Increased Plasma Caveolin-1 Reflects Insulin Resistance and Vascular Dysfunction in Type 2 Diabetes.
Hyde, George   (University of Michigan-Ann Arbor)
Mentor: Haus, Jacob M. (University of Michigan)
It is generally accepted that caveolin-1 (Cav-1) functions to regulate endothelial nitric oxide synthase (eNOS) by repressing eNOS activity via direct binding and that both increased eNOS activity and reduced Cav-1 expression play a role in the pathology of vascular disease. Further, studies exploring Cav-1 regulation under conditions of oxidative stress (OS) have concluded that OS promotes Cav-1 phosphorylation and accumulation in the monomeric form. Following monomerization, Cav-1 is targeted for ubiquitinoylation and degradation by the proteasome and undergoes exocytosis, thus indicating that increased plasma appearance of Cav-1 indicates cellular Cav-1 degradation. We have previously demonstrated reduced endothelial Cav-1 and increased eNOS activity with concomitant impaired microvascular function, reduced nitric oxide bioavailability in tissue biopsies from type 2 diabetes patients (T2D). The mechanisms by which repeated pathophysiological insults such as insulin resistance and compensatory hyperinsulinemia evolve into endothelial dysfunction and vascular disease are needed to better understand the causes, and to identify, novel treatment strategies for cardiovascular disease. Thus, we tested the hypothesis that experimental hyperinsulinemia would induce an increase in plasma Cav-1 and that plasma Cav-1 under these conditions would correlate with the degree of insulin resistance and markers of OS and inflammation. We enrolled 10 lean healthy (BMI: 18-25 kg/m2) controls and 9 obese (BMI: 26-40 kg/m2) T2D men and women aged between 18 – 70 years. Blood was taken from each participant following an overnight fast (10-12 h) and during the steady-state periods of a hyperinsulinemic (40 mU/m2/min)-euglycemic (90 mg/dL) clamp procedure where glucose disposal rates were also derived. Plasma Cav-1 (ng/mL) was measured via ELISA. A significant group effect (LHC v. T2D) was found for plasma Cav-1 (F=50.12, p < 0.001). In addition, when compared to LHC, there was a significant increase in plasma Cav-1 (T2D: 0.60±0.41 basal; 0.80±0.19 insulin, LHC: 0.65±1.27 basal; 0.34±0.17 insulin, p=0.003) after insulin stimulation. Inverse correlations were found between plasma Cav-1 and clamp-derived glucose disposal rates (R= -0.71, p=0.03), whereas positive correlations (p<0.05) were found between plasma Cav-1 and age, fasting glucose, TBARS and TNF-alpha. In summary, these data demonstrate an insulin-stimulated dynamic between plasma Cav-1 and mediators of cardiometabolic health and support a role for plasma Cav-1 as a viable biomarker for microvascular dysfunction. A better understanding of the inflammatory response associated with chronic vascular disease will be critical for developing new therapeutic approaches, enabling early diagnosis, and for creation of more efficient treatments that rescue endothelial cell Cav-1 expression and vascular homeostasis.