Journal of Diabetes and Its Complications 28 (2014) 124–129
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Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes☆,☆☆ Somlak Chuengsamarn a,⁎, Suthee Rattanamongkolgul b, Siwanon Jirawatnotai c a b c
Division of Endocrinology and Metabolism, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornnayok, Thailand Department of Preventive and Social Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornnayok, Thailand Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 25 August 2013 Received in revised form 1 December 2013 Accepted 4 December 2013 Available online 12 December 2013 Keywords: Uric acid Microalbuminuria Chronic vascular complications Type 2 diabetes
a b s t r a c t Aims: To investigate an association between serum uric acid/microalbuminuria and chronic micro/macrovascular complications in type 2 diabetic patients. Methods: This cross-sectional study enrolled 608 patients with type 2 diabetes. All subjects were examined and basic information on health of the subjects was recorded for inclusion criteria. Several chemical parameters (fasting plasma glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, uric acid, and microalbuminuria), and related chronic vascular complications were measured and recorded in data forms. Results: Logistic regressions were used to analyse odds ratios between uric acid/microalbuminuria levels and several chronic vascular complications. Prevalence of chronic vascular complications in T2DM patients, namely coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy was significantly correlated with increase of uric acid level [2.29 (1.01–5.2), 16.01 (4.74–54.09), 9.99 (4.4–22.8), 4.43 (1.3–15.1), 4.37 (1.5–12.9)], and of microalbuminuria level [7.0 (3.6–13.8), 3.2 (1.2–8.7), NA, 14.7 (5.1–42.7), 7.2 (2.9–17.7)]. Conclusion: Both elevated uric acid and microalbuminuria levels were significantly associated with diabetic chronic micro/macro-vascular complications. Monitoring of uric acid and microalbuminuria levels provides a predictive value for a presence of chronic micro/macro-vascular complications in patients with type 2 diabetes. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chronic vascular complications in type 2 diabetes (T2DM) are the deteriorating conditions underlined by inflammation (Ceriello & Motz, 2004). The chronic vascular complications in diabetes mellitus (DM) are classified by vascular size into macro- and microvascular diseases. The chronic vascular complications are a serious problem, since they generally yield devastating outcomes for the T2DM patients, which include coronary arterial disease (CAD), cerebrovascular disease (CVD), peripheral arterial disease (PAD), diabetic nephropathy (DN), diabetic retinopathy (DR), and diabetic peripheral neuropathy (PN) (Alberti & Zimmet, 1998). ☆ Conflict of interest: The authors declare that they have no conflict of interest. ☆☆ Grant support: This study was funded by a research grant to S.C. from Faculty of Medicine for Medical Science, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University. ⁎ Corresponding author at: Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, 63 M 7 Rungsit-Nakornnayok Rd., Ongkarak, Nakornnayok, Thailand. 26120. Tel.: +66 37 395085 6x11001; fax: +66 37 395085 6x11003. E-mail address: [email protected] (S. Chuengsamarn). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2013.12.002
Elevated levels of uric acid and microalbuminuria are commonly found in patients with severe cardiovascular diseases, such as stroke, and ischemic heart disease (Fukui et al., 2008; Hayden & Tyagi, 2004; Klausen, Scharling, Jensen, & Jensen, 2005; Redon, 2006). The elevated levels correlate with the severity of the conditions, namely, the higher the levels, the more severe the conditions (Kanellis & Kang, 2005; Kim et al., 2011; Newman et al., 2005; Tai et al., 1990). Although it is still unclear, the heightened levels are presumably a result of an upregulation of inflammatory cytokines, such as interleukin-6 (IL-6), C-reactive protein (CRP), and increased oxidative stress (Ceriello & Motz, 2004; Deckert et al., 1992; Giacco & Brownlee, 2010; Koenig & Meisinger, 2008; Newman et al., 2005). High levels of inflammation are regularly found in patients with T2DM. This observation is accompanied by the findings that there are correlations between increase of the serum uric acid level/microalbuminuria and severity of the insulin resistance and metabolic profiles (Costa, Iguala, Bedini, Quinto, & Conget, 2002; Dehghan, Van Hoek, Sijbrands, Hofman, & Witteman, 2008; Festa et al., 2000; Hsu et al., 2011; Kodama et al., 2009). It is not known; whether the inflammation associated with T2DM contributes to the elevated levels of serum uric acid and microalbuminuria, and whether or not there is a relationship
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between uric acid/microalbuminuria, and the inflammatory-driven chronic vascular conditions found in the T2DM patients. In the hope of identifying a reliable parameter that will allow an early detection of the micro- and macro-vascular complications in T2DM population, we investigated the relationships between levels of serum uric acid/ microalbuminuria, and the chronic vascular conditions in a T2DM population through a cross-sectional observation. The study also took into the consideration the information on other indicative parameters, such as duration of diabetes, hypertension status, smoking status, history of CAD, history of CVD, dyslipidemia status, uric acid, microalbuminuria (MAU), fasting plasma glucose (FPG), and hemoglobin A1C (HbA1C).
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lipoprotein cholesterol (b 40 mg/dl in men, b50 mg/dl in women), hypertension (≥ 130/85 mm/Hg), impaired fasting glucose (FPG ≥ 100 mg/dl). DN is defined by abnormalities in albumin excretion; the level of microalbuminuria (MAU) is ≥30 mg/g Cr, and the subject has positive results twice, consecutively (Klausen et al., 2005; Redon, 2006).The MAU was used by measurement of the albumin-to-creatinine ratio in an early morning spot urine, by the immunoassay method (Silver, Dawnay, Landon, & Cattell, 1986). MAU was classified into three groups; normal, microalbuminuria and macroalbuminuria as the following value of b 30, 30–299, ≥300 mg/g Cr, respectively (Klausen et al., 2005). Urinary infections were diagnosed by positive test of nitrites or leucocytes ≥ 250 leucocytes/ml in the urine sample.
2. Patients and methods 2.1. Subjects and designed study This study was a cross-sectional study by design. It included all patients who attended diabetic clinic in the outpatient unit of the Internal Medicine Department at HRH Princess Mahachakri Sirindhorn Medical Center, Faculty of Medicine, Srinakharinwirot University during the years 2007–2008. Inclusion criteria were type 2 diabetes aged of 35 or more. Type 2 diabetes was diagnosed according to the Report of the expert committee on the diagnosis and classification of diabetes mellitus (2003). We excluded patients taking any medications that might affect serum uric acid concentrations such as, thiazides, salicylates, pyrazinamide, ethambutol, nicotinic acid, and cyclosporine. Patients with advanced renal dysfunction by serum creatinine more than 2.0 mg/dl or urinary tract infection were excluded. The subjects were checked for blood chemistry profiles and examined for diabetic micro and macro-vascular complications by endocrinologists after the details of the project were explained to them and after they signed the consent form. This study was approved by the Ethic Committee of Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand (serial number: SWUEC 9/2550) in accordance with the Declaration of Helsinki. Participants were informed, and gave their consent before participation. 2.2. Data collection Basic information of patients and factors associated with increased diabetic complications were collected using case record form containing information of age, sex, weight, height, waist circumference, duration of diabetes, hypertension status, smoking status, history of CAD, and history of CVD, dyslipidemia status, uric acid, fasting plasma glucose(FPG), and haemoglobin A1C (HbA1C). The circumferences of the waist were measured at the level of the iliac crest. Blood samples were collected after a 12 h overnight fasting. Serum uric acid concentrations in our reference range (2.6– 7.2 mg/dl) were assessed using enzyme colorimetric method. Plasma fasting glucose was assessed using standard enzymatic method. Serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations were measured by standard enzymatic methods. The high-performance liquid chromatography was used for assay in HbA1C level. 2.3. Metabolic syndrome and chronic vascular complications Metabolic syndrome criteria were defined by the joint criteria (2009) (Alberti et al., 2009). Patients have metabolic syndrome, if they have central obesity by waist circumference (WC) ≥90 cm in men, or ≥80 cm in women (according to the recommendation by the joint criteria (2009) for Asian population), and any two of the following: elevated triglyceride (≥ 150 mg/dl), low High-density
Table 1 Characteristics of subjects in the study. Characteristics
Total Number (Mean)
Percent (S.D.)
