely explains a few discrepancies that do not appear as clinically meaningful. Reduction of probe fragility and confirmed sensor accuracy in hypoglycaemia would further support applicability of GlucoDay at exercise.

Evaluation of a standardized hyperglucidic breakfast test in postprandial reactive hypoglycaemia

SummaryThe oral glucose tolerance test is not specific for diagnosing postprandial reactive hypoglycaemia, since it too frequently induces low blood glucose values in subjects who have never complained of symptoms of this. By contrast, the mixed meal tests are deceptive for this purpose because they do not induce hypoglycaemia in subjects who have complained of of hypoglycaemic symptoms. We investigated the frequency of hypoglycaemia after a standardized hyperglucidic breakfast test in three groups of subjects:group A, 43 control subjects; group B, 38 postprandial reactive hypoglycaemic patients; group C, 1193 asymptomatic subjects undergoing assessment of glycoregulation. In the 38 subjects with suspected reactive hypoglycaemia the mean blood glucose nadir was 3.48±0.08 mmol/l, i. e. lower than in control subjects (4.83±0.13 p<0.0001). Blood glucose levels less than 3.3 mmol/l were found in 47.3% of subjects with suspected postprandial reactive hypoglycaemia (group B), i.e more frequently than in control subjects (group A: 2.2% p=1.6×10−6) and asymptomatic subjects (group C: 1% p=8× 10−22). This markedly higher frequency of low blood glucose values in subjects with postprandial symptoms compared with control and asymptomatic subjects suggests that this test detects a tendency to hypoglycaemia after a standardized hyperglucidic breakfast. Since this test mimics average French eating habits, the results suggest that the patients undergo such symptoms in their everyday life, and that the hyperglucidic breakfast test is a simple alternative to ambulatory glucose sampling for diagnosis of postprandial reactive hypoglycaemia.