SUMMARY
Since uric acid to HDL cholesterol ratio (UHR) is proposed as a novel predictor of metabolic and inflammatory disorders, we aimed to study UHR levels in patients with new onset type 2 diabetes mellitus (T2DM) and compare them to those in healthy controls. Patients with new onset T2DM were enrolled and control subjects were volunteers to participate without any established diseases. Laboratory data including UHR, fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were compared. The mean UHR of the T2DM and control groups was 16±8% and 10±3%, respectively (p<0.001). Moreover, UHR was significantly and positively correlated with HbA1c (r=0.75, p<0.001), FBG (r=0.64, p<0.001), waist circumference (r=0.35, p<0.001), body mass index (r=0.20, p=0.002) and inversely correlated with glomerular filtration rate (r=-0.24, p<0.001). High levels of UHR might be associated with increased mean blood glucose levels for a long time, since UHR was correlated with both FBG and HbA1c in patients with new onset T2DM.
Key words: Type 2 diabetes mellitus, Uric acid to HDL cholesterol ratio, HbA1c, Fasting blood glucose
Introduction
Type 2 diabetes mellitus (T2DM) is the most common metabolic disorder among humans. It is strongly associated with other metabolic consequences such as obesity, dyslipidemia and metabolic syndrome (1, 2).
Uric acid is the end-product of the degradation of dietary and endogenously generated purine nucleotides (3). About 2/3 to 3/4 of uric acid is excreted by the kidney and the remaining burden is removed from the body by the gastrointestinal tract (4, 5). Higher serum uric acid levels than a threshold of 6.8 mg/dL is referred to as hyperuricemia (6). Increased serum levels of uric acid reflect a bundle of underlying etiologies including genetic defects in purine metabolism, reduced renal excretion and increased production (7). The serum uric acid/HDL cholesterol ratio (UHR) has been proposed as a better predictor in metabolic diseases (8, 9). Moreover, UHR has been associated with various conditions (10, 11).
In the present retrospective analysis, we aimed to compare serum UHR in patients with new onset T2DM and those recorded in healthy subjects. We also aimed to reveal the possible correlation between UHR and other metabolic indices including glycated hemoglobin (HbA1c), fasting blood glucose (FBG) and body mass index (BMI) levels in newly diagnosed T2DM patients.
Materials and Methods
Ethics statement
Upon approval from the institutional Ethics Committee (No. 2020/80 as of April 7, 2020), subjects diagnosed with T2DM in internal medicine outpatient clinics of our institution between January 2018 and January 2020 were enrolled in the study. Data on the participants were retrospectively analyzed. Control group included healthy volunteers visiting our clinic for routine check-up. Exclusion criteria were history of previous use of any antidiabetic agent, use of any medication that may interact with serum levels of uric acid, chronic kidney disease, malignant conditions, pregnancy, and age <18 years.
Study population and study design
Anthropometric measures and physical examination findings were recorded from patient files kept at our clinic. Age, gender, height, weight, waist circumference, systolic and diastolic blood pressure were noted. The BMI was calculated by dividing weight (kg) by the square of height (m2).
Laboratory data on the study population, serum uric acid, creatinine, blood urea, aspartate and alanine transaminases (AST and ALT), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting plasma glucose (FPG) and HbA1c levels were noted from institutional computerized database. Estimated glomerular filtration rate (GFR) was calculated by Cockcroft-Gault equation. UHR was obtained by dividing serum uric acid by HDL cholesterol (uric acid/HDL cholesterol). Moreover, white blood cell count (WBC), hemoglobin (Hb), hematocrit (Htc) and platelet count (Plt) were obtained from hemogram test results.
Statistical analyses
Statistical analyses were conducted with SPSS software (SPSS 15.0 for Windows, IBM Co., Chicago, IL, USA). Distribution of variables between the groups was analyzed with Shapiro-Wilk test. Study parameters with normal distribution were expressed as mean ± standard deviation, while parameters without normal distribution were expressed as median (min-max). Comparison of variables with and without normal distribution was done with independent samples t test and Mann Whitney U test, respectively. Correlation between study parameters was revealed with Pearson’s correlation test. The level of statistical significance was set at p<0.05.
Results
Study population consisted of 238 subjects, i.e., 136 in T2DM group and 102 in control group, mean age 49±9 and 47±7 years, respectively. Age difference between the groups was not statistically significant (p=0.18). There were 79 (58%) men and 57 (42%) women in T2DM group, and 61 (60%) men and 41 (40%) women in control group. Gender was not statistically different between the groups (p=0.79).
