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 (ß = 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 (ß = -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 (ß = -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.

Failure to increase postprandial blood flow in subcutaneous adipose tissue is associated with tissue resistance to adrenergic stimulation.

AIMS: Adequate adipose tissue blood flow (ATBF) is essential for its metabolic and endocrine functions. From a metabolic point of view, sufficient increases in ATBF after meals permits full storage of excess energy into fat, thus protecting other tissues against the toxic effects of fatty acids and glucose spillover. It was previously shown that postprandial increases in ATBF are blunted in obese and insulin-resistant subjects, and that much of the postprandial ATBF response is the result of ß-adrenergic activation. Examination of previously recorded data on postprandial ATBF responses revealed an underlying heterogeneity, with postprandial ATBF being largely unresponsive to food stimuli in a substantial proportion of normal weight healthy people (low responders). Our study tests the hypothesis that this unresponsive pattern is due to resistance to ß-adrenergic stimulation in adipose tissue. METHODS: Five responders and five low responders were selected from a previously studied cohort and matched for BMI (20.5±0.7 vs 22±1 kg/m(2), respectively), gender (male/female: 2/3) and age (30±3 vs 37±6 years). Subcutaneous adipose tissue microinfusions of stepwise increasing doses of isoproterenol were performed with concomitant monitoring of blood flow, using the (133)Xenon washout technique. RESULTS: Although BMI was similar between responders and low responders, there were significant differences in fat mass (9.9±1.6 vs 14.4±1.6 kg; P<0.05) and four-point skinfold thickness (33±4 vs 52±16 mm; P<0.05). Lack of ATBF response to oral glucose was confirmed in the low responder group. In responders, ATBF was higher at baseline (5.4±1 vs 3.4±1 mL/min/100 g of tissue) and responded more distinctly to increasing isoproterenol doses (10(-8) M: 7.6±1.4 vs 4.9±1; 10(-6) M: 12.5±1.7 vs 7.5±1.6; and 10(-4) M: 20 ±1.7 vs 9±0.9 mL/min/100 g of tissue). CONCLUSION: These data suggest that the lack of glucose-stimulated ATBF is associated with resistance to sympathetic activation in adipose tissue.

Weight gain since menopause and its associations with weight loss maintenance in obese postmenopausal women.

OBJECTIVE: To examine the association between weight gain since menopause and weight regain after a weight loss program. METHODS: Participants were 19 obese women who participated in a 15-week weight loss program and a 12-month follow-up. Main outcomes were: body composition, resting metabolic rate, energy intake, energy expenditure, and weight regain at follow-up. RESULTS: All body composition measures significantly decreased after intervention (all P ≤ 0.01) while all measures of fatness increased significantly after the 12-month follow-up (P ≤ 0.01). Body weight gain since menopause was associated with body weight regain (r = 0.65; P = 0.003) after follow-up even after adjustment for confounders. CONCLUSION: Weight gain since menopause is associated with body weight regain following the weight loss program. Therefore, weight gain since menopause should be considered as a factor influencing weight loss maintenance in older women.

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. Participant's 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.

Quality of life in type 2 diabetes patients under intensive multitherapy.

AIM: To assess the impact of an intensive multitherapy (IMT) on perceived quality of life (QOL), attitudes, knowledge and diabetes self-management in patients with poorly controlled type 2 diabetes. METHODS: A 12-month randomized trial was conducted in 72 patients with type 2 diabetes, HbA1c>or=8%, blood pressure (BP)>130/80 mmHg and dyslipidemia. Subjects were assigned to the IMT or control group, each n=36. IMT consisted in monthly visits including clinical and biochemical assessment, education sessions on diet, physical exercise, medical management of diabetes and associated diseases and adjustments in medication. Control patients were under the care of their physicians. We developed and validated a diabetes-specific questionnaire assessing QOL, attitudes, knowledge, diabetes self-management and socio-demographic data for this study. Outcomes were measured at 0, 6 and 12 months. RESULTS: Subjects were 54.8+/-8.1 years old (duration of diabetes: 10.3+/-7.2 years). At baseline, questionnaires showed no difference in QOL between groups. At 12 months, QOL improved significantly in the IMT group when compared to controls (+13.2+/-10.3/+5.6+/-13.2%, P=0.003), particularly with respect to the satisfaction scale (+25.3+/-13.9/+5.4+/-21.7%, P<0.001). QOL was not affected by complications or hypoglycaemic episodes. QOL scores improved in IMT subjects who began insulin therapy during the trial. Attitude scores, in the high normal range at baseline, did not change. Knowledge (+18.2+/-26.3/+8.9+/-30.4%, P=0.047) and diabetes self-management (+22.6+/-35.3/+6.8+/-20.1%, P<0.001) improved. CONCLUSIONS: In poorly controlled subjects, QOL improved statistically despite the inherent constraints imposed by IMT.

