Miaoxin Chen

Altered Glucose Metabolism in Mouse and Humans Conceived by IVF

In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat–overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m2/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans.

Does in vitro Fertilisation Increase Type 2 Diabetes and Cardiovascular Risk

Since the first in-vitro fertilisation (IVF) birth in 1978, the number of children born by assisted reproductive technologies (ART) continues to increase worldwide. However, the safety issues surrounding these procedures remain controversial, and the long term impact on human health is unknown. There is emerging evidence to indicate that IVF may predispose individuals to increased incidence of obesity, elevated blood pressure, fasting glucose and triglycerides and subclinical hypothyroidism. However, few studies have been conducted to date and the underlying mechanisms are unclear. This review will summarize the existing evidence in animal models and in humans, and will discuss epigenetic alterations, which may link manipulation of the pre-implantation embryo with increased risk of the later development of obesity, insulin resistance, type 2 diabetes and cardiovascular disease in offspring. Since these diseases are the leading cause of mortality and can be delayed or prevented by lifestyle modification, prospective follow up studies in IVF born adults are now urgently required to determine the degree of risks utilizing gold standard measures in human and animal models.

Obesity alone or with type 2 diabetes is associated with tissue specific alterations in DNA methylation and gene expression of PPARGC1A and IGF2

Abstract Background: Epigenetic modifications of key genes have been linked to the development of aging related diseases, such as type 2 diabetes, with increased DNA methylation of the transcriptional co-activator,

Impaired Glucose Metabolism in Response to High Fat Diet in Female Mice Conceived by In Vitro Fertilization (IVF) or Ovarian Stimulation Alone

Individuals conceived by in vitro fertilization (IVF) may be at increased risk of cardio-metabolic disorders. We recently reported that IVF conceived male mice displayed impaired glucose metabolism at normal and high body weights. In this study, we examined glucose metabolism in mature female C57BL/6J mice that were conceived by natural conception (NC), by ovarian stimulation (OS) or by IVF following chow or high-fat diet (HFD) for 8 weeks. By design, litter size was comparable between groups, but interestingly the birth weight of IVF and OS females was lower than NC females (p≤0.001). Mature IVF female mice displayed increased fasting glucose as compared to NC and OS mice, irrespective of diet. Mature IVF and OS mice were also more susceptible to the metabolic consequences of high fat diet as compared with NC females, with impaired glucose tolerance (p≤0.01), whereas peripheral insulin resistance and increased hepatic expression of gluconeogenic genes Ppargc1α, Pck1 and G6pc was observed in IVF mice only (p<0.05). This study suggests that ovarian stimulation alone and IVF program distinct metabolic effects in females, but that high fat diet may be required to unmask these effects. This study adds to the growing body of literature that assisted reproduction procedures may increase the risk of developing type 2 diabetes in an obesity prone environment.

Selenoprotein P is elevated in individuals with obesity, but is not independently associated with insulin resistance.

Selenoprotein P (SeP) is secreted primarily by the liver and postulated to cause insulin resistance. The aim of this study was to measure plasma SeP in individuals who are lean (N=29) or overweight/obese (N=34), and examine relationships between circulating SeP, SEPP1 (SeP, plasma 1) expression in subcutaneous adipose tissue, and markers of insulin resistance. SeP was higher in individuals who were overweight/obese (P<0.001), and associated with insulin resistance by HOMA-IR and by clamp, but not independently of BMI. SEPP1 mRNA was correlated negatively with BMI, suggesting there may be tissue specific regulation. This study suggests that obesity, rather than insulin resistance, is central to the increase in SeP.

Acute Overfeeding Does Not Alter Liver or Adipose Tissue-Derived Cytokines in Healthy Humans

Background/Aims: The secretions of liver-derived cytokines angiopoietin-like 6, insulin-like growth factor 1, selenoprotein-P and C-reactive protein and adipokines, adiponectin and monocyte chemoattractant protein-1 are altered in obese individuals, and they directly induce insulin resistance in both cellular and animal models. This study is aimed at examining the effects of acute overnutrition on these cytokines in healthy individuals, and identifying association with markers of insulin resistance. Methods: Thirty-one young healthy individuals (10 men, body mass index (BMI) 22.4 ± 2.7; 21 women, BMI 23.3 ± 4.9) were enrolled for the study. Metabolic assessments were done 3 days after an energy balanced diet (30% fat) and 3 days of a high-fat overfeeding diet (+1,250 kcal/day, 45% fat), and the assessments included the fasting body weight and blood samples to analyze the selected cytokines and evaluate the insulin sensitivity by a hyperinsulinemic euglycemic clamp (80 mU/m2/min). Results: Three days of overfeeding increased the body weight, fasting glucose and insulin, and thus the homeostasis model assessment of insulin resistance. However, there were no changes in peripheral insulin sensitivity, or in the circulating cytokines assessed. Conclusions: The hepatokines and adipokines assessed were not acutely sensitive to overnutrition in healthy individuals, despite increases in markers of hepatic insulin resistance.