Age (total, mean, SD.) Sex - Male -Female Smoking status - Current Smoking - Ex-Smoking - Non-Smoking Serum creatinine (mg/dL) mean MDRD-GFR (ml/min per 1.73m2) (total, mean, SD.) Insulin user (%) ACEI user (%) ARB user (%) Statin user (%) History of hypertension (%) Body mass index (kg/m2) (total, mean, SD.) Waist circumference (cm.) Systolic blood pressure (mmHg) Diastolic blood pressure(mmHg) Duration of diabetes (years) (total, mean, SD.) Fasting plasma glucose (mg/dL) (total, mean, SD.) Total cholesterol (mg/dL) (total, mean, SD.) Low-density lipoprotein cholesterol (mg/dL) (total, mean, SD.) High- density lipoprotein cholesterol (mg/dL) (total, mean, SD.) Triglyceride (mg/dL) (total, mean, SD.) Uric acid (mg/dL) (total, mean, SD.) Microalbuminuria (mg/g Cr.) (total, mean, SD.) Chronic vascular complications Coronary arterial disease Cerebrovascular disease Diabetic nephropathy Diabetic retinopathy Diabetic peripheral neuropathy Number of chronic vascular complications 0 chronic vascular complication 1 chronic vascular complication 2 chronic vascular complications 3 chronic vascular complications 4 chronic vascular complications 5 chronic vascular complications Metabolic components - Waist circumference (IDF) - Triglyceride (IDF) - High- density lipoprotein cholesterol (IDF) - Blood pressure (IDF) - Fasting plasma glucose (IDF) - Body mass index (WHO) - Microalbuminuria (WHO) - Uric acid
608 608
(13.4)
(57.8) 180 428
29.6 70.4
608 608
33 60 514 1.1 70.2
5.4 9.9 84.7 0.6 26.3
608 608 608 608 605 608 608 601 601 460 608
187 302 80 473 445 27.1 90.9 131.7 81.0 7.85 138.9
30.8 49.7 13.2 77.8 73.6 5.6 13.1 18.9 7.2 8.1 52.6
607 607
217.3 128.1
48.2 46.8
607
43.9
9.7
607 608 586
175.0 6.6 75.3
73.3 2.1 97.5
607 608 608 606 608
112 37 264 154 102
18.5 6.1 43.4 25.4 16.8
608 608 608 608 608 608
334 74 76 58 61 5
54.9 12.2 12.5 9.5 10.0 0.8
607 607 607
446 384 422
73.4 63.2 69.4
603 608 608 575 608
446 455 485 296 286
73.4 74.8 79.8 48.7 47.0
607
MDRD-GFR, Modification of Diet in Renal Disease-glomerular filtration rate; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers.
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Table 2 Numbers and percents of subjects with five chronic vascular complications among different levels of uric acid and microalbuminuria. Categories
Coronary arterial Disease
Cerebrovascular disease
No
Yes
No
20 6.2% 18 21.2% 22 32.8% 52 39.7% 24 5.5% 39 43.3% 49 58.3%
Uric acid (mg/dl) 2.6–7.2
304 93.8% 7.3–8.0 67 78.8% 8.1–8.5 45 67.2% 8.6–13.1 79 60.3% Microalbuminuria (mg/g Cr.) b 57.7 409 94.5% 57.8–299 51 56.7% ≥ 300 35 41.7%
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
Yes
No
No
Yes
No
Yes
316 97.5% 69 81.2% 62 92.5% 124 93.9%
8 2.5% 16 18.8% 5 7.5% 8 6.1%
259 79.9% 29 34.1% 18 26.9% 38 28.8%
65 20.1% 56 65.9% 49 73.1% 94 71.2%
282 87.3% 56 66.7% 37 55.2% 77 58.3%
41 12.7% 28 33.3% 30 44.8% 55 41.7%
302 93.2% 66 77.6% 45 67.2% 93 70.5%
22 6.8% 19 22.4% 22 32.8% 39 29.5%
419 96.5% 78 86.7% 74 88.1%
15 3.5% 12 13.3% 10 11.9%
344 79.3% 0 .0% 0 .0%
90 20.7% 90 100.0% 84 100.0%
397 91.9% 35 38.9% 20 23.8%
35 8.1% 55 61.1% 64 76.2%
418 96.3% 53 58.9% 35 41.7%
16 3.7% 37 41.1% 49 58.3%
Patients with positive test of urinary infections were excluded from the statistical analysis. The urinary albumin concentrations were determined by immunoassay (Dade Behring, Dimension RxL). DR was evaluated by an ophthalmologist and graded as: absent, background, non-proliferative and proliferative (Klein et al., 1986). Diabetic peripheral neuropathy (PN) was assessed by a history of symptoms and physical examination (10 g monofilament, deep tendon reflex, 128-Hz vibration). Patients having neuropathic symptoms with more than one sign or using medication to relieve neuropathic pain were considered to have peripheral neuropathy. CAD and CVD were examined from the history of myocardial infarction and strokes from medical records. The diagnosis of CAD was also based on the presence of angina symptom and abnormalities in resting electrocardiography (ECG).
Yes
(S.D., 97.49), respectively. The most common chronic vascular complications of diabetes in this population were diabetic nephropathy (43.4%), diabetic retinopathy (25.4%) and coronary arterial disease (18.5%). 54.9% of the subjects had no complication, while 45.1% had 1–5 complications. A high prevalence of metabolic syndromes, based on International Diabetes Federation (IDF) and World Health Organization (WHO) criteria was found; high BMI (79.8%), and over-limited levels of fasting plasma glucose (74.8%), waist circumference (73.4%), and blood pressure (73.4%). Numbers and proportion of complications with particular categories of uric acid and microalbuminuria levels are shown in Table 2. We observed that, in the T2DM population, severity of complications, such as coronary arterial disease, diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy, was increasing in a similar
2.4. Statistical analysis
3. Results Characteristics of the subjects in the study are shown in the Table 1. Six hundred subjects were included with an average age of 57.8 years old. The majority are females (70.4%). Average body mass index (BMI) and waist circumference were 27.08 kg/m 2 (S.D., 5.60), and 90.94 cm. (S.D., 13.13) respectively. Mean levels of uric acid, and microalbuminuria were 6.61 mg/dL (S.D., 2.10) and 75.34 mg/g Cr.
Levels of uric acid (mg/dl)
A 10 9 8 7 6 5 4 3 2 1 0 0
1
2
3
4
5
Number of chronic vasuclar complications
B Levels of microalbuminuria (mg/g Cr.)
The data were analyzed by SPSS version 11.5. Percents and means with standard deviations of variables were calculated for descriptive statistics, and logistic regressions were used to estimate odds ratios between uric acid and microalbuminuria levels to chronic vascular complications. Subjects with the various levels of uric acid were categorized into normal (not more than 7.2 mg/dL) (Chizynski & Rozycka, 2005); subjects with the levels that were higher than 7.2 mg/dL were divided into 3 groups equally to make 4 groups in total. Microalbuminuria levels were initially grouped into normal (b30 mg/g Cr.), positive microalbuminuria (30–299 mg/g Cr.), and macroalbuminuria (≥ 300 mg/g Cr.) (Klausen et al., 2005). Then the positive microalbuminuria group was divided into two groups of equal number, and the group with lower level was combined with the normal group. Finally, a total of three groups were created. A combination of complications was calculated by combining the five complications that include coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy. A two-sided p-value of b 0.05 was considered statistically significant.
