Independent Association of Phase Angle with Fasting Blood Glucose and Hemoglobin A1c in Korean Type 2 Diabetes Patients

Bioelectrical impedance analysis (BIA) is a simple, reliable, non-expensive, reproducible, and non-invasive method for assessing body composition and nutritional status in the clinical situation [1]. Thus, BIA is a method commonly used for estimating clinical conditions, as well as body fat and muscle mass in patients [2]. BIA determines the electric impedance of an electric current passing through the body [3]. The electrical impedance consists of resistance and reactance [3]. Low resistance is correlated to lean body mass (LBM), and high resistance is correlated to a reduced LBM. Resistance is the opposition of a conductor to the alternating electrical current, and it is the same in non-biological systems. Reactance is generated by the additional opposition to the current from the storage effects of tissue interfaces and cell membranes [4].

Phase angle (PhA) is an established bioelectrical impedance parameter for the monitoring of malnutrition and diagnosis of clinical prognosis, both associated with changes in cellular integrity and alterations in fluid balance [5, 6]. PhA expresses both changes in the amount as well as the quality of soft tissue mass (i.e., cell membrane permeability and soft tissue hydration). PhA can be affected by changes in the amount and quality of the soft tissues, in cell size and mass, in cell membrane permeability, or intracellular composition [7]. PhA can be directly calculated as resistance and reactance as arc-tangent (reactance/resistance) × 180°/π. Therefore, the PhA is dependent on the cell size, cellularity, integrity of the cell membrane, and the hydration of the tissue [8].

The PhA values change depending on age, sex, body mass index (BMI), ethnic group, body shape, and clinical conditions of the patient [9, 10, 11]. Máttar has reported that in most people, PhA is represented between 3–15° [11]. PhA levels in Asians are generally lower compared to other ethnic groups [9, 10, 11]. The mean PhA of men and women were 6.5 ± 0.5° and 5.3 ± 0.5°, respectively, with a significant difference (p < 0.001) to healthy Korean [12]. PhA has been known as a prognostic factor for assessing cell health, however, its biological indications remain to be elucidated. It was reported that PhA was positively correlated with cell health, membrane integrity, and function of cells [13, 14].

Clinical studies have reported that BIA and PhA might serve as a prognostic indicator for the nutritional assessment of liver cirrhosis, several types of cancer, sepsis, diabetes mellitus (DM) and renal diseases [15, 16, 17, 18, 19, 20]. Low levels of PhA are related to the inability to store energy and selective penetrability of cell tissue. High levels of PhA mean high reactance and low resistance, which is coincide high amount of intact cell mass, suggesting healthy status [14]. The metabolic changes, including cell membranes, are first affected by malnutrition. Thus, PhA reflects the quantity of fat and muscle mass as well as hydration status and may be able to reflect malnutrition at an early stage and might be useful in assessing the effectiveness of nutrition intervention [21]. PhA is measured by secondary analysis of BIA without using anthropometric data. Therefore, it can be used as a useful parameter for patients with difficult anthropometry [5]. A decreased PhA was associated with an increased mortality rate in a variety of diseases [22]. PhA values are also used as a predicting marker to monitor DM complications, the progression and duration of DM [23].

The relationship between PhA of BIA and glycemic parameters in type 1 and type 2 DM (T2DM) patients has also been investigated. However, their application in DM may be limited in Korea. Therefore, this study was conducted to establish sex-, age-, and BMI-specific reference values for PhA in Korean diabetes patients.

The PhA calculation derives from resistance and reactance. Resistance is related to tissue hydration, whereas reactance is generating by the cell membrane capacitance in human body [24]. Recently, PhA has been used as a prognostic parameter for evaluating clinical outcomes and nutritional status in patients with different diseases [22, 25]. PhA plays a key role for monitoring and screening disease progress in patients undergoing DM, hemodialysis, liver cirrhosis, several cancer and mortality of diseases [16, 17, 18, 19, 20]. The 50 KHz are most commonly used in humans to measure both maximum electric resistance and reactance. Thus, as most previous studies have referred to PhA values obtained at 50 kHz [5], we measured the PhA at 50 kHz.

