Bone-specific alkaline phosphatase is elevated in insulin resistance: implications for vascular calcification in diabetes

Abstract

Purpose: Previous studies showed that alkaline phosphatase (ALP) is a predictor of mortality and cardiovascular event. Insulin resistance (IR) is associated with vascular calcification, but the relationship between IR and ALP is unclear. We therefore studied the relationship between ALP (total and bone-specific) and IR-related traits. Methods: Data on 3,986 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2004 aged ≥20 years and free of diabetes were analyzed. Plasma glucose and serum insulin were measured from fasting blood samples using hexokinase enzymatic method and RIA, respectively. The homeostasis model assessment calculator was used to calculate the HOMA2 beta cell function (%B), insulin sensitivity (%S), and IR. Multivariable linear regression was used to assess the association of IR-related traits with ALP levels. Results: In linear regression, HOMA2-IR, HOMA2-B, and insulin were positively associated with bone-specific ALP, whereas HOMA2-S was negatively associated with bone-specific ALP, after adjustment for smoking, drinking, race/ethnicity, education, physical activity, age, and body mass index. After further adjustment for C-reactive protein, total cholesterol, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, triglycerides, HDL-cholesterol, and mean arterial pressure, the associations were attenuated but remained statistically significant (P<0.001). No significant association with total ALP was found. Conclusions: IR-related traits are strongly and independently associated with serum bone-specific ALP levels, but not total ALP levels. Whereas IR is expected to be associated with liver inflammation, the association with bone-specific ALP is novel and provides a mechanistic link between IR and vascular calcification. This raises the possibility that ALP inhibitors may prevent vascular calcification in people with diabetes.