350 300 250 200 150 100 50 0 0
1
2
3
4
5
Number of chronic vascular complications Fig. 1. Means and standard deviations of levels of uric acid (A) and microalbuminuria (B) among subjects with a number of chronic vascular complications.
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Table 3 Numbers and percents of subjects with five chronic vascular complications among different levels of uric acid and microalbuminuria. Categories
Coronary arterial disease
Un-adjusted ORs Uric acid (mg/dl) 2.6–7.2 7.3–8.0
1 4.1 2.0–8.1 8.1–8.5 7.4 3.8–14.7 8.6–13.1 10 5.6–17.7 Microalbuminuria (mg/g Cr.) b 57.7 1 57.8–299 ≥ 300
13 7.3–23.4 23.9 13.1–43.4
Adjusted ORs Uric acid (mg/dl) 2.6–7.2 7.3–8.0
1 2.5 1.1–5.6 8.1–8.5 2.5 1.1–5.5 8.6–13.1 3.9 2.0–7.7 Microalbuminuria (mg/g Cr.) b 57.7 1 57.8–299 ≥ 300
2.8 1.4–5.6 7.6 3.4–16.8
Cerebrovascular disease
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
1 9.2 3.8–22.3 3.2 1.01–10.1 2.5 0.9–6.9
1 7.7 4.6–13.0 10.8 5.9–19.9 9.9 6.2–15.7
1 3.4 2.0–6.0 5.6 3.1–10.0 4.9 3.1–7.9
1 4 2.0–7.7 6.7 3.4–13.1 5.8 3.2–10.2
1
1
1
4.3 1.9–9.5 3.8 1.6–8.7
NA NA NA NA NA NA
17.8 10.3–30.8 36.3 19.7–66.8
18.2 9.5–35.0 36.6 18.9–70.9
1 13.1 3.9–43.4 3.4 0.8–14.0 2.6 0.7–9.6
1 10.2 4.5–23.2 4.7 2.1–10.6 6.6 3.4–13.0
1 3.5 1.5–8.0 1.9 0.9–3.9 2.0 1.1–3.9
1 3.2 1.4–7.5 2.4 1.1–5.2 2.3 1.1–4.6
1
NA NA NA NA NA NA
1
1
1.9 1.1–3.5 6.6 3.1–14.2
2.5 1.3–5.1 6.1 2.8–13.3
0.9 0.3–2.6 1.5 0.4–4.9
Adjusted for MDRD-GFR, smoking, statin user, ACEI user and ARB user including microalbuminuria and uric acid for each other.
proportion as serum uric acid increase; in other words, higher levels of serum uric acid are found, in the T2DM patients with more complications (Fig. 1-A). Similar relationships were observed in the relationship between microalbuminuria and the complications (Fig. 1-B), with the exception of diabetic nephropathy. The associations between chronic vascular complications and levels of uric acid and microalbuminuria were reported in non-adjusted and adjusted odds ratios (see Table 3). The data from unadjusted and adjusted odds ratios were mostly similar. The odds ratios for microalbuminuria were found to be higher than those of uric acid (Fig. 1-A, and B). Notably, we did not calculate the odd ratios between diabetic nephropathy and microalbuminuria, because the level of microalbuminuria was one of the diagnostic parameters used to diagnose the diabetic nephropathy complication. The levels of uric acid at average of 5.6 and 6.3 mg/dl were correlated to increased percentage in chronic vascular complications of microvascular complications (diabetic nephropathy or DN, diabetic retinopathy or DR, and diabetic peripheral neuropathy or PN) and macrovascular complications (cerebrovascular disease or CVD and coronary arterial disease or CAD), respectively as shown in Fig. 2-A. Microalbuminuria at the approximate level of 10.8 mg/ g Cr. was associated with elevated number in percent of chronic vascular complications (CVD, CAD, DR, and PN) with the exception of DN (Fig. 2-B). The linear regression equations describing the associations between the levels of uric acid and microalbuminuria to diabetic chronic vascular complications (CAD, CVD, DN, DR and PN), were shown in Table 4. The ROC curve at sensitivities of 100% shows that the levels of uric acid (4.1, 4.2, 3.1, 3.1, and 4.1 mg/dl); microalbuminuria (15.5, 8.6, 31.3, 3.3, and 15.3 mg/g Cr.) were correlated respectively to these chronic vascular complications: cerebrovascular disease, coronary arterial disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy (Table 5).
4. Discussion Our study showed the positive correlations between the increasing levels of uric acid/microalbuminuria and the severity of chronic vascular complications in T2DM patients. Both elevated uric acid and microalbuminuria levels may be rendered by common underlying pathogenesis of insulin resistance in T2DM (Hsu et al., 2011; Modan, Halkin, Karasik, & Lusky, 1987). Hyperinsulinemia resulting from insulin resistance in T2DM negatively affects renal excretion, increases rates of renal reabsorption, and the production of uric acid (Modan et al., 1987). It was also proposed that the abnormality of metabolic components in DM could also promote increase of uric acid and microalbuminuria levels by raising excretion of purine metabolism (Nakagawa et al., 2006) and increasing transvascular albumin leakage and glomerular hypertension (Stehouwer et al., 2002). Uric acid and microalbuminuria levels have been shown to play roles in an induction of some inflammatory cytokines (hs-CRP, IL-6, and TNF-α), and oxidative stress. The induction of the cytokines and oxidative stress was speculated to contribute to the pathogenesis of diabetic vascular complications (Ceriello & Motz, 2004; Costa, Canani, Lisboa, Tres, & Gross, 2004; Deckert et al., 1992; Giacco & Brownlee, 2010; Isomaa et al., 2001; Nakagawa et al., 2006; Newman et al., 2005). Metabolic syndrome in DM, which is a cluster of cardiovascular risk factors (insulin resistance or hyperinsulinemia, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and obesity) and is a proposed predictor for diabetic vascular complications, was suggested to be correlated with microalbuminuria (Brantsma et al., 2005) and hyperuricemia (Chien et al., 2008; Costa et al., 2002; Ishizaka, Ishizaka, Toda, Nagai, & Yamakado, 2005). Both hyperuricemia and microalbuminuria now share a respected inclusion as two of the novel risk markers—risk factors related between
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Fig. 2. Percent of chronic vascular complications (cerebrovascular disease or CVD, coronary arterial disease or CAD, diabetic nephropathy or DN, diabetic retinopathy or DR and peripheral neuropathy or PN) at various levels of uric acid (A) and microalbuminuria (B).
