Researchers have discovered for the first time, a genetic defect present in a type of microRNA in the fat cells of both women with PCOS and women with insulin resistance. The discovery paves the way for the development of new, targeted therapies to address the cause of both PCOS and insulin resistance. The research was published in the current issue of the journal Diabetes, and accompanied by a press release by the Medical College of Georgia, issued on Mar. 19, 2013.
A group of tiny RNA molecules with a big role in regulating gene expression also appear to have a role in causing insulin resistance in women with polycystic ovary syndrome and, perhaps, in all women, researchers report.
MicroRNAs (miRNA or ?RNA) are single-stranded RNA molecules of 21-23 nucleotides in length, which regulate gene expression. miRNAs are encoded by genes from whose DNA they are transcribed but miRNAs are not translated into protein.
Research in the journal Diabetes, indicates that high activity levels of a microRNA called miR-93 in fat cells impedes insulin’s use of glucose, contributing to PCOS as well as insulin resistance, said Dr. Ricardo Azziz, reproductive endocrinologist and PCOS expert at the Medical College of Georgia at Georgia Regents University.
“This is one of the first reports of a defect that may occur both in women who are insulin resistant and, in particular, in women with PCOS,” said Azziz, the study’s corresponding author. “Identifying this molecular mechanism helps us understand these common conditions better and points us toward targeted therapies to correct these problems in women.”
PCOS affects about 10 percent of women, though some estimates put that figure as high as 25 percent. The condition appears to be more prevalent in lesbian women than in heterosexual women, though it is not known why this is. Polycystic ovarian syndrome is characterized by excess levels of male hormones which are triggered by excess levels of insulin which act upon the theca cells of the ovaries stimulating them to produce testosterone, irregular ovulation and menstruation which can lead to infertility and is associated with an increased risk for insulin resistance, which can lead to diabetes and heart disease. PCOS is the leading cause of female infertility and the disease greatly increases the risk of premature cardiovascular disease including heart attack and stroke.
Researchers looked at fat cells from the lower abdomen of 21 women with PCOS and 20 controls. In all the women with PCOS, they found over expression of miR-93 and decreased expression of GLUT4, a key protein that regulates fat’s use of glucose for energy. GLUT4 is the major transporter for glucose uptake into the cells and in many tissues in the body it is made available in the plasma membrane of the cell through the action of insulin. When GLUT4 does not respond sufficiently to insulin, insulin resistance occurs, along with the cascade of metabolic and hormonal disturbances that ensue.
GLUT4 expression was lowest in the women with PCOS who also were insulin resistant. They also found the expression was low in members of the control group who were insulin resistant. Fat, a large organ in even a thin individual, is where a lot of glucose usage via insulin occurs, with muscle being another major utilizer of insulin-mediated glucose.
“Low levels of GLUT4 in fat appear to be affecting insulin resistance in general and to have a more dramatic impact in PCOS,” Azziz said. MiR-93 was known to impact GLUT4 in other cell types and to have a role in reproduction, infertility and lipid metabolism. “There has been no clear mechanism to describe insulin resistance in PCOS and we believe this is one of the pathways,” said Dr. Yen-Hao Chen, cell biologist at MCG and the study’s first author.
Interestingly, the investigators found that two other microRNAS – miR-133 and miR-223, which are known to regulate GLUT4 expression in heart muscle cells – also were over expressed but only in the fat cells of PCOS patients, Chen said. This exclusivity implicates the tiny molecules in the underlying condition of PCOS, Chen said. The researchers don’t know yet if the two are related to miR-93. “We are just beginning to understand the role of these small molecules in PCOS and insulin resistance and much work remains to be done,” Azziz said.
Follow up studies include better understanding just how microRNAs impact GLUT4, identifying other microRNAS that do – including looking further at miR-133 and 223 – and identifying what factors impact the tiny RNA molecules.
Humans use both insulin and non-insulin related mechanisms to use blood sugar, or glucose, as an energy source. Dr Azziz and his colleagues also published research just last month which investigated the relationship between insulin-mediated and non-insulin-mediated glucose uptake in PCOS patients compared to healthy controls.
The results, published in Journal of Clinical Endocrinology & Metabolism, showed that women with PCOS have defects in both mechanisms. In fact, PCOS women who had the most difficulty controlling glucose via insulin were also the ones with the greatest declines in their ability to use non-insulin approaches. More typically, when insulin resistance increases, the body’s non-insulin dependent usage increases, apparently to help compensate.
Humans use insulin and other non-insulin mechanisms to convert blood sugar, or glucose, into energy and control levels in the blood, where it becomes a destructive force.
The study compared 28 healthy women to 28 women with PCOS and showed the latter have declines in both approaches, said Dr. Azziz.
Most surprising was the finding that the PCOS women who had the most difficulty controlling glucose via insulin were also the ones with declines in their ability to use non-insulin approaches. More typically, when insulin resistance increases, the body’s non-insulin dependent usage increases, apparently to help compensate. In these women, non-insulin activity was essentially unchanged except in those with the most insulin resistance, where it dropped.
“Women with PCOS who have the highest levels of insulin resistance, the greatest difficulty controlling their sugar and the highest risk for diabetes, appear to have a double defect in how glucose is controlled, which affects both the mechanisms that use insulin and those that do not,” Azziz said.
While the amount of fat around the internal organs, called visceral fat, predicted the degree to which insulin had difficulty controlling glucose, the regulation of glucose by non-insulin means was more closely associated with the amount of fat under the skin, or subcutaneous fat.
“If the fat is not as sensitive to insulin, that obviously means blood sugar levels, and probably fat and cholesterol levels as well, increase and the pancreas responds by producing more insulin,” Azziz said. “Fat abnormalities can have a tremendous impact on how we feel and how we function.”
The body uses insulin to convert sugar into energy for the cells in response to eating, stress or other acute causes of blood sugar increases. Fat is a big user of this approach. However, some tissues, such as the brain, red blood cells and adrenal gland, don’t require insulin to convert glucose to energy.
“That’s one reason why regulating only insulin does not cure diabetes,” said Azziz, noting that when fasting, about 80 percent of the body’s glucose usage occurs independent of insulin.
Next steps include understanding the molecular mechanisms behind these significant differences in how PCOS affects glucose usage, Azziz said.
The study concluded that increased general obesity, high levels of subcutaneous fat and hyperandrogenism or the symptoms resulting from high levels of male hormones such as hirsutism, male pattern baldness and acne are primary predictors of the deterioration of of the body’s ability to utilise glucose by any means.
Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, Chen BS, Chazenbalk G, & Azziz R. (2013) miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of Polycystic Ovary Syndrome patients and women with insulin resistance. Diabetes. PMID: 23493574
Ezeh U, Pall M, Mathur R, Dey D, Berman D, Chen IY, Dumesic DA, & Azziz R. (2013)Effects of Endogenous Androgens and Abdominal Fat Distribution on the Interrelationship Between Insulin and Non-Insulin-Mediated Glucose Uptake in Females.The Journal of clinical endocrinology and metabolism. PMID: 23450052
Roldán B, San Millán JL, & Escobar-Morreale HF. (2004) Genetic basis of metabolic abnormalities in polycystic ovary syndrome: implications for therapy. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice, 4(2), 93-107. PMID: 15059032