‘Alternative’ markers of insulin resistance can predict osteoarthritis
Key takeaways:
- Surrogate insulin resistance measures short of the “gold standard” were able to predict OA.
- Triglyceride-glucose index combined with waist-height ratio had greatest diagnostic efficacy.
Surrogate measures of insulin resistance, based on the triglyceride-glucose index, can be used to predict the development of osteoarthritis, according to data published in Scientific Reports.
“Previous studies have drawn a link between OA and metabolic syndrome (MetS), which is characterized by hypertension, hyperglycemia, dyslipidemia, and abdominal obesity,” Youmian Lan, of the First Affiliated Hospital of Shantou University Medical College, in China, and colleagues wrote. “... The hyperinsulinemic euglycemic clamp serves as the gold standard for diagnosing [insulin resistance (IR)], but its invasiveness, complexity, and cost limit its use in epidemiological studies. While the homeostasis model assessment of IR is convenient to use, it is not suitable for diagnosing patients undergoing insulin therapy.
“In this context, alternative markers derived from blood glucose and lipid profiles, as well as specific anthropometric measurements, such as the visceral adiposity index (VAI), lipid accumulation product (LAP), and triglyceride-glucose index (TyG), are increasingly employed as simple and effective tools for identifying IR,” they added. “Extensive research indicates that these surrogate IR indexes are significantly associated with the prevalence of cardiovascular disease, ischemic stroke, and diabetes. Obesity is a major contributor to OA and interacts with IR in its development.”
To examine the links between surrogate markers of insulin resistance and OA, as well as their ability to predict OA, Lan and colleagues conducted a cross-sectional study of 14,715 U.S. adults, 11% (n = 1,579) of whom had OA, using data from the National Health and Nutrition Examination Survey.
The researchers used patient data to calculate scores on various surrogate insulin resistance indexes, including VAI, LAP and TyG, as well as several combining obesity measures with TyG, such as waist-to-height ratio (TyG-WHtR), waist circumference (TyG-WC) or BMI (TyG-BMI).
According to the researchers, all six indexes were positively associated with the presence of OA, both in an unadjusted logistic regression model and in a model adjusted for age and sex. However, after adjusting for socioeconomic factors, as well as alcohol, smoking, hypertension and diabetes, significant correlations remained for:
- TyG-WC (fourth quartile OR = 2.3475; 95% CI, 1.8388-2.9971),
- TyG-BMI (fourth quartile OR = 2.4969; 95% CI, 1.9808-3.1474),
- TyG-WHtR (fourth quartile OR = 2.2444; 95% CI, 1.7604-2.8615) and
- LAP (fourth quartile OR = 1.8395; 95% CI, 1.4515-2.3312).
Using receiver operating curve analysis, the researchers found that TyG-WHtR demonstrated the highest diagnostic efficacy, with an area under the curve of 0.633.
“OA accounts for a significant proportion of the population and is one of the leading causes of disability among the elderly, and represents a considerable social burden,” Lan and colleagues wrote. “Therefore, identifying potential risk and prognostic factors could lead to cost savings in the management of this population.”
Perspective
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The triglyceride-glucose index is a simple, cost-effective method for assessing insulin resistance (IR), calculated using fasting triglyceride and plasma glucose levels. IR is an early indicator of type 2 diabetes, often developing 10 to 20 years before diagnosis.
Recent studies have also linked IR to osteoarthritis, with 82% of patients with OA demonstrating elevated serum insulin levels. High insulin concentrations have been found to contribute to cartilage degradation, while prolonged overnutrition induces inflammation in key metabolic tissues, including fat, muscle, liver and blood vessels.
The connection between IR, inflammation, and OA is supported by increased levels of cytokines, chemokines and acute-phase proteins in both type 2 diabetes and OA. Proinflammatory cytokines such as TNF-α and interleukin (IL)-6 disrupt insulin signaling, leading to hyperglycemia. Obesity further exacerbates this issue by promoting a chronic, low-grade inflammatory response, with M1 macrophages infiltrating the OA synovium before cartilage degradation begins.
Gene expression studies have identified significant differences in inflamed OA synovium, compared to healthy tissue, with elevated levels of IL-1α, IL-18 and TNF-α correlating with OA severity and progression. Additionally, patients with knee OA exhibit increased IL-6 release from the infrapatellar fat pad, with higher baseline BMI and serum IL-6 levels predicting OA development over time.
Chronic inflammation, a hallmark of metabolic diseases like OA and type 2 diabetes, is characterized by immune cell proliferation, excessive cytokine production and persistent activation of inflammatory pathways. Elevated levels of IL-1β, IL-6, and CRP are predictive markers for type 2 diabetes, and differences in cytokine profiles distinguish OA from healthy individuals.
Increased expression of IL-1β and TNF-α in the blood of patients with OA correlates with cartilage loss, as seen in lower knee cartilage volume associated with higher circulating IL-6, TNF-α, and CRP levels.
Overall, obesity, type 2 diabetes, OA and cardiovascular disease share a common metabolic environment dominated by IR and chronic low-grade inflammation, driven by cytokine-mediated intracellular signaling pathways like JNK and IKKβ/NF-κB. These findings highlight the interconnected nature of metabolic and inflammatory diseases.
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