metabolic control and diabetic vascular complications in DM by inflammatory responses via reactive oxygen species (Dehghan et al., 2008; Festa et al., 2000; Hayden & Tyagi, 2004). Several proatherogenic properties have been attributed to uric acid and microalbuminuria including activation of endothelial cells (Chapman et al., 1997; Goldberg, 2009; Stehouwer, Lambert, Donker, & Van Hinsbergh, 1997; Stehouwer et al., 2002), platelets activation, and increased platelet adhesiveness (Goldberg, 2009; Johnson et al., 2003; Stehouwer et al., 1997, 2002). Uric acid and microalbuminuria have also been shown to stimulate production of interleukin 1β, interleukin 6, tumor necrosis factor α in human mononuclear cells, as well as C-reactive protein in cultured human vascular cells (Goldberg, 2009; Kanellis & Kang, 2005; Stehouwer et al., 1997, 2002). A recent study (Nakagawa et al., 2006) showed that uric acid may have a causal role in the metabolic syndrome. Reducing uric acid level in fructose-fed rats can improve the components of metabolic syndrome, namely hyperinsulinemia, hypertriglyceridemia, hypertension, and body weight (Nakagawa et al., 2006). In agreement to that, another study found that high uric acid level maybe associated with hyperinsulinemia and the early onset or increased progression to overt nephropathy in the patients with DM (Bo et al., 2001). Two recent studies showed that increased serum level of uric acid in T2DM was associated with presence and severity of diabetic peripheral neuropathy (PN) (sudomotor dysfunction, evaluated by the Neuropad test) (Papanas et al., 2011), and peripheral neuropathy (diagnosed by the Neuropathy Disability Score) (Papanas et al., 2011). Several studies also suggested that an increase of uric acid and microalbuminuria levels may be novel surrogate markers to predict incidence of DM (Brantsma et al., 2005; Chien et al., 2008; Costa et al., 2002; Dehghan et al., 2008; Kodama et al., 2009; Kramer, Von Muhlen,
Jassal, & Barrett-Connor, 2009), microvascular complications (DN, DR, and DPN) (Fukui et al., 2008; Stehouwer et al., 2002; Tai et al., 1990), and macrovascular complications (CAD, CVD, and PAD) (Festa et al., 2000; Fukui et al., 2008; Hayden & Tyagi, 2004; Ishizaka et al., 2005; Zoppini et al., 2009). Importantly, data from a study showed the highly significant correlations between urinary albumin and long-term cardiovascular risk in acute coronary syndrome patients (Nazer, Ray, Murphy, Gibson, & Cannon, 2013). We were interested to see, if the levels of uric acid and microalbuminuria may be used as a marker to predict the progression of the complications in T2DM patients. Our study showed that the two points of uric acid levels equal to or greater than 5.6 and 6.3 mg/dl could be closely monitored for potential occurrence of both microvascular complications (diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy), and macrovascular complications (cerebrovascular disease and coronary arterial disease). In addition, the results indicated that the MAU level equal to or over 10.8 mg/g Cr. may be a rather highly sensitive threshold that indicates the abnormality of metabolic components. It may be used for monitoring an emerging of the chronic vascular complications (cerebrovascular disease, coronary arterial disease, diabetic retinopathy, and diabetic peripheral neuropathy). This present study is the first to report on linear associations of both higher uric acid and microalbuminuria levels to the increasing numbers of chronic micro/macro-vascular complications in DM. Of note, our data demonstrated that the levels, which are well below the recommended levels for hyperuricemia (Chizynski & Rozycka, 2005) and MAU (30 mg/g Cr.) (Kanellis & Kang, 2005), could be predictive for both chronic microvascular and macrovascular complications in DM. We also demonstrated a linear regression equation that describes the association between the levels of uric acid and microalbuminuria to diabetic chronic vascular complications (CAD, CVD, DN, DR and PN) (Table 4).Thus, our data may be used as early signs in a general clinical practice for monitoring the levels of uric acid and microalbuminuria in order to control the metabolic abnormality in T2DM patients for prevention of chronic vascular complications. Because of the nature of the cross-sectional design of this study, there may be interference among the data. This could be influenced by the treatments of diabetes, hypertension, and dyslipidemia received by patients. Such ongoing treatments necessarily complicated analyses of the patients with DM, yet were essential for the patients. In our study, only a small number of our subjects that eventually developed cerebrovascular complications were observed (only 6% of the total number of subjects). This may affect the power of the statistical analysis of our study. Larger prospective trials and intervention studies are required to better assess the associations. In conclusion, we found that increase of both uric acid and microalbuminuria levels was significantly associated with the severity of the chronic vascular complications in the T2DM patients. We proposed that they may be useful as predictors for monitoring the chronic micro/macro-vascular complications in patients with type 2 diabetes. Regular measurements of uric acid and microalbuminuria
Table 4 Linear regression equations for the associations between uric acid level (Fig. 2A)/MAU (Fig. 2B), and complications. Linear regression equations for the association between uric acid level and complications
Linear regression equation for the association between MAU and complications
CAD: CVD: DN: DR: PN: CAD: CVD: DN: DR: PN:
y y y y y y y y y y
= = = = = = = = = =
0.046x 0.009x 0.084x 0.052x 0.040x 0.071x 0.015x 0.148x 0.097x 0.071x
− + − − − − − − − −
0.077; 0.007; 0.040; 0.032; 0.054; 0.196; 0.024; 0.341; 0.257; 0.208;
R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
= = = = = = = = = =
0.873 0.308 0.910 0.858 0.868 0.866 0.496 0.796 0.855 0.823
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Table 5 Levels of uric acid and microalbuminuria from ROC curve at sensitivities of 100%, 95% and 90%. Levels
Sensitivity
Cerebrovascular disease
Coronary arterial disease
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
Uric acid (mg/dl)
100% 95% 90% 100% 95% 90%
4.1 5.0 5.4 15.5 38.2 38.9
4.2 4.8 5.3 8.6 39.8 46.8
3.1 4.5 5.2 31.3 38.9 43.7
3.1 4.8 5.2 3.3 42.7 46.8
4.1 4.8 5.3 15.3 46.8 49.4
Microalbuminuria (mg/g Cr.)
levels in patients with type 2 diabetes could help physicians in clinical practice to be alerted to the development of chronic vascular complications. Acknowledgments This study was funded by a research grant to S.C. from faculty of medicine for medical science, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University. S.J. is supported by “Chalermphrakiat” Grant, Faculty of Medicine Siriraj Hospital, Mahidol University. References Alberti, K. G., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, K. A., et al. (2009). Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 120(16), 1640–1645. Alberti, K. G., & Zimmet, P. Z. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine, 15(7), 539–553. Bo, S., Cavallo-perin, P., Gentile, L., Repetti, E., & Pagano, G. (2001). Hypouricemia and hyperuricemia in type 2 diabetes: Two different phenotypes. European Journal of Clinical Investigation, 31(4), 318–321. Brantsma, A. H., Bakker, S. J., Hillege, H. L., De Zeeuw, D., De Jong, P. E., & Gansevoort, R. T. (2005). Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care, 28(10), 2525–2530. Ceriello, A., & Motz, E. (2004). Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(5), 816–823. Chapman, P. T., Yarwood, H., Harrison, A. A., Stocker, C. J., Jamar, F., Gundel, R. H., et al. (1997). Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: In vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1. Arthritis and Rheumatism, 40(5), 955–965. Chien, K. L., Chen, M. F., Hsu, H. C., Chang, W. T., Su, T. C., Lee, Y. T., et al. (2008). Plasma uric acid and the risk of type 2 diabetes in a Chinese community. Clinical Chemistry, 54(2), 310–316. Chizynski, K., & Rozycka, M. (2005). Hyperuricemia. Polski Merkuriusz Lekarski, 19(113), 693–696. Costa, L. A., Canani, L. H., Lisboa, H. R., Tres, G. S., & Gross, J. L. (2004). Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabetic Medicine, 21(3), 252–255. Costa, A., Iguala, I., Bedini, J., Quinto, L., & Conget, I. (2002). Uric acid concentration in subjects at risk of type 2 diabetes mellitus: Relationship to components of the metabolic syndrome. Metabolism, 51(3), 372–375. Deckert, T., Kofoed-Enevoldsen, A., Norgaard, K., Borch-Johnsen, K., Feldt-Rasmussen, B., & Jensen, T. (1992). Microalbuminuria. Implications for micro- and macrovascular disease. Diabetes Care, 15(9), 1181–1191. Dehghan, A., Van Hoek, M., Sijbrands, E. J., Hofman, A., & Witteman, J. C. (2008). High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care, 31(2), 361–362. Festa, A., D'Agostino, R., Howard, G., Mykkanen, L., Tracy, R. P., & Haffner, S. M. (2000). Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney International, 58(4), 1703–1710. Fukui, M., Tanaka, M., Shiraishi, E., Harusato, I., Hosoda, H., Asano, M., et al. (2008). Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metabolism, 57(5), 625–629. Giacco, F., & Brownlee, M. (2010). Oxidative stress and diabetic complications. Circulation Research, 107(9), 1058–1070. Goldberg, R. B. (2009). Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. Journal of Clinical Endocrinology and Metabolism, 94(9), 3171–3182. Hayden, M. R., & Tyagi, S. C. (2004). Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle. Nutrition & Metabolism (London), 1(1), 10.
