Why PCOS Causes Insulin Resistance and Diabetes
PCOS causes insulin resistance through a specific molecular defect: excessive serine phosphorylation of the insulin receptor, which impairs the receptor's signaling capacity for metabolic pathways while paradoxically preserving mitogenic (growth-promoting) pathways. 1, 2
The Core Molecular Mechanism
Insulin resistance in PCOS is intrinsic to the syndrome itself, occurring independently of obesity. 3 The fundamental defect involves:
- Post-receptor signaling dysfunction caused by increased serine phosphorylation of both the insulin receptor and insulin receptor substrate-1 (IRS-1), which selectively disrupts metabolic pathways while leaving mitogenic pathways intact 1, 2
- This serine phosphorylation appears to be caused by constitutive activation of serine kinases in the MAPK-ERK pathway, which interferes with insulin's metabolic actions in skeletal muscle 1
- The defect affects approximately 50-70% of women with PCOS, making it a defining feature rather than a secondary consequence 4
Why This Leads to Diabetes
Women with PCOS have a 5- to 10-fold increased risk of developing type 2 diabetes compared to women without PCOS. 4 The progression occurs through several mechanisms:
Impaired Glucose Metabolism
- Skeletal muscle shows profound defects in insulin-stimulated glucose uptake, particularly affecting glycogen synthesis (the primary pathway for glucose disposal) and to a lesser extent glucose oxidation 5
- Insulin signaling defects occur at multiple points in the cascade: IRS1, PI3-kinase, Akt2, and AS160/TBC1D4, all of which are critical for glucose transport into cells 5
- Young women with PCOS demonstrate insulin resistance comparable to middle-aged patients with established type 2 diabetes, suggesting a unique and severe pathogenesis 5
Beta Cell Dysfunction
- Women with PCOS have abnormalities in pancreatic beta cell function, with adolescents showing a 50% reduction in first-phase insulin secretion when glucose intolerance is present 3
- Among women with PCOS, 31% have impaired glucose tolerance and 7.5-16% already have type 2 diabetes 3
The Vicious Cycle
- Hyperinsulinemia (the compensatory response to insulin resistance) paradoxically worsens the syndrome by acting as a co-gonadotropin through the insulin receptor to stimulate ovarian androgen production 1
- Androgens themselves contribute to insulin resistance, creating a self-perpetuating cycle where insulin resistance drives hyperandrogenism, which further worsens insulin resistance 1
Clinical Implications for Screening
All women with PCOS require diabetes screening regardless of body weight or BMI, as insulin resistance occurs independently of obesity and affects both lean and overweight women equally 6:
- Perform a 2-hour oral glucose tolerance test with 75g glucose load (not just fasting glucose) to detect both diabetes and impaired glucose tolerance 3, 6
- Screen at diagnosis and repeat every 2 years, or more frequently if additional risk factors develop 3
- Calculate BMI and waist-to-hip ratio to assess central obesity, which compounds the intrinsic insulin resistance 3, 6
- Look for acanthosis nigricans (darkened, velvety skin on neck, axillae, under breasts, or vulva), which indicates severe underlying insulin resistance 3, 6
The Selective Nature of Insulin Resistance
A critical feature distinguishing PCOS from other forms of insulin resistance is that the defect is selective: 1, 2
- Metabolic pathways (glucose uptake, glycogen synthesis) are severely impaired
- Mitogenic pathways (cell growth, proliferation) remain intact or even enhanced
- This explains why insulin can still stimulate ovarian androgen production and contribute to other growth-related effects despite profound metabolic insulin resistance
Additional Metabolic Consequences
Beyond diabetes risk, the insulin resistance in PCOS creates a cascade of cardiometabolic abnormalities 3, 7:
- Dyslipidemia: elevated triglycerides, increased small dense LDL cholesterol, and decreased HDL cholesterol 3
- Increased risk of metabolic syndrome, particularly pronounced in East Asian women with PCOS despite lower BMI 3
- Endothelial dysfunction and subclinical atherosclerosis, contributing to cardiovascular disease risk 3, 7
- Fatty liver disease and increased prothrombotic state 7
Treatment Implications
Interventions that improve insulin sensitivity are beneficial for both metabolic and reproductive outcomes 3:
- Weight loss and regular exercise should be first-line interventions before pharmacotherapy 3
- Metformin improves glucose tolerance over time and may prevent progression to diabetes, though it lacks FDA approval specifically for PCOS treatment 3
- Insulin-sensitizing agents decrease circulating androgens, improve glucose tolerance, and enhance ovulation rates 3