We investigated the association with PhA, body composition, and glycemic indicators of 321 T2DM Korean patients. The PhA, BCM, ECM, LBM, ICW, ECW, TBW as well as fasting blood glucose and HbA1c of T2DM Korean subjects were significantly higher in men than in women. Statistically significant correlations were observed between PhA and age, BCM, ECM, ECM/BCM, ICW, ECW, ECW/ICW, and ECW/TBW for both sexes. Especially, HbA1_C and fasting blood glucose levels were independently associated with PhA.

Mattiello et al. [14] reported that PhA gradually increases throughout puberty, stabilizes in the adult ages, and then decreases continuously in older patients. In this study, the PhA and BCM were significantly higher in men than in women. These results might be explained due to the higher amount of BCM in men compared to women [8, 26]. Thus, our results are in line with those of previous studies.

Data regarding PhA in the DM patients are not fully understood. Buscemi et al. [27] reported that PhA values significantly lowered in young adult T1DM men subjects compared to control subjects, whereas this difference was insignificant in women. Dittmar et al. [23] showed that the lower PhA was found with T2DM subjects compared to a control group. They also found negative correlations between the PhA and HbA1c and suggested that lower PhA might indicate catabolism and long duration of the disease in T2DM patients. Di Mauro et al. [28] reported that DM patients have a reduced ECW and exchangeable potassium due to an alteration of the osmolarity in plasma and a decreased active cell mass. These results suggest that decreased PhA in DM patients indicates cell death or a decrease in cell mass. Hyperglycemia induced the osmolarity of the extracellular compartment, which causes water movement from the intracellular into the extracellular compartment, may cause advanced renal failure complications [29, 30]. Changes in increased ECW have been found in T2DM subjects [31]. These results provide evidence that the PhA could be used as independent prognostic markers in T2DM patients, especially in those with uncontrolled fasting blood glucose.

The PhA values are influenced by age, sex, BMI, ethnic group, and clinical conditions [9, 10, 11]. A few studies are represented that the diets can affect the PhA [32, 33]. Higher dietary quality decreased the odds of low PhA in health adults [32]. Barrea et al. [33] also reported that the mediterranean diet was associated to larger PhA independent of sex, age and BMI., as expression of cell membrane integrity [33]. Therefore, PhA evaluation could be a useful screening tool to assess the nutrition status as well as health condition.

This study had some limitations. We did not investigate a control group. Thus, there was a lack of consideration of the difference in PhA between the normal control group and the DM group. Additionally, we did not investigate correlation between PhA and disease duration in subjects. Thus, it is considered that a comparative study of PhA by disease duration is necessary for future studies. Another limitation is related to not analyzing the consumption of diet. Further studies are need to confirm the mechanism of dietary intake and PhA.

In conclusion, PhA reflected the cell function and BCM in T2DM subjects. We also found the independently association among the fasting blood glucose, HbA1c, and PhA. These findings of the present study indicate that PhA may be useful in assessment of clinical outcomes and severity of the T2DM patients. However, in order for PhA to be used as a prognostic indicator for diabetic patients, further studies are needed to evaluate the relationship with other parameters, such as inflammatory cytokine and antioxidant status, and the disease duration.

The PhA has been known as an indicator of cell health and function of cells. However, its key role of DM patients remains unclear. This study classified of the according to sex and examined the association of PhA with fasting blood glucose and HbA1c in Korean T2DM patients. The present data showed that the PhA were significant associations with age, BCM, ECM, ECM/BCM, ICW, ECW, ECW/ICW, and ECW/TBW of all subjects. HbA1c and fasting blood glucose were also independently negatively associated with the PhA of all subjects. Thus, the PhA could be a biomarker for assessing general health and regulation of fasting blood glucose in T2DM patients in Korea.