Hsu, C. C., Chang, H. Y., Huang, M. C., Hwang, S. J., Yang, Y. C., Tai, T. Y., et al. (2011). Association between insulin resistance and development of microalbuminuria in type 2 diabetes: A prospective cohort study. Diabetes Care, 34(4), 982–987. Ishizaka, N., Ishizaka, Y., Toda, E., Nagai, R., & Yamakado, M. (2005). Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(5), 1038–1044. Isomaa, B., Henricsson, M., Almgren, P., Tuomi, T., Taskinen, M. R., & Groop, L. (2001). The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes. Diabetologia, 44(9), 1148–1154. Johnson, R. J., Kang, D. H., Feig, D., Kivlighn, S., Kanellis, J., Watanabe, S., et al. (2003). Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension, 41(6), 1183–1190. Kanellis, J., & Kang, D. H. (2005). Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Seminars in Nephrology, 25(1), 39–42. Kim, E. S., Kwon, H. S., Ahn, C. W., Lim, D. J., Shin, J. A., Lee, S. H., et al. (2011). Serum uric acid level is associated with metabolic syndrome and microalbuminuria in Korean patients with type 2 diabetes mellitus. Journal of Diabetes and its Complications, 25(5), 309–313. Klausen, K. P., Scharling, H., Jensen, G., & Jensen, J. S. (2005). New definition of microalbuminuria in hypertensive subjects: Association with incident coronary heart disease and death. Hypertension, 46(1), 33–37. Klein, R., Klein, B. E., Magli, Y. L., Brothers, R. J., Meuer, S. M., Moss, S. E., et al. (1986). An alternative method of grading diabetic retinopathy. Ophthalmology, 93(9), 1183–1187. Kodama, S., Saito, K., Yachi, Y., Asumi, M., Sugawara, A., Totsuka, K., et al. (2009). Association between serum uric acid and development of type 2 diabetes. Diabetes Care, 32(9), 1737–1742. Koenig, W., & Meisinger, C. (2008). Uric acid, type 2 diabetes, and cardiovascular diseases: Fueling the common soil hypothesis? Clinical Chemistry, 54(2), 231–233. Kramer, C. K., Von Muhlen, D., Jassal, S. K., & Barrett-Connor, E. (2009). Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: The Rancho Bernardo Study. Diabetes Care, 32(7), 1272–1273. Modan, M., Halkin, H., Karasik, A., & Lusky, A. (1987). Elevated serum uric acid—a facet of hyperinsulinaemia. Diabetologia, 30(9), 713–718. Nakagawa, T., Hu, H., Zharikov, S., Tuttle, K. R., Short, R. A., Glushakova, O., et al. (2006). A causal role for uric acid in fructose-induced metabolic syndrome. American Journal of Physiology. Renal Physiology, 290(3), F625–F631. Nazer, B., Ray, K. K., Murphy, S. A., Gibson, C. M., & Cannon, C. P. (2013). Urinary albumin concentration and long-term cardiovascular risk in acute coronary syndrome patients: A PROVE IT-TIMI 22 substudy. Journal of Thrombosis and Thrombolysis, 36(3), 233–239. Newman, D. J., Mattock, M. B., Dawnay, A. B., Kerry, S., McGuire, A., Yaqoob, M., et al. (2005). Systematic review on urine albumin testing for early detection of diabetic complications. Health Technology Assessment, 9(30), iii-vi–xiii-163. Papanas, N., Demetriou, M., Katsiki, N., Papatheodorou, K., Papazoglou, D., Gioka, T., et al. (2011). Increased serum levels of uric acid are associated with sudomotor dysfunction in subjects with type 2 diabetes mellitus. Experimental Diabetes Research, 2011, 346051. Papanas, N., Katsiki, N., Papatheodorou, K., Demetriou, M., Papazoglou, D., Gioka, T., et al. (2011). Peripheral neuropathy is associated with increased serum levels of uric acid in type 2 diabetes mellitus. Angiology, 62(4), 291–295. Redon, J. (2006). New insights into urinary proteins as markers of cardiovascular risk in hypertension. Journal of Hypertension, 24(3), 447–449. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care, 26(Suppl. 1). (2003)., S5–S20. Silver, A., Dawnay, A., Landon, J., & Cattell, W. R. (1986). Immunoassays for low concentrations of albumin in urine. Clinical Chemistry, 32(7), 1303–1306. Stehouwer, C. D., Gall, M. A., Twisk, J. W., Knudsen, E., Emeis, J. J., & Parving, H. H. (2002). Increased urinary albumin excretion, endothelial dysfunction, and chronic lowgrade inflammation in type 2 diabetes: Progressive, interrelated, and independently associated with risk of death. Diabetes, 51(4), 1157–1165. Stehouwer, C. D., Lambert, J., Donker, A. J., & Van Hinsbergh, V. W. (1997). Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovascular Research, 34(1), 55–68. Tai, T. Y., Chuang, L. M., Tseng, C. H., Wu, H. P., Chen, M. S., & Lin, B. J. (1990). Microalbuminuria and diabetic complications in Chinese non-insulin-dependent diabetic patients: A prospective study. Diabetes Research and Clinical Practice, 9(1), 59–63. Zoppini, G., Targher, G., Negri, C., Stoico, V., Perrone, F., Muggeo, M., et al. (2009). Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care, 32(9), 1716–1720.
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Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes☆,☆☆ Somlak Chuengsamarn a,⁎, Suthee Rattanamongkolgul b, Siwanon Jirawatnotai c a b c
Division of Endocrinology and Metabolism, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornnayok, Thailand Department of Preventive and Social Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornnayok, Thailand Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 25 August 2013 Received in revised form 1 December 2013 Accepted 4 December 2013 Available online 12 December 2013 Keywords: Uric acid Microalbuminuria Chronic vascular complications Type 2 diabetes
a b s t r a c t Aims: To investigate an association between serum uric acid/microalbuminuria and chronic micro/macrovascular complications in type 2 diabetic patients. Methods: This cross-sectional study enrolled 608 patients with type 2 diabetes. All subjects were examined and basic information on health of the subjects was recorded for inclusion criteria. Several chemical parameters (fasting plasma glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, uric acid, and microalbuminuria), and related chronic vascular complications were measured and recorded in data forms. Results: Logistic regressions were used to analyse odds ratios between uric acid/microalbuminuria levels and several chronic vascular complications. Prevalence of chronic vascular complications in T2DM patients, namely coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy was significantly correlated with increase of uric acid level [2.29 (1.01–5.2), 16.01 (4.74–54.09), 9.99 (4.4–22.8), 4.43 (1.3–15.1), 4.37 (1.5–12.9)], and of microalbuminuria level [7.0 (3.6–13.8), 3.2 (1.2–8.7), NA, 14.7 (5.1–42.7), 7.2 (2.9–17.7)]. Conclusion: Both elevated uric acid and microalbuminuria levels were significantly associated with diabetic chronic micro/macro-vascular complications. Monitoring of uric acid and microalbuminuria levels provides a predictive value for a presence of chronic micro/macro-vascular complications in patients with type 2 diabetes. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Chronic vascular complications in type 2 diabetes (T2DM) are the deteriorating conditions underlined by inflammation (Ceriello & Motz, 2004). The chronic vascular complications in diabetes mellitus (DM) are classified by vascular size into macro- and microvascular diseases. The chronic vascular complications are a serious problem, since they generally yield devastating outcomes for the T2DM patients, which include coronary arterial disease (CAD), cerebrovascular disease (CVD), peripheral arterial disease (PAD), diabetic nephropathy (DN), diabetic retinopathy (DR), and diabetic peripheral neuropathy (PN) (Alberti & Zimmet, 1998). ☆ Conflict of interest: The authors declare that they have no conflict of interest. ☆☆ Grant support: This study was funded by a research grant to S.C. from Faculty of Medicine for Medical Science, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University. ⁎ Corresponding author at: Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, 63 M 7 Rungsit-Nakornnayok Rd., Ongkarak, Nakornnayok, Thailand. 26120. Tel.: +66 37 395085 6x11001; fax: +66 37 395085 6x11003. E-mail address: [email protected] (S. Chuengsamarn). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2013.12.002
