Heteroplasmic mitochondrial DNA 3310 mutation in NADH dehydrogenase subunit 1 associated with type 2 diabetes, hypertrophic cardiomyopathy, and mental retardation in a single patient.

I t is well known that hyperglycemia is associated with increased mortality from cardiovascular disease (CVD) and all-cause mortality. It has recently been reported that subjects with low fasting plasma glucose (FPG) levels also had a high risk of CVD and all-cause mortality (1). However, there is a paucity of information about the etiologic basis underlying the association between low FPG and increased CVD and all-cause mortality. Thus, in the present study, we investigated the association of FPG levels with white blood cell (WBC) counts, which indicate a state of low-grade systemic inflammation. We investigated the cross-sectional association of WBC counts with FPG levels among 3,256 Japanese men aged 34–69 years. The subjects were divided into six categories according to FPG level: 80 mg/dl, 80 to 90 mg/dl, 90 to 100 mg/dl, 100 to 110 mg/dl, 110 to 126 mg/dl, and diabetes. The crude mean WBC counts were 6,409, 6,308, 6,111, 6,111, 6,109, and 6,610 cells/mm in the subjects with FPG levels of 80 mg/dl, 80 to 90 mg/dl, 90 to 100 mg/dl, 100 to 110 mg/dl, 110 to 126 mg/dl, and diabetes, respectively. The crude mean WBC counts differed significantly by FPG category and showed a U-shaped association with FPG levels (P value for quadratic trend 0.001). Even after adjusting for age, BMI, smoking, alcohol, health status, and other factors associated with elevated WBC count or glycometabolism, the respective adjusted-mean WBC counts were 6,273, 6,255, 6,175, 6,165, 6,075, and 6,429 cells/mm. The WBC count maintained a U-shaped association with FPG level (P value for quadratic trend 0.041). Although it is well known that hyperglycemia is the cause of microvascular complications in several organs, there are few studies on the adverse effect of hypoglycemia. Early studies of hypoglycemia focused on brain damage and heart dysfunction. An acute decrease in FPG is recognized as the cause of them, whereas the long-term effect of low FPG remains unclear. Infection and inflammation may contribute to vascular injury and atherogenesis. Inflammation may also promote atherosclerotic plaque ruptures and thrombosis (2,3). WBC serves as an important biomarker for these disease processes. This study shows that the U-shaped association between WBC counts and FPG levels (especially low FPG levels) involves higher WBC counts that could not be linked to inflammatory disease or other factors or to any disease known to increase WBC counts. These findings suggest that a state of low-grade systemic inflammation may be present not only in diabetic subjects but also in people with low FPG, possibly explaining in part the high risk of CVD and all-cause mortality of such people.