Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome

Abstract

Objective:Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS.Methods:Normal-weight girls with PCOS [n =18, age 15.9 ± 1.8 years, body mass index (BMI) percentile 68 ± 18] and normal-weight controls (NWC; n = 20; age 15.0 ± 2.1 years, BMI percentile 60 ± 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31P MR spectroscopy.Results:Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 ± 2.4 mg/kg/min vs 12.7 ± 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL ± 26 vs 41 ± 25, P = <0.001 and 119 ± 22 mg/dL vs 85 ± 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS.Conclusions:Normal-weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS.

Circulating levels of C1q/TNF‐α‐related protein 6 (CTRP6) in polycystic ovary syndrome

“…One proposed mechanism that could disrupt this balance is through mitochondrial dysfunction, characterized by mitochondrial DNA (mtDNA) depletion. It has been associated with the pathogenesis of PCOS, including hyperglycemia, insulin resistance, hyperandrogenism, and anovulation . mtDNA depletion downregulates adiponectin expression, while it stabilizes CTRP6 mRNA, inhibiting its decay .…”

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

“…Furthermore, it stands to reason that the propagation of these mitochondria from a fertilized egg to a blastocyst and ultimately a live-born offspring should result in abnormal mitochondrial function throughout the body. Recent studies in a rat PCOS model have noted mitochondrial dysfunction in the pancreas (57) and kidney (58), and human studies have now reported altered mitochondrial function in skeletal muscle (59) as well as follicular fluid and cumulus cells of PCOS patients (46).…”

Muscle Insulin Resistance in Youth with Obesity and Normoglycemia is Associated with Altered Fat Metabolism

“…Data from youth aged 12 to 21 years recruited from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) study and the Androgens and Insulin Resistance Study (AIRS) cohorts (studies performed prior to ClinicalTrials.gov identifier requirements) were used for this secondary data analysis. Inclusion criteria were BMI ≥ 95th percentile specific for sex and age for the group with obesity, BMI = 10th to 84th percentile for the normal‐weight participants in the control group, and sedentary status, to minimize impacts of varying physical activity on IS (< 3 hours of regular exercise per week, validated with both a 3‐day activity recall and 7 days of accelerometer use).…”

“…Informed consent was obtained from all participants ≥ 18 years of age, and parental consent and participant assent were obtained from all participants < 18 years of age. The two groups included in this secondary analysis were originally enrolled as the normal‐weight control group to match those with type 1 diabetes and lean PCOS participants and the control group with obesity to match those with PCOS and T2D participants with obesity. The comparison of the two different weight control groups has not been performed.…”