Introduction: Metabolic syndrome (MetS) is a risk factor for type 2 diabetes and cardiovascular disease. The underlying pathophysiology encompasses insulin resistance (IR), abdominal obesity, ectopic lipid deposition and glucose intolerance. However, individual subjects may exhibit distinct MetS subtypes.

Hypothesis and Aim: We hypothesized that MetS has IR and non-IR subtypes. The specific aim was to identify and compare these subtypes, in human subjects without diabetes, using data from the 2015-2016 U.S. National Health and Nutrition Examination Survey.

Methods: The inclusion criterion was ages ≥ 12, and the exclusion criteria were diabetes, pregnancy, fasting < 8 h or TG ≥ 885 mg/dL. The 2,325 subjects were categorized into four groups: no MetS and no hyperinsulinemia (NN; n=1,149), no MetS with hyperinsulinemia (NY; 497), MetS without hyperinsulinemia (YN; 249), and MetS with hyperinsulinemia (YY; 430); insulin cut point 11.25 µIU/mL. Parameter distributions were compared using non-parametric Kruskal-Wallis and Steel-Dwass tests, and 95% CI.

Results: Compared with YY, the YN subtype had significantly higher median age, blood pressure, HDL and smoking frequency, and lower waist circumference, TG and hs-CRP. Despite a large difference in median HOMA-IR for YY (2.33; 95% CI 2.26, 2.40) vs. YN (1.07; 95% CI 1.04, 1.14), the median fasting glucose and HbA1c were statistically identical for YY and YN. Most subjects in the YN group had impaired fasting glucose (median 104.7 mg/dL; 95% CI 103.2, 106.0). By contrast, median fasting glucose for the NN and NY groups were 95.8 (95% CI: 95.2, 96.3) and 97.6 mg/dL (95% CI: 96.8, 98.5), respectively.

Conclusion: In subjects without diabetes, the YN subtype of metabolic syndrome is characterized by glucose intolerance without insulin resistance. Thus, diabetes risk for YN subjects must arise from a loss of beta-cell function by IR-independent mechanisms. Therapeutic strategies designed to improve insulin sensitivity are unlikely to be effective in the YN subtype.


C. Lukose: None. E. Campbell: None. D.P. Cistola: None.


National Institutes of Health (R21HL143030)

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