Although Hb (p=0.16) and Htc (p=0.17) were not statistically different between the T2DM and control group, systolic (p<0.001) and diastolic (p<0.001) blood pressure (SBP and DBP), BMI (p<0.001), waist circumference (p<0.001), body weight (p<0.001), serum uric acid (p<0.001), creatinine (p=0.002), blood urea (p<0.001), total cholesterol (p<0.001), LDL-cholesterol (p<0.001), triglycerides (p<0.001), AST (p=0.008) and ALT (p=0.01) were significantly higher in T2DM group compared to healthy controls. On the other hand, GFR (p<0.001), WBC (p=0.001), Plt (p<0.001) and HDL cholesterol (p<0.001) levels were significantly lower in T2DM group compared to control group. General characteristics and laboratory data of the T2DM and control groups are summarized in Table 1.
Table 1. Characteristics and data of the study groups.
| T2DM group | Control group | p | ||
|---|---|---|---|---|
| Sex | Men, n (%) | 79 (58) | 61 (60) | 0.79 |
| Women, n (%) | 57 (42) | 41 (40) | ||
| Mean ± SD | ||||
| Age (years) | 49±9 | 47±7 | 0.18 | |
| BMI (kg/m2) | 31±3.9 | 25±4.3 | <0.001 | |
| UHR (%) | 16±8 | 10±3 | <0.001 | |
| Uric acid (mg/dL) | 6.3±1.4 | 5±0.9 | <0.001 | |
| HbA1c (%) | 8.9±2.3 | 5.1±0.3 | <0.001 | |
| LDL cholesterol (mg/dL) | 133±39 | 110±22 | <0.001 | |
| Triglycerides (mg/dL) | 233±150 | 120±67 | <0.001 | |
| WBC (K/mm3) | 7.7±2.3 | 8.5±0.7 | 0.001 | |
| Hb (g/dL) | 14.4±1.7 | 14.7±0.4 | 0.16 | |
| Htc (%) | 43±5 | 44±1 | 0.17 | |
| Plt (K/mm3) | 271±70 | 350±27 | <0.001 | |
| Median (min-max) | ||||
| SBP (mm Hg) | 135 (90-180) | 110 (90-130) | <0.001 | |
| DBP (mm Hg) | 80 (50-100) | 70 (50-80) | <0.001 | |
| Waist circumference (cm) | 108 (85-132) | 88 (65-108) | <0.001 | |
| Weight (kg) | 85 (58-105) | 69 (55-86) | <0.001 | |
| FPG (mg/dL) | 135 (126-514) | 93 (79-99) | <0.001 | |
| Urea (mg/dL) | 28 (15-60) | 23 (13-49) | <0.001 | |
| Creatinine (mg/dL) | 0.82 (0.56-2.7) | 0.75 (0.5-1.1) | 0.002 | |
| Total cholesterol (mg/dL) | 223 (119-375) | 190 (114-248) | <0.001 | |
| HDL cholesterol (mg/dL) | 45 (21-63) | 57 (34-85) | <0.001 | |
| AST (U/L) | 20 (9-86) | 17 (9-27) | 0.008 | |
| ALT (U/L) | 19 (6-94) | 18 (6-40) | 0.01 | |
| GFR (%) | 95 (29-117) | 112 (109-121) | <0.001 | |
T2DM = type 2 diabetes mellitus; SD = standard deviation; BMI = body mass index; UHR = uric acid to HDL cholesterol ratio; HbA1c = glycated hemoglobin; LDL = low-density lipoprotein; WBC = white blood cell count; Hb = hemoglobin; Htc = hematocrit; Plt; platelet; SBP = systolic blood pressure; DBP = diastolic blood pressure; FPG = fasting plasma glucose; HDL = high-density lipoprotein; AST = aspartate transaminase; ALT = alanine transaminase; GFR = glomerular filtration rate
Mean UHR was 16±8% and 10±3% in T2DM and control groups, respectively (p<0.001). Expectedly, FPG (135 (126-514) mg/dL in T2DM group vs. 93 (79-99) mg/dL in control group) and HbA1c (8.9±2.3% in T2DM group vs. 5.1±0.3% in control group) were significantly higher in diabetic subjects compared to healthy controls (p<0.001 for both FPG and HbA1c).
