Jean-Luc Ardilouze

Effects of aerobic physical exercise in the elderly with type 2 diabetes mellitus

The objective of this study was to determine the impact of an aerobic physical exercise program in the treatment of a group of elderly patients with type 2 diabetes mellitus (DM) in relation to metabolic control, physical capacity, quality of life (QOL) and attitudes toward diabetes. Patients were randomly assigned to either an experimental (n=19) or a control (n=20) group. The following measurements were conducted at baseline and after week 16: glycosylated hemoglobin (hbA1c), fructosamine, 3 h oral glucose tolerance test, treadmill test (Balke-Naughton), and a questionnaire on QOL and attitudes toward DM. After the intervention, the experimental group showed a significant decrease of glucose excursion during the oral glucose tolerance test (OGTT) (area under the curve) (16.6+/-3.8 vs. 15.3+/-3.1, P<0.05) and an increase in total time on the treadmill (s) (423+/-207 vs. 471+/-230, P<0.05). An improvement in the attitudes toward DM was observed in the experimental group (P=0.01) but not in the control group. Female gender, higher body mass index and hbA1c were factors associated with a response to the intervention. This study suggests that physical exercise has significant effects on glucose excursion during an OGTT and exercise tolerance in elderly patients with type 2 DM.

Reproducibility of the 6-minute walk test in obese adults.

The six-minute walk test (6MWT) is an inexpensive, quick and safe tool to evaluate the functional capacity of patients with heart failure and chronic obstructive pulmonary disease. The aim of this study was to determine the reproducibility of the 6MWT in overweight and obese individuals. We thus undertook a prospective repeated-measure validity study taking place in our academic weight management outpatient clinic. The 6MWT was conducted twice the same day in 21 overweight or obese adult subjects (15 females and 6 males). Repeatability of walking distance was the primary outcome. Anthropometric measures, blood pressure and heart rate were also recorded. Participants mean BMI was 37.2+/-9.8 kg/m(2) (range: 27.0-62.3 kg/m(2)). Walking distance in the morning (mean=452+/-90 m) and in the afternoon (mean=458+/-97 m) were highly correlated (r=0.948; 95% Confidence Interval 0.877-0.978; p<0.001). Walking distance was negatively correlated with BMI (r=-0.47, p=0.03), waist circumference (r=-0.43, p=0.05) and pre-test heart rate (r=-0.54, p=0.01). Our findings indicate that the 6MWT is highly reproducible in obese subjects and could thus be used as a fitness indicator in clinical studies and clinical care in this population.

Effects of insulin on adipose tissue blood flow in man

Adipose tissue blood flow (ATBF) rises after nutrient ingestion. It is not clear whether this is due to insulin. The aim of this study was to investigate the role of insulin in the regulation of subcutaneous ATBF. We have investigated the role of insulin in the regulation of ATBF in normal, healthy subjects in a three‐step procedure to determine the functional level at which insulin may potentially exert its effect. Fifteen subjects were studied on two occasions. On the first visit, 75 g oral glucose was given. In the second, similar plasma concentrations of insulin and glucose were achieved by dynamic intravenous infusions of insulin and glucose. The increase in ATBF after oral glucose (4.2 ± 1.4 ml min−1 (100 g tissue)−1, P= 0.01) was significantly greater (P < 0.05) than that after intravenous infusions (1.5 ± 0.6 ml min−1 (100 g tissue)−1P < 0.05). For the local delivery of potentially vasoactive substances and simultaneous measurement of ATBF, we describe a novel combination of methods, which we have called ‘microinfusion’. We have used this technique to show that locally infused insulin, even at pharmacological concentrations, had no demonstrable effect on ATBF in nine subjects. We conclude that whilst insulin does not have a direct effect on ATBF, it is likely to be an important mediator, possibly acting via sympathetic activation. In the postprandial state, other candidate peptides and hormones are also likely to play important roles.

Lower Adiponectin Levels at First Trimester of Pregnancy Are Associated With Increased Insulin Resistance and Higher Risk of Developing Gestational Diabetes Mellitus

OBJECTIVE To evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women. RESEARCH DESIGN AND METHODS We performed anthropometric measurements and collected blood samples at 1st (6–13 weeks) and 2nd (24–28 weeks) trimesters. Diagnosis of GDM was made at 2nd trimester based on a 75-g oral glucose tolerance test (International Association of the Diabetes and Pregnancy Study Groups criteria). Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCinsulin/glucose), and β-cell compensation (insulin secretion sensitivity index-2). Adiponectin was measured by radioimmunoassay. RESULTS Among the 445 participants included in this study, 38 women developed GDM. Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance). Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA1c at 1st trimester). Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = −0.22, P < 0.0001) and Matsuda index (r = 0.28, P < 0.0001, and r = 0.29, P < 0.0001). After adjustment for confounding factors, we found no significant association with HOMA-B and AUCinsulin/glucose. CONCLUSIONS Pregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements.