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/m(2)). Measurements of ATBF were performed using (133)xenon 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.

Evaluation of postural stability in elderly with diabetic neuropathy.

OBJECTIVE: The objective of this study was to compare clinical and biomechanical characteristics of balance in diabetic polyneuropathic elderly patients and normal age-matched subjects. RESEARCH DESIGN AND METHODS: Fifteen elderly with distal neuropathy (DNP) and 15 healthy age-matched subjects were evaluated with the biomechanical variable COP-COM, which represents the distance between the center of pressure (COP) and the center of mass (COM). Measurements were taken in the quiet position with a double-leg stance, in eyes-open (EO) and eyes-closed (EC) conditions. Subjects were also assessed with clinical balance evaluations. RESULTS: The COP-COM variable was statistically significantly larger in the DNP group than in the healthy group in anterior-posterior (A/P) and medial-lateral (M/L) directions. Furthermore, the DNP group showed statistically significantly larger amplitudes of the COP-COM variable without vision. The severity of the neuropathy, as quantified using the Valk scoring system, was correlated with COP-COM amplitude in both directions. CONCLUSIONS: Evaluation of the postural stability of an elderly diabetic population using the COP-COM variable can detect a very small change in postural stability and could be helpful in identifying elderly with DNP at risk of falling.

The degree of hyperinsulinemia and impaired glucose tolerance predicts plasma leptin concentrations in women only: a new exploratory paradigm.

Plasma leptin has been shown to correlate positively with many indices of obesity, as well as insulin resistance. For a given body weight, the levels are higher in women than in men, but the reasons for this difference are not clear. Insulin has been shown to stimulate leptin production by adipose tissue in vivo and in vitro. Previous studies have reported that leptin levels are similar in diabetic and nondiabetic individuals. However, these studies were not performed in newly diagnosed diabetics, and other variables (such as gender) could have confounded the results. Therefore, the goal of the present cross-sectional study is to examine the effect of metabolic variables (such as glucose and insulin) on plasma leptin concentrations in men and women separately. We measured leptin levels in 48 subjects (17 with newly diagnosed type 2 diabetes mellitus, 13 with impaired glucose tolerance [IGT], and 18 normal individuals). The 3 groups were well matched for gender, age, and body mass index (BMI). When adjusted for the BMI and gender, a statistically significant gender-related difference in mean plasma leptin was observed across the 3 glucose tolerance subgroups (P < .03 by analysis of covariance [ANCOVA]). More specifically, plasma leptin levels were, on average, 44% lower in women with diabetes or IGT versus normal women (P < .02). No such between-group difference was observed in the men. In univariate analysis in the same female subgroup, plasma leptin correlated positively with fasting insulin (rs = +.43, P < .06) and negatively with 2-hour post-75-g glucose load plasma glucose concentration (rs = -.54, P < .02). In a multiple regression model controlling for the BMI in the female subgroup, circulating insulin and glucose concentrations 2 hours after the 75-g glucose load were good predictors of fasting plasma leptin (r = +.38, P = .02 and r = -.70, P < .001, respectively). Leptin levels in women appear to be influenced independently and to an important degree by ambient plasma glucose and plasma insulin concentrations. These findings suggest that the synthesis of leptin by adipose tissue is more susceptible to in vivo regulation by insulin and glucose in women than in men. Plasma leptin concentrations were also lower in women with IGT or type 2 diabetes versus normal women, suggesting that fasting and/or postprandial hyperglycemia interferes with the stimulatory effect of plasma insulin on the synthesis of leptin by adipose tissue in women only.

[Abnormal response of growth hormone to oral glucose tolerance test in obesity]. / Réponse anormale de l'hormone de croissance au cours de l'hyperglycémie provoquée orale chez le sujet obèse.

In obesity, it is well known that basal growth hormone (GH) levels can be suppressed and they may show an impaired response to various stimuli like hypoglycemia, stress, and GHRH. However, the inhibitory effect of hyperglycemia on GH in this condition has not been well studied. We analyzed the GH response to an oral glucose tolerance test (OGTT) in 25 unselected patients with morbid obesity who were not diabetic, glucose intolerant or affected by renal or hepatic disease. Ten (40%) of the 25 subjects had an abnormal response of GH to the OGTT, expressed by a lack of suppression of GH levels below 2 micrograms/L within 60 minutes of glucose administration. Three subjects even had a paradoxal increase of GH levels of more than 50% of the basal level. There was no significant difference between these subjects regarding their age, BMI and, serum levels of glucose, insulin, C peptide, or insulin/glucose ratio. After weight loss, three of four patients normalized their GH response. Thus, we conclude that patients with morbid obesity frequently have an abnormal response of GH to OGTT (40% vs 4-8% in normal subjects). This finding must be taken into consideration when interpreting GH levels in these patients. A normalization of this response can be expected after weight loss.