Elevated levels of uric acid and microalbuminuria are commonly found in patients with severe cardiovascular diseases, such as stroke, and ischemic heart disease (Fukui et al., 2008; Hayden & Tyagi, 2004; Klausen, Scharling, Jensen, & Jensen, 2005; Redon, 2006). The elevated levels correlate with the severity of the conditions, namely, the higher the levels, the more severe the conditions (Kanellis & Kang, 2005; Kim et al., 2011; Newman et al., 2005; Tai et al., 1990). Although it is still unclear, the heightened levels are presumably a result of an upregulation of inflammatory cytokines, such as interleukin-6 (IL-6), C-reactive protein (CRP), and increased oxidative stress (Ceriello & Motz, 2004; Deckert et al., 1992; Giacco & Brownlee, 2010; Koenig & Meisinger, 2008; Newman et al., 2005). High levels of inflammation are regularly found in patients with T2DM. This observation is accompanied by the findings that there are correlations between increase of the serum uric acid level/microalbuminuria and severity of the insulin resistance and metabolic profiles (Costa, Iguala, Bedini, Quinto, & Conget, 2002; Dehghan, Van Hoek, Sijbrands, Hofman, & Witteman, 2008; Festa et al., 2000; Hsu et al., 2011; Kodama et al., 2009). It is not known; whether the inflammation associated with T2DM contributes to the elevated levels of serum uric acid and microalbuminuria, and whether or not there is a relationship
S. Chuengsamarn et al. / Journal of Diabetes and Its Complications 28 (2014) 124–129
between uric acid/microalbuminuria, and the inflammatory-driven chronic vascular conditions found in the T2DM patients. In the hope of identifying a reliable parameter that will allow an early detection of the micro- and macro-vascular complications in T2DM population, we investigated the relationships between levels of serum uric acid/ microalbuminuria, and the chronic vascular conditions in a T2DM population through a cross-sectional observation. The study also took into the consideration the information on other indicative parameters, such as duration of diabetes, hypertension status, smoking status, history of CAD, history of CVD, dyslipidemia status, uric acid, microalbuminuria (MAU), fasting plasma glucose (FPG), and hemoglobin A1C (HbA1C).
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lipoprotein cholesterol (b 40 mg/dl in men, b50 mg/dl in women), hypertension (≥ 130/85 mm/Hg), impaired fasting glucose (FPG ≥ 100 mg/dl). DN is defined by abnormalities in albumin excretion; the level of microalbuminuria (MAU) is ≥30 mg/g Cr, and the subject has positive results twice, consecutively (Klausen et al., 2005; Redon, 2006).The MAU was used by measurement of the albumin-to-creatinine ratio in an early morning spot urine, by the immunoassay method (Silver, Dawnay, Landon, & Cattell, 1986). MAU was classified into three groups; normal, microalbuminuria and macroalbuminuria as the following value of b 30, 30–299, ≥300 mg/g Cr, respectively (Klausen et al., 2005). Urinary infections were diagnosed by positive test of nitrites or leucocytes ≥ 250 leucocytes/ml in the urine sample.
2. Patients and methods 2.1. Subjects and designed study This study was a cross-sectional study by design. It included all patients who attended diabetic clinic in the outpatient unit of the Internal Medicine Department at HRH Princess Mahachakri Sirindhorn Medical Center, Faculty of Medicine, Srinakharinwirot University during the years 2007–2008. Inclusion criteria were type 2 diabetes aged of 35 or more. Type 2 diabetes was diagnosed according to the Report of the expert committee on the diagnosis and classification of diabetes mellitus (2003). We excluded patients taking any medications that might affect serum uric acid concentrations such as, thiazides, salicylates, pyrazinamide, ethambutol, nicotinic acid, and cyclosporine. Patients with advanced renal dysfunction by serum creatinine more than 2.0 mg/dl or urinary tract infection were excluded. The subjects were checked for blood chemistry profiles and examined for diabetic micro and macro-vascular complications by endocrinologists after the details of the project were explained to them and after they signed the consent form. This study was approved by the Ethic Committee of Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand (serial number: SWUEC 9/2550) in accordance with the Declaration of Helsinki. Participants were informed, and gave their consent before participation. 2.2. Data collection Basic information of patients and factors associated with increased diabetic complications were collected using case record form containing information of age, sex, weight, height, waist circumference, duration of diabetes, hypertension status, smoking status, history of CAD, and history of CVD, dyslipidemia status, uric acid, fasting plasma glucose(FPG), and haemoglobin A1C (HbA1C). The circumferences of the waist were measured at the level of the iliac crest. Blood samples were collected after a 12 h overnight fasting. Serum uric acid concentrations in our reference range (2.6– 7.2 mg/dl) were assessed using enzyme colorimetric method. Plasma fasting glucose was assessed using standard enzymatic method. Serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations were measured by standard enzymatic methods. The high-performance liquid chromatography was used for assay in HbA1C level. 2.3. Metabolic syndrome and chronic vascular complications Metabolic syndrome criteria were defined by the joint criteria (2009) (Alberti et al., 2009). Patients have metabolic syndrome, if they have central obesity by waist circumference (WC) ≥90 cm in men, or ≥80 cm in women (according to the recommendation by the joint criteria (2009) for Asian population), and any two of the following: elevated triglyceride (≥ 150 mg/dl), low High-density
Table 1 Characteristics of subjects in the study. Characteristics
Total Number (Mean)
Percent (S.D.)
Age (total, mean, SD.) Sex - Male -Female Smoking status - Current Smoking - Ex-Smoking - Non-Smoking Serum creatinine (mg/dL) mean MDRD-GFR (ml/min per 1.73m2) (total, mean, SD.) Insulin user (%) ACEI user (%) ARB user (%) Statin user (%) History of hypertension (%) Body mass index (kg/m2) (total, mean, SD.) Waist circumference (cm.) Systolic blood pressure (mmHg) Diastolic blood pressure(mmHg) Duration of diabetes (years) (total, mean, SD.) Fasting plasma glucose (mg/dL) (total, mean, SD.) Total cholesterol (mg/dL) (total, mean, SD.) Low-density lipoprotein cholesterol (mg/dL) (total, mean, SD.) High- density lipoprotein cholesterol (mg/dL) (total, mean, SD.) Triglyceride (mg/dL) (total, mean, SD.) Uric acid (mg/dL) (total, mean, SD.) Microalbuminuria (mg/g Cr.) (total, mean, SD.) Chronic vascular complications Coronary arterial disease Cerebrovascular disease Diabetic nephropathy Diabetic retinopathy Diabetic peripheral neuropathy Number of chronic vascular complications 0 chronic vascular complication 1 chronic vascular complication 2 chronic vascular complications 3 chronic vascular complications 4 chronic vascular complications 5 chronic vascular complications Metabolic components - Waist circumference (IDF) - Triglyceride (IDF) - High- density lipoprotein cholesterol (IDF) - Blood pressure (IDF) - Fasting plasma glucose (IDF) - Body mass index (WHO) - Microalbuminuria (WHO) - Uric acid
608 608
(13.4)
(57.8) 180 428
29.6 70.4
608 608
33 60 514 1.1 70.2
5.4 9.9 84.7 0.6 26.3
608 608 608 608 605 608 608 601 601 460 608
187 302 80 473 445 27.1 90.9 131.7 81.0 7.85 138.9
30.8 49.7 13.2 77.8 73.6 5.6 13.1 18.9 7.2 8.1 52.6
607 607
217.3 128.1
48.2 46.8
607
43.9
9.7
607 608 586
175.0 6.6 75.3
73.3 2.1 97.5
607 608 608 606 608
112 37 264 154 102
18.5 6.1 43.4 25.4 16.8
608 608 608 608 608 608
334 74 76 58 61 5
54.9 12.2 12.5 9.5 10.0 0.8
607 607 607
446 384 422
73.4 63.2 69.4
603 608 608 575 608
446 455 485 296 286
73.4 74.8 79.8 48.7 47.0
607
MDRD-GFR, Modification of Diet in Renal Disease-glomerular filtration rate; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers.
