Fetuin-A and risk of diabetes-related vascular complications: a prospective study

Abstract

Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Effect of Combined Antiretroviral Therapy on the Levels of Selected Parameters Reflecting Metabolic and Inflammatory Disturbances in HIV-Infected Patients

“…It has been shown that high levels of FETU-A can be considered a risk factor for insulin resistance, T2DM, CVD by inhibition of adiponectin expression, peroxisome proliferator-activated receptor-γ (PPARγ) or activating the toll-like receptor 4 (TLR-4), and as a factor reducing the risk of coronary artery disease [ 41 ]. The level of FETU-A, as a negative acute phase protein, decreases in the course of inflammation and increases again after recovery [ 41 ]. FETU-A may therefore be useful in monitoring inflammation in HIV patients.…”

Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

“…A lower fetuin-A concentration is associated with greater risk of microvascular and macrovascular complications in T2DM patients. 71 Interestingly, individuals with T2DM and NAFLD often present with a cardiac autonomic nervous system imbalance, displaying an increase in sympathetic tone, 72 , 73 which is associated with increased blood pressure and risk of ventricular arrythmia in T2DM. 74–76 …”

Potential Mechanisms for How Long-Term Physical Activity May Reduce Insulin Resistance

“…An interesting hepatokine with regards to IR is fetuin-A [ 127 , 128 , 129 , 130 ]. Fetuin-A is also linked to diabetes microvascular complications [ 131 ] and the development of nonalcoholic fatty liver disease (NAFLD) [ 132 ]. Saturated fatty acids may induce IR either by providing substrate for ceramide biosynthesis [ 133 ], or by activating toll-like receptor 4 (TLR4) signaling [ 123 ].…”