In Pearson’s correlation analysis, UHR was significantly and positively correlated with HbA1c (r=0.75, p<0.001), FPG (r=0.64, p<0.001), waist circumference (r=0.35, p<0.001) and BMI (r=0.20, p=0.002), and inversely correlated with GFR (r=-0.24, p<0.001). Figures 1 and 2 show the UHR correlation with HbA1c and FPG, respectively.
Fig. 1.
Correlation between UHR and HbA1c. UHR = uric acid to HDL cholesterol ratio; HbA1c = glycated hemoglobin
Fig. 2.
Correlation between UHR and FBG. UHR = uric acid to HDL cholesterol ratio; FBG = fasting blood glucose
Discussion
Significantly elevated UHR levels in patients with T2DM compared to healthy individuals and strong positive correlation between UHR and HbA1c, and between UHR and FBG were the main findings of the present study.
Serum uric acid levels are associated with various metabolic conditions. Although its serum levels are higher in men compared to women probably due to the estrogen inhibitory effect on the reabsorption of uric acid, the rate of hyperuricemia increases after menopause in female population (12). Elevated levels of serum uric acid have been suggested to be related with hypertension and T2DM (13). The risk of new onset diabetes mellitus has been supposed to be significantly correlated with uric acid levels (14). The risk of developing impaired fasting glucose has been reported to be increased in male subjects with elevated serum uric acid levels (15). Positive correlation has been suggested to exist between serum uric acid levels and both incident T2DM and impaired fasting glucose (16). Indeed, it has been shown that 1 mg/dL elevation in serum uric acid increases the risk of T2DM by 6% (17). Moreover, elevated serum uric acid increases the risk of hypertension too. It has been reported that hypertension risk was increased by 25% in subjects with a serum uric acid level higher than 6.5 mg/dL (18). Grayson et al. found the risk of hypertension to increase by more than 10% per 1 mg/dL elevation in serum uric acid levels (19). Besides these uric acid associations, we report on elevated UHR in new onset type 2 diabetic subjects in the present study.
Decreased HDL cholesterol is also associated with some risks in the general population. Low HDL cholesterol is one of the five components of metabolic syndrome. Besides, decreased HDL cholesterol levels are a well-established independent risk factor for cardiovascular diseases (20). Madsen et al. report that low HDL cholesterol is associated with a high risk of autoimmune disease in individuals from the general population (21). Lower HDL cholesterol levels have been reported in diabetic subjects compared to controls in the literature (22). Some authors suggest that HDL cholesterol has suppressing effects on inflammation (23). Thus, decreased HDL could be a consequence of inflammatory burden. UHR is the ratio between serum uric acid and HDL cholesterol. UHR has been suggested as a better predictor of metabolic syndrome than either of its components, uric acid and HDL cholesterol (8). Elevated UHR has also been reported in vascular pathologies. Mansiroglu et al. showed that patients with coronary artery fistula had increased UHR levels compared to subjects with normal coronary arteries (11). Furthermore, Zhang et al. report that increased UHR could be a marker of non-alcoholic fatty liver disease (10). Similar to the literature, we found that patients with new onset T2DM had a significantly higher UHR than healthy controls.
Another important result of the present study was a significant positive correlation of UHR with HbA1c, FBG, waist circumference, and BMI. These parameters are indicators of altered metabolism, thus, as a novel inflammatory and metabolic predictor, UHR showed positive correlation with them. Moreover, UHR was negatively correlated with GFR levels. Similarly, significant negative correlation was demonstrated between uric acid levels and GFR in the literature (24).
Elevated UHR is not only an indicator of new onset T2DM. Recent studies have reported high UHR levels in other diseases characterized by chronic, low-grade inflammation such as non-alcoholic fatty liver disease (25), diabetic nephropathy (26), hypertension (27), and Hashimoto’s thyroiditis (28). All of these conditions are characterized with a high burden of inflammation as new onset T2DM is. Therefore, our results are consistent with literature data.
There were several limitations of the present study. Retrospective design could make our results difficult to interpret. A relatively small study population could be considered as another limitation. Single center nature of the work is the third limitation.
In conclusion, elevated UHR levels could predict T2DM in recently diagnosed DM patients, thus, we suggest routine screening of serum uric acid and HDL cholesterol levels to enable UHR measurement, especially in subjects at a high risk of T2DM. Higher levels of UHR might be associated with increased mean blood glucose levels for a long time, since UHR was correlated with both FPG and HbA1c.
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