Efficacy of intensive multitherapy for patients with type 2 diabetes mellitus: a randomized controlled trial

Background: National guidelines for managing diabetes set standards for care. We sought to determine whether a 1-year intensive multitherapy program resulted in greater goal attainment than usual care among patients with poorly controlled type 2 diabetes mellitus. Methods: We identified patients with poorly controlled type 2 diabetes receiving outpatient care in the community or at our hospital. Patients 30–70 years of age with a hemoglobin A1c concentration of 8% or greater were randomly assigned to receive intensive multitherapy (n = 36) or usual care (n = 36). Results: The average hemoglobin A1c concentration at entry was 9.1% (standard deviation [SD] 1%) in the intensive therapy group and 9.3% (SD 1%) in the usual therapy group. By 12 months, a higher proportion of patients in the intensive therapy group than in the control group had achieved Canadian Diabetes Association (CDA) goals for hemoglobin A1c concentrations (goal ≤ 7.0%: 35% v. 8%), diastolic blood pressure (goal < 80 mm Hg: 64% v. 37%), low-density lipoprotein cholesterol (LDL-C) levels (goal < 2.5 mmol/L: 53% v. 20%) and triglyceride levels (goal < 1.5 mmol/L: 44% v. 14%). There were no significant differences between the 2 groups in attaining the targets for fasting plasma glucose levels, systolic blood pressure or total cholesterol:high-density lipoprotein cholesterol ratio. None of the patients reached all CDA treatment goals. By 18 months, differences in goal attainment were no longer evident between the 2 groups, except for LDL-C levels. Quality of life, as measured by a specific questionnaire, increased in both groups, with a greater increase in the intensive therapy group (13% [SD 10%] v. 6% [SD 13%], p < 0.003). Interpretation: Intensive multitherapy for patients with poorly controlled type 2 diabetes is successful in helping patients meet most of the goals set by a national diabetes association. However, 6 months after intensive therapy stopped and patients returned to usual care, the benefits had vanished.

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10−11; N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (β = −0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = −0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Dose-Dependent Delay of the Hypoglycemic Effect of Short-Acting Insulin Analogs in Obese Subjects With Type 2 Diabetes A pharmacokinetic and pharmacodynamic study

OBJECTIVE Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Euglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m2) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the 133Xe-washout technique. RESULTS ATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (Tmax) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (Cmax)/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIRmax: 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, Tmax (88.6 and 130.0 min, respectively) and time to GIRmax (175 and 245 min) were further delayed and dose related (r2 = 0.51, P = 0.0004 and r2 = 0.76, P < 0.0001, respectively). CONCLUSIONS Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes.

Short- and long-term effects of continuous versus intermittent restrictive diet approaches on body composition and the metabolic profile in overweight and obese postmenopausal women: a pilot study

ObjectiveThe objective of this study was to compare changes in body composition and the metabolic profile between women taking an intermittent diet (ID) and women taking a continuous diet (CD). MethodsTwenty-five obese postmenopausal women were randomized to an ID (n = 13) or a CD (n = 12). In the ID, 5-week energy restriction periods were followed by 5-week weight stabilization periods. In the CD, 15 weeks of energy restriction was followed by 5 weeks of weight stabilization. Outcome measures before, during, and after weight loss, as well as after a 1-year follow-up, were body weight and composition, waist circumference, resting metabolic rate, and fasting lipid and glucose levels. ResultsBody weight, waist circumference, percentage fat mass, and fat mass decreased significantly and similarly in both groups (P < 0.0001). Both groups showed similar overall decreases in plasma total cholesterol and triglycerides (all P < 0.05). Low-density lipoprotein cholesterol improved significantly in the CD group only, whereas fasting glucose decreased significantly in the ID group only. High-density lipoprotein cholesterol and resting metabolic rate remained stable in both groups. Fasting plasma triglyceride and glucose levels were the only metabolic variables to further improve after the fifth week of the protocol. At the 1-year follow-up, both interventions were associated with successful and similar weight loss maintenance and improvements in fasting plasma glucose levels. ConclusionsThe ID resulted in similar short- and long-term changes in body composition and metabolic profile compared with a CD. Most improvements occurred during the first 5 weeks of treatment in both interventions.

Subcutaneous adipose tissue blood flow varies between superior and inferior levels of the anterior abdominal wall

OBJECTIVE: Blood flow regulation is thought to mediate the metabolic functions of adipose tissue. Different depots, and even different layers within the subcutaneous adipose tissue, may vary in metabolic activity and blood flow. Therefore, we investigated if any differences in subcutaneous adipose tissue blood flow (ATBF) exist at different locations of the anterior abdominal wall.METHODS: ATBF was measured 8–10 cm above or below the umbilicus, at 8–10 cm (both sides) from the midline, in 18 healthy subjects (BMI range 18–33 kg/m2). Measurements of ATBF were performed using 133xenon washout, during a stable baseline period and after ingestion of 75 g of glucose.RESULTS: At baseline, ATBF was greater at the upper level compared to the lower level (4.4±0.3 vs 3.8±0.2 ml min−1 100 g tissue−1, P=0.005), but was not different between the right and the left sides at either level. ATBF increased in response to oral glucose at all sites. The mean increase at the superior level was also greater than the inferior level (3.5±0.7 vs 2.2±0.6 ml min−1 100 g tissue−1, P=0.001).CONCLUSIONS: Even at a constant depth and with only 16–20 cm difference between sites, there are significant differences in function of the same adipose depot. These findings have physiological and methodological implications for in vivo metabolic studies of human adipose tissue.

Update on adipose tissue blood flow regulation.

According to Ficks principle, any metabolic or hormonal exchange through a given tissue depends on the product of the blood flow to that tissue and the arteriovenous difference. The proper function of adipose tissue relies on adequate adipose tissue blood flow (ATBF), which determines the influx and efflux of metabolites as well as regulatory endocrine signals. Adequate functioning of adipose tissue in intermediary metabolism requires finely tuned perfusion. Because metabolic and vascular processes are so tightly interconnected, any disruption in one will necessarily impact the other. Although altered ATBF is one consequence of expanding fat tissue, it may also aggravate the negative impacts of obesity on the bodys metabolic milieu. This review attempts to summarize the current state of knowledge on adipose tissue vascular bed behavior under physiological conditions and the various factors that contribute to its regulation as well as the possible participation of altered ATBF in the pathophysiology of metabolic syndrome.