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S. Chuengsamarn et al. / Journal of Diabetes and Its Complications 28 (2014) 124–129
Table 2 Numbers and percents of subjects with five chronic vascular complications among different levels of uric acid and microalbuminuria. Categories
Coronary arterial Disease
Cerebrovascular disease
No
Yes
No
20 6.2% 18 21.2% 22 32.8% 52 39.7% 24 5.5% 39 43.3% 49 58.3%
Uric acid (mg/dl) 2.6–7.2
304 93.8% 7.3–8.0 67 78.8% 8.1–8.5 45 67.2% 8.6–13.1 79 60.3% Microalbuminuria (mg/g Cr.) b 57.7 409 94.5% 57.8–299 51 56.7% ≥ 300 35 41.7%
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
Yes
No
No
Yes
No
Yes
316 97.5% 69 81.2% 62 92.5% 124 93.9%
8 2.5% 16 18.8% 5 7.5% 8 6.1%
259 79.9% 29 34.1% 18 26.9% 38 28.8%
65 20.1% 56 65.9% 49 73.1% 94 71.2%
282 87.3% 56 66.7% 37 55.2% 77 58.3%
41 12.7% 28 33.3% 30 44.8% 55 41.7%
302 93.2% 66 77.6% 45 67.2% 93 70.5%
22 6.8% 19 22.4% 22 32.8% 39 29.5%
419 96.5% 78 86.7% 74 88.1%
15 3.5% 12 13.3% 10 11.9%
344 79.3% 0 .0% 0 .0%
90 20.7% 90 100.0% 84 100.0%
397 91.9% 35 38.9% 20 23.8%
35 8.1% 55 61.1% 64 76.2%
418 96.3% 53 58.9% 35 41.7%
16 3.7% 37 41.1% 49 58.3%
Patients with positive test of urinary infections were excluded from the statistical analysis. The urinary albumin concentrations were determined by immunoassay (Dade Behring, Dimension RxL). DR was evaluated by an ophthalmologist and graded as: absent, background, non-proliferative and proliferative (Klein et al., 1986). Diabetic peripheral neuropathy (PN) was assessed by a history of symptoms and physical examination (10 g monofilament, deep tendon reflex, 128-Hz vibration). Patients having neuropathic symptoms with more than one sign or using medication to relieve neuropathic pain were considered to have peripheral neuropathy. CAD and CVD were examined from the history of myocardial infarction and strokes from medical records. The diagnosis of CAD was also based on the presence of angina symptom and abnormalities in resting electrocardiography (ECG).
Yes
(S.D., 97.49), respectively. The most common chronic vascular complications of diabetes in this population were diabetic nephropathy (43.4%), diabetic retinopathy (25.4%) and coronary arterial disease (18.5%). 54.9% of the subjects had no complication, while 45.1% had 1–5 complications. A high prevalence of metabolic syndromes, based on International Diabetes Federation (IDF) and World Health Organization (WHO) criteria was found; high BMI (79.8%), and over-limited levels of fasting plasma glucose (74.8%), waist circumference (73.4%), and blood pressure (73.4%). Numbers and proportion of complications with particular categories of uric acid and microalbuminuria levels are shown in Table 2. We observed that, in the T2DM population, severity of complications, such as coronary arterial disease, diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy, was increasing in a similar
2.4. Statistical analysis
3. Results Characteristics of the subjects in the study are shown in the Table 1. Six hundred subjects were included with an average age of 57.8 years old. The majority are females (70.4%). Average body mass index (BMI) and waist circumference were 27.08 kg/m 2 (S.D., 5.60), and 90.94 cm. (S.D., 13.13) respectively. Mean levels of uric acid, and microalbuminuria were 6.61 mg/dL (S.D., 2.10) and 75.34 mg/g Cr.
Levels of uric acid (mg/dl)
A 10 9 8 7 6 5 4 3 2 1 0 0
1
2
3
4
5
Number of chronic vasuclar complications
B Levels of microalbuminuria (mg/g Cr.)
The data were analyzed by SPSS version 11.5. Percents and means with standard deviations of variables were calculated for descriptive statistics, and logistic regressions were used to estimate odds ratios between uric acid and microalbuminuria levels to chronic vascular complications. Subjects with the various levels of uric acid were categorized into normal (not more than 7.2 mg/dL) (Chizynski & Rozycka, 2005); subjects with the levels that were higher than 7.2 mg/dL were divided into 3 groups equally to make 4 groups in total. Microalbuminuria levels were initially grouped into normal (b30 mg/g Cr.), positive microalbuminuria (30–299 mg/g Cr.), and macroalbuminuria (≥ 300 mg/g Cr.) (Klausen et al., 2005). Then the positive microalbuminuria group was divided into two groups of equal number, and the group with lower level was combined with the normal group. Finally, a total of three groups were created. A combination of complications was calculated by combining the five complications that include coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy. A two-sided p-value of b 0.05 was considered statistically significant.
350 300 250 200 150 100 50 0 0
1
2
3
4
5
Number of chronic vascular complications Fig. 1. Means and standard deviations of levels of uric acid (A) and microalbuminuria (B) among subjects with a number of chronic vascular complications.
S. Chuengsamarn et al. / Journal of Diabetes and Its Complications 28 (2014) 124–129
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Table 3 Numbers and percents of subjects with five chronic vascular complications among different levels of uric acid and microalbuminuria. Categories
Coronary arterial disease
Un-adjusted ORs Uric acid (mg/dl) 2.6–7.2 7.3–8.0
1 4.1 2.0–8.1 8.1–8.5 7.4 3.8–14.7 8.6–13.1 10 5.6–17.7 Microalbuminuria (mg/g Cr.) b 57.7 1 57.8–299 ≥ 300
13 7.3–23.4 23.9 13.1–43.4
Adjusted ORs Uric acid (mg/dl) 2.6–7.2 7.3–8.0
1 2.5 1.1–5.6 8.1–8.5 2.5 1.1–5.5 8.6–13.1 3.9 2.0–7.7 Microalbuminuria (mg/g Cr.) b 57.7 1 57.8–299 ≥ 300
2.8 1.4–5.6 7.6 3.4–16.8
Cerebrovascular disease
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
1 9.2 3.8–22.3 3.2 1.01–10.1 2.5 0.9–6.9
1 7.7 4.6–13.0 10.8 5.9–19.9 9.9 6.2–15.7
1 3.4 2.0–6.0 5.6 3.1–10.0 4.9 3.1–7.9
1 4 2.0–7.7 6.7 3.4–13.1 5.8 3.2–10.2
1
1
1
4.3 1.9–9.5 3.8 1.6–8.7
NA NA NA NA NA NA
17.8 10.3–30.8 36.3 19.7–66.8
18.2 9.5–35.0 36.6 18.9–70.9
1 13.1 3.9–43.4 3.4 0.8–14.0 2.6 0.7–9.6
1 10.2 4.5–23.2 4.7 2.1–10.6 6.6 3.4–13.0
1 3.5 1.5–8.0 1.9 0.9–3.9 2.0 1.1–3.9
1 3.2 1.4–7.5 2.4 1.1–5.2 2.3 1.1–4.6
1
NA NA NA NA NA NA
1
1
1.9 1.1–3.5 6.6 3.1–14.2
2.5 1.3–5.1 6.1 2.8–13.3
0.9 0.3–2.6 1.5 0.4–4.9
Adjusted for MDRD-GFR, smoking, statin user, ACEI user and ARB user including microalbuminuria and uric acid for each other.
