Marie-Claude Battista

Insulin and hyperandrogenism in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.

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.

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.

Impact of maternal use of asthma-controller therapy on perinatal outcomes

Background Asthma during pregnancy usually requires treatment with controller medications about which more safety information is needed. The objectives are to assess the impact of the use of long-acting β2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA). Methods A cohort of women with asthma giving birth from 1998 to 2008 was constructed from Québec (Canada) administrative databases. LBW was defined as weight <2500 g, PB as delivery before 37 weeks’ gestation and SGA as a birth weight below the 10th percentile. The impact of the use of LABAs and the dose of ICSs during pregnancy on the outcomes was determined with generalised-estimating-equation models. Results The cohort included 7376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. All LABA users also received ICSs. The prevalence of LBW, PB and SGA was 7.7%, 9.5% and 13.5%, respectively. LABA use was not found to be associated with increased prevalence of LBW (OR 0.81; 95% CI 0.58 to 1.12), PB (OR 0.84; 95% CI 0.61 to 1.15) or SGA (OR 0.92; 95% CI 0.70 to 1.20). Mean ICSs doses >125 μg/day (fluticasone-equivalent) were associated with a non-significant trend of increased LBW, PB and SGA. Conclusions Despite the possibility of residual confounding due to uncontrolled or more severe asthma or smoking status, the use of LABA and low to moderate doses of ICSs were not associated with increased prevalence of perinatal outcomes. Additional research on higher ICSs doses is required to better evaluate their safety during pregnancy.

Intergenerational Cycle of Obesity and Diabetes: How Can We Reduce the Burdens of These Conditions on the Health of Future Generations?

Prepregnancy overweight or obesity and excessive gestational weight gain have been associated with increased risk of maternal and neonatal complications. Moreover, offspring from obese women are more likely to develop obesity, diabetes mellitus, and cardiovascular diseases in their lifetime. Gestational diabetes mellitus (GDM) is one of the most common complications associated with obesity and appears to have a direct impact on the future metabolic health of the child. Fetal programming of metabolic function induced by obesity and GDM may have intergenerational effect and thus perpetuate the epidemic of cardiometabolic conditions. The present paper thus aims at discussing the impact of maternal obesity and GDM on the developmental programming of obesity and metabolic disorders in the offspring. The main interventions designed to reduce maternal obesity and GDM and their ability to break the vicious circle that perpetuates the transmission of obesity and metabolic conditions to the next generations are also addressed.

Steroidogenesis-adrenal cell signal transduction.

The purpose of this article is to review fundamentals in adrenal gland histophysiology. Key findings regarding the important signaling pathways involved in the regulation of steroidogenesis and adrenal growth are summarized. We illustrate how adrenal gland morphology and function are deeply interconnected in which novel signaling pathways (Wnt, Sonic hedgehog, Notch, β-catenin) or ionic channels are required for their integrity. Emphasis is given to exploring the mechanisms and challenges underlying the regulation of proliferation, growth, and functionality. Also addressed is the fact that while it is now well-accepted that steroidogenesis results from an enzymatic shuttle between mitochondria and endoplasmic reticulum, key questions still remain on the various aspects related to cellular uptake and delivery of free cholesterol. The significant progress achieved over the past decade regarding the precise molecular mechanisms by which the two main regulators of adrenal cortex, adrenocorticotropin hormone (ACTH) and angiotensin II act on their receptors is reviewed, including structure-activity relationships and their potential applications. Particular attention has been given to crucial second messengers and how various kinases, phosphatases, and cytoskeleton-associated proteins interact to ensure homeostasis and/or meet physiological demands. References to animal studies are also made in an attempt to unravel associated clinical conditions. Many of the aspects addressed in this article still represent a challenge for future studies, their outcome aimed at providing evidence that the adrenal gland, through its steroid hormones, occupies a central position in many situations where homeostasis is disrupted, thus highlighting the relevance of exploring and understanding how this key organ is regulated.

TNFα Dynamics During the Oral Glucose Tolerance Test Vary According to the Level of Insulin Resistance in Pregnant Women

INTRODUCTION TNFα is suspected to play a role in inflammation and insulin resistance leading to higher risk of metabolic impairment. Controversies exist concerning the role of TNFα in gestational insulin resistance. We investigated the interrelations between TNFα and insulin resistance in a large population-based cohort of pregnant women. METHODS Women (n = 756) were followed prospectively at 5-16 weeks and 24-28 weeks of pregnancy. Anthropometric measures and blood samples were collected at both visits. A 75-g oral glucose tolerance test (OGTT) was conducted at the second trimester to assess insulin sensitivity status (homeostasis model of assessment of insulin resistance and Matsuda index). TNFα was measured at the first trimester (nonfasting) and at each time point of the OGTT. RESULTS Participants were 28.4 ± 4.4 years old and had a mean body mass index of 25.5 ± 5.5 kg/m(2) at first trimester. Median TNFα levels were 1.56 (interquartile range, 1.18-2.06) pg/mL at first trimester and 1.61 (interquartile range, 1.12-2.13) pg/mL at second trimester (1 h after glucose load). At second trimester, higher TNFα levels were associated with higher insulin resistance index levels (r = 0.37 and -0.30 for homeostasis model of assessment of insulin resistance and Matsuda index, respectively; P < .0001), even after adjustment for age, body mass index, triglycerides, and adiponectin. Women with higher insulin resistance showed a continuing decrease in TNFα levels during the OGTT, whereas women who were more insulin sensitive showed an increase in TNFα at hour 1 and a decrease at hour 2 of the test. CONCLUSION Higher insulin resistance is associated with higher levels of circulating TNFα at first and second trimesters of pregnancy. TNFα level dynamics during an OGTT at second trimester vary according to insulin-resistance state.

Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells.

BACKGROUND Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenemia, from ovarian and adrenal origin, and is characterized by insulin resistance (IR). Studies found that raising in vivo non-esterified fatty acid (NEFA) levels, which induces lipotoxicity, increases androgen levels and IR. The aim of this study was therefore to determine the effects of in vitro over-exposure to NEFA on androgen synthesis in a bovine adrenocortical cell model. METHODS Bovine fasciculata/reticularis cells were cultured for 2days in the absence or presence of ACTH (10nmol/L) or Forskolin (fsk, 10μmol/L), alone or in combination with the saturated fatty acid (FA) palmitate (100μmol/L). Steroid production was measured in medium and corrected for initial cell seeding count. CYP17 protein expression and ERK1/2 phosphorylation were assessed by Western blotting. RESULTS Under unstimulated conditions, dehydroepiandrosterone (DHEA) levels were barely detected and no difference was observed after palmitate exposure, which was also the case for CYP17 expression and ERK1/2 phosphorylation. Under stimulation, palmitate exposure increased DHEA production by 38% and 69%, for ACTH and fsk, respectively, as compared to untreated conditions (Ps⩽0.05). In palmitate-treated vs untreated cells, fsk-stimulated ERK1/2 phosphorylation was reduced by 46% (P=0.0047), but stimulated CYP17 expression was not significantly affected. CONCLUSION In a model of androgen-producing cells, under stimulated conditions, overexposure to saturated FAs significantly increases androgen production and reduces MEK/ERK activation. Therefore, this study is the first to demonstrate that lipotoxicity can directly trigger androgen overproduction in vitro, in addition to its well-described impact on IR, which strongly supports a central role of lipotoxicity in PCOS pathophysiology.

Dietitian-coached management in combination with annual endocrinologist follow up improves global metabolic and cardiovascular health in diabetic participants after 24 months.

This 24 month study evaluated the effect of dietitian coaching combined with minimal endocrinologist follow up on the glycemic control and cardiovascular risks of diabetic participants, compared with conventional endocrinologist follow up. Participants with type 1 or type 2 diabetes were assigned to either the control group with conventional endocrinologist follow up (C; n = 50) or the dietitian-coached group (DC; n = 51) with on-site diabetes self-management education every 3 months combined with annual endocrinologist followup. Over the 24 month intervention, weight (-0.7 vs. +2.1 kg; p = 0.04), BMI (+0.3 vs. +0.7 kg/m(2); p = 0.009), and waist circumference (-1.3 vs. +2.4 cm; p = 0.01) significantly differed between the DC and control groups. HbA(1C) dropped significantly in participants of the DC versus the control group (-0.6% vs.-0.3%; p = 0.04). This was accompanied by improved overall energy intake (-548 vs. -74 kcal/day; p = 0.04). However, no link associated glycemic control to nutrient intake or intensiveness of pharmacotherapy. Coaching by a dietitian improves glycemic control and reduces certain cardiovascular risk factors in diabetic subjects, demonstrating that a joint dietitian-endocrinologist model of care provides a convenient strategy for cardiovascular risk management in the diabetic population.

24-Dehydrocholesterol Reductase/Seladin-1: A Key Protein Differentially Involved in Adrenocorticotropin Effects Observed in Human and Rat Adrenal Cortex

DHCR24 (24-dehydrocholesterol reductase), or seladin-1, is one of the most expressed genes in the adrenal gland. Because the rat and human adult adrenal cortex differ in their respective functional properties, the aim of the present study was to verify whether seladin-1 may be differentially involved in basal and ACTH-stimulated steroidogenesis and oxidative stress management. Seladin-1 expression was predominantly observed in both human and rat zona fasciculata, with a predominant cytoplasmic localization in human cells and a nucleo-cytoplasmic distribution in rat cells. In human fasciculata cells, localization of the protein was primarily associated with the endoplasmic reticulum. Although its expression was increased by ACTH, its intracellular localization was not altered by ACTH treatment (10 nm) or by the seladin-1 inhibitor U18666A (75 nm). Preincubation with U18666A did not modify the ACTH-induced increase in cortisol secretion but abolished the ACTH-induced increase in dehydroepiandrosterone secretion. In rat fasciculata cells, ACTH induced a massive redistribution of seladin-1 from the cytoplasm (cis-Golgi apparatus) to the nucleus, which was inhibited by preincubation with U18666A. Preincubation with U18666A also decreased ACTH-induced seladin-1 and 11beta-hydroxylase protein expression as well as corticosterone production, increased ACTH-induced ROS production but decreased ACTH-induced expression of the detoxifying protein aldo-ketoreductase 1b7. Thus, protection against acutely elevated ACTH-induced oxidative stress in rat fasciculata cells is correlated with nuclear relocalization of seladin-1 and its effects on cellular detoxifying machinery. Altogether, these results indicate that seladin-1 expression and intracellular localization are correlated with both the intensity and nature of ACTH-induced steroidogenesis and resultant oxidative stress.