Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality

Abstract

Background: Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality.

Objectives: To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality.

Methods: Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3-21.7 years follow-up.

Results: An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14-1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all-cause mortality (1229 events; HR = 1.12, CI = 1.05-1.19, P = 0.001) after full multivariable adjustment.

Conclusion: Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.

Keywords: diabetes mellitus; furin; mortality; population-based cohort; risk prediction.

Figure 1

Association between baseline furin levels and incidence of diabetes mellitus in the MDC‐CC. The Kaplan–Meier plot shows cumulative percentages of diabetes mellitus events during follow‐up according to the quartiles of fasting plasma furin levels at baseline examination (Q1; lowest and Q4; highest). The numbers at risk are shown at 5‐year intervals.

Figure 2

Association between baseline furin levels and all‐cause mortality in the MDC‐CC. The Kaplan–Meier plot shows the survival rate during follow‐up according to the quartiles of fasting plasma furin levels at baseline examination (Q1; lowest and Q4; highest). Follow‐up time is displayed at 5‐year intervals.