The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS

Anu Sharma; Benjamin Krick; Ying Li; Scott A. Summers; Mary C. Playdon; Corrine Welt

Disclosures

J Endo Soc. 2022;6(11) 

In This Article

Abstract and Introduction

Abstract

Context: Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness after 12 weeks.

Objective: We evaluated whether, in women with PCOS, lower baseline ceramide, diacylglycerol (DAG), and triacylglycerol (TAG) concentrations were associated with improved metabolic response to metformin.

Methods: Women (n = 29), aged 29 ± 5 years and diagnosed with PCOS by the NIH criteria underwent an intravenous glucose tolerance test (IVGTT) before and after 12-week treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness, specifically, the ability of glucose to stimulate uptake and suppress production, after metformin treatment.

Results: Twelve weeks of metformin resulted in weight loss (−1.7 ± 2.6 kg, P < 0.01) and a reduction in BMI (−0.6 ± 0.9 kg/m2, P < 0.01) with no change in HbA1c. The concentrations of Cer(d18:1/22:0), Cer(d18:1/24:0), total ceramides, total Cer(d16:0), total Cer(d18:2), DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (P < 0.05). Baseline total Cer(d16:0) concentration <204.1 pmol/mL was 82% sensitive (AUC 0.72, P = 0.03) and total DHSM concentration <32237 pmol/mL was 100% specific (AUC 0.73, P = 0.03) in predicting improved metabolic response to metformin, as measured by IVGTT.

Conclusion: Lower total Cer(16:0) and DHSM concentrations are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements.

Introduction

Polycystic ovarian syndrome (PCOS) is a common[1] yet complex disorder that showcases the intricate interaction of metabolic disruption with reproductive dysfunction. The diagnostic clinical criteria are based on the manifestations of the woman's altered hypothalamic-pituitary-ovarian axis (menstrual irregularities, hyperandrogenism, and/or polycystic ovaries on ultrasound);[2] however, up to 65% of women are also afflicted with metabolic derangements largely driven by insulin resistance.[3,4] Metformin has therefore been a drug of choice, targeting insulin resistance in women with PCOS.[5–7] Indeed, metformin has been shown to improve glucose effectiveness, promote weight loss, and restore ovulation in 61% of women with PCOS after 10 to 12 weeks of treatment.[8]

Emerging data have revealed the importance of ceramides, diacylglycerol (DAG), and triacylglycerol (TAG) in insulin signaling, insulin sensitivity, fatty acid metabolism, and mitochondrial function.[9–13] Ceramides induce insulin resistance and have been used as a marker for metabolic impairment and cardiovascular disease.[14,15] Women with PCOS have increased concentrations of ceramides, sphingosine-1-phosphate (S1P), and sphingomyelins, with subtle changes in concentrations based on phenotype (nonobese vs obese; insulin resistant vs non–insulin resistant).[16] In addition, ceramides have a crucial role in hypothalamic-pituitary signaling for pubertal initiation.[17] Sphingosine-1-phosphate is an essential stimulator of follicular development and ovulation.[18] Taken together, ceramides are associated with both the metabolic and reproductive phenotypes in PCOS.

In women with PCOS, 12 weeks of treatment with metformin was associated with a change in ceramide and sphingolipid concentrations.[19] However, not all women with PCOS improve when treated with metformin. We therefore hypothesized that in women with PCOS, metabolic dysfunction characterized by baseline ceramide, DAG, and TAG concentrations will predict metabolic response to metformin.

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