Blockade of insulin sensitive steady-state R-type Ca2+ channel by PN 200-110 in heart and vascular smooth muscle.

The effect of high K+ concentration, insulin and the L-type Ca2+ channel blocker PN 200-110 on cytosolic intracellular free calcium ([Ca2+]i) was studied in single ventricular myocytes of 10-day-old embryonic chick heart, 20-week-old human fetus and rabbit aorta (VSM) single cells using the Ca(2+)-sensitive fluorescent dye, Fura-2 microfluorometry and digital imaging technique. Depolarization of the cell membrane of both heart and VSM cells with continuous superfusion of 30 mM [K+]o induced a rapid transient increase of [Ca2+]i that was followed by a sustained component. The early transient increase of [Ca2+]i by high [K+]o was blocked by the L-type calcium channel antagonist nifedipine. However, the sustained component was found to be insensitive to this drug. PN 200-110 another L-type Ca2+ blocker was found to decrease both the early transient and the sustained increase of [Ca2+]i induced by depolarization of the cell membrane with high [K+]o. Insulin at a concentration of 40 to 80 microU/ml only produced a sustained increase of [Ca2+]i that was blocked by PN 200-110 or by lowering the extracellular Ca2+ concentration with EGTA. The sustained increase of [Ca2+]i induced by high [K+]o or insulin was insensitive to metabolic inhibitors such as KCN and ouabain as well to the fast Na+ channel blocker, tetrodotoxin and to the increase of intracellular concentrations of cyclic nucleotides. Using the patch clamp technique, insulin did not affect the L-type Ca2+ current and the delayed outward K+ current. These results suggest that the early increase of [Ca2+]i during depolarization of the cell membrane of heart and VSM cells with high [K+]o is due to the opening and decay of an L-type Ca2+ channel. However, the sustained increase of [Ca2+]i during a sustained depolarization is due to the activation of a resting (R) Ca2+ channel that is insensitive to lowering [ATP]i and sensitive to insulin.

[Comparison of the efficacy of cefotaxime alone and the combination cefazolin-tobramycin in the treatment of enterobacterial septicemia]. / Comparaison de l'efficacité du céfotaxime seul et de l'association céfazoline-tobramycine dans le traitement des septicémies à Entérobactéries.

In a prospective, randomized study we compared cefotaxime (C) with tobramycin plus cefazolin (C + T) in the treatment of Enterobacterial septicemia. Twenty-five patients received C and twenty two C + T. There are 8 treatment failures, in C + T group, 3 in C group. We observed 5 adverse effects, 2 in the C group (1 reversible collapse and 1 Pseudomonas aeruginosa superinfection) and 3 in the C + T group (acute renal failures). We conclude that C may be more effective and less toxic than cefazolin plus tobramycin for patients with Enterobacterial septicemia.

[Longitudinal study of the changes in glycosylated hemoglobin in normal pregnancy]. / Etude longitudinale des variations de l'hémoglobine glycosylée au cours de la grossesse normale.

A longitudinal study of HbA1c levels during normal pregnancy was carried out on 54 women. Three measurements were systematically performed around the 14th, the 24th and the 33rd weeks of gestation. On average, an initial decrease was observed in the first period, followed by a significant increase in the second period. The latter increase was negatively related to age (r = -0.33; p less than 0.05) and to prepregnancy weight (r = -0.26; p = 0.06), but neither to the birth weight of the offspring nor to total weight gain. The variation of HbA1c in the first period was not related to any of these four factors.

[Ovarian pregnancy: its status in 1982. Apropos of 6 cases operated, review of the literature]. / Grossesses ovariennes: le point en 1982. A propos de 6 cas opérés, revue de la littérature.

The authors compare six personal cases of ovarian pregnancy with those in the literature. They point out that there is no specific clinical sign which makes it possible to tell whether one is dealing with an ovarian or a tubal pregnancy. They show the value of laparoscopy and especially of laparotomy and the histo-pathology of the specimen. Finally they show that although ectopic pregnancy rarely occurs in this site it is easy to treat and nearly always can be treated conservatively.