Circulating Sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans.

CONTEXT: Secreted frizzled-related protein-5 (Sfrp5) is a novel adipocyte-secreted hormone that has been shown to link obesity with diabetes. Studies in mice have revealed that Sfrp5 represents a potential target for the control of obesity-linked abnormalities in glucose homeostasis. OBJECTIVE: Our objective was to gain insight into the physiological role of circulating Sfrp5 in humans. PATIENTS AND DESIGN: We conducted a series of cross-sectional and interventional studies of the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Subjects included 104 healthy subjects, 101 with impaired glucose tolerance, and 112 with newly diagnosed type 2 diabetes mellitus and, in a separate study, 30 healthy women, and 32 women with polycystic ovarian syndrome (PCOS). Oral glucose tolerance test and euglycemic-hyperinsulinemic clamp were performed to assess glucose tolerance and insulin sensitivity. RESULTS: Circulating Sfrp5 was significantly lower in both impaired glucose intolerance and newly diagnosed type 2 diabetes mellitus than in individuals with normal glucose tolerance (P < 0.01). Overweight/obese subjects had significantly lower Sfrp5 levels than lean individuals (P < 0.01), but females had higher Sfrp5 levels than males (P < 0.05). In a separate study, Sfrp5 levels were lower in PCOS women than healthy women (P < 0.05). Moreover, circulating Sfrp5 correlated with markers of adiposity, including body mass index, waist-to-hip ratio, percent body fat, homeostasis model assessment of insulin resistance, lipid profile, and adiponectin. Hyperglycemia decreased circulating Sfrp5 levels, whereas liraglutide increased Sfrp5 levels. In the euglycemic-hyperinsulinemic state, circulating Sfrp5 was significantly decreased in healthy women but not in PCOS women. CONCLUSIONS: We conclude that circulating Sfrp5 is likely to play a major role in insulin resistance in humans.