proportion as serum uric acid increase; in other words, higher levels of serum uric acid are found, in the T2DM patients with more complications (Fig. 1-A). Similar relationships were observed in the relationship between microalbuminuria and the complications (Fig. 1-B), with the exception of diabetic nephropathy. The associations between chronic vascular complications and levels of uric acid and microalbuminuria were reported in non-adjusted and adjusted odds ratios (see Table 3). The data from unadjusted and adjusted odds ratios were mostly similar. The odds ratios for microalbuminuria were found to be higher than those of uric acid (Fig. 1-A, and B). Notably, we did not calculate the odd ratios between diabetic nephropathy and microalbuminuria, because the level of microalbuminuria was one of the diagnostic parameters used to diagnose the diabetic nephropathy complication. The levels of uric acid at average of 5.6 and 6.3 mg/dl were correlated to increased percentage in chronic vascular complications of microvascular complications (diabetic nephropathy or DN, diabetic retinopathy or DR, and diabetic peripheral neuropathy or PN) and macrovascular complications (cerebrovascular disease or CVD and coronary arterial disease or CAD), respectively as shown in Fig. 2-A. Microalbuminuria at the approximate level of 10.8 mg/ g Cr. was associated with elevated number in percent of chronic vascular complications (CVD, CAD, DR, and PN) with the exception of DN (Fig. 2-B). The linear regression equations describing the associations between the levels of uric acid and microalbuminuria to diabetic chronic vascular complications (CAD, CVD, DN, DR and PN), were shown in Table 4. The ROC curve at sensitivities of 100% shows that the levels of uric acid (4.1, 4.2, 3.1, 3.1, and 4.1 mg/dl); microalbuminuria (15.5, 8.6, 31.3, 3.3, and 15.3 mg/g Cr.) were correlated respectively to these chronic vascular complications: cerebrovascular disease, coronary arterial disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy (Table 5).
4. Discussion Our study showed the positive correlations between the increasing levels of uric acid/microalbuminuria and the severity of chronic vascular complications in T2DM patients. Both elevated uric acid and microalbuminuria levels may be rendered by common underlying pathogenesis of insulin resistance in T2DM (Hsu et al., 2011; Modan, Halkin, Karasik, & Lusky, 1987). Hyperinsulinemia resulting from insulin resistance in T2DM negatively affects renal excretion, increases rates of renal reabsorption, and the production of uric acid (Modan et al., 1987). It was also proposed that the abnormality of metabolic components in DM could also promote increase of uric acid and microalbuminuria levels by raising excretion of purine metabolism (Nakagawa et al., 2006) and increasing transvascular albumin leakage and glomerular hypertension (Stehouwer et al., 2002). Uric acid and microalbuminuria levels have been shown to play roles in an induction of some inflammatory cytokines (hs-CRP, IL-6, and TNF-α), and oxidative stress. The induction of the cytokines and oxidative stress was speculated to contribute to the pathogenesis of diabetic vascular complications (Ceriello & Motz, 2004; Costa, Canani, Lisboa, Tres, & Gross, 2004; Deckert et al., 1992; Giacco & Brownlee, 2010; Isomaa et al., 2001; Nakagawa et al., 2006; Newman et al., 2005). Metabolic syndrome in DM, which is a cluster of cardiovascular risk factors (insulin resistance or hyperinsulinemia, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and obesity) and is a proposed predictor for diabetic vascular complications, was suggested to be correlated with microalbuminuria (Brantsma et al., 2005) and hyperuricemia (Chien et al., 2008; Costa et al., 2002; Ishizaka, Ishizaka, Toda, Nagai, & Yamakado, 2005). Both hyperuricemia and microalbuminuria now share a respected inclusion as two of the novel risk markers—risk factors related between
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Fig. 2. Percent of chronic vascular complications (cerebrovascular disease or CVD, coronary arterial disease or CAD, diabetic nephropathy or DN, diabetic retinopathy or DR and peripheral neuropathy or PN) at various levels of uric acid (A) and microalbuminuria (B).
metabolic control and diabetic vascular complications in DM by inflammatory responses via reactive oxygen species (Dehghan et al., 2008; Festa et al., 2000; Hayden & Tyagi, 2004). Several proatherogenic properties have been attributed to uric acid and microalbuminuria including activation of endothelial cells (Chapman et al., 1997; Goldberg, 2009; Stehouwer, Lambert, Donker, & Van Hinsbergh, 1997; Stehouwer et al., 2002), platelets activation, and increased platelet adhesiveness (Goldberg, 2009; Johnson et al., 2003; Stehouwer et al., 1997, 2002). Uric acid and microalbuminuria have also been shown to stimulate production of interleukin 1β, interleukin 6, tumor necrosis factor α in human mononuclear cells, as well as C-reactive protein in cultured human vascular cells (Goldberg, 2009; Kanellis & Kang, 2005; Stehouwer et al., 1997, 2002). A recent study (Nakagawa et al., 2006) showed that uric acid may have a causal role in the metabolic syndrome. Reducing uric acid level in fructose-fed rats can improve the components of metabolic syndrome, namely hyperinsulinemia, hypertriglyceridemia, hypertension, and body weight (Nakagawa et al., 2006). In agreement to that, another study found that high uric acid level maybe associated with hyperinsulinemia and the early onset or increased progression to overt nephropathy in the patients with DM (Bo et al., 2001). Two recent studies showed that increased serum level of uric acid in T2DM was associated with presence and severity of diabetic peripheral neuropathy (PN) (sudomotor dysfunction, evaluated by the Neuropad test) (Papanas et al., 2011), and peripheral neuropathy (diagnosed by the Neuropathy Disability Score) (Papanas et al., 2011). Several studies also suggested that an increase of uric acid and microalbuminuria levels may be novel surrogate markers to predict incidence of DM (Brantsma et al., 2005; Chien et al., 2008; Costa et al., 2002; Dehghan et al., 2008; Kodama et al., 2009; Kramer, Von Muhlen,
Jassal, & Barrett-Connor, 2009), microvascular complications (DN, DR, and DPN) (Fukui et al., 2008; Stehouwer et al., 2002; Tai et al., 1990), and macrovascular complications (CAD, CVD, and PAD) (Festa et al., 2000; Fukui et al., 2008; Hayden & Tyagi, 2004; Ishizaka et al., 2005; Zoppini et al., 2009). Importantly, data from a study showed the highly significant correlations between urinary albumin and long-term cardiovascular risk in acute coronary syndrome patients (Nazer, Ray, Murphy, Gibson, & Cannon, 2013). We were interested to see, if the levels of uric acid and microalbuminuria may be used as a marker to predict the progression of the complications in T2DM patients. Our study showed that the two points of uric acid levels equal to or greater than 5.6 and 6.3 mg/dl could be closely monitored for potential occurrence of both microvascular complications (diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy), and macrovascular complications (cerebrovascular disease and coronary arterial disease). In addition, the results indicated that the MAU level equal to or over 10.8 mg/g Cr. may be a rather highly sensitive threshold that indicates the abnormality of metabolic components. It may be used for monitoring an emerging of the chronic vascular complications (cerebrovascular disease, coronary arterial disease, diabetic retinopathy, and diabetic peripheral neuropathy). This present study is the first to report on linear associations of both higher uric acid and microalbuminuria levels to the increasing numbers of chronic micro/macro-vascular complications in DM. Of note, our data demonstrated that the levels, which are well below the recommended levels for hyperuricemia (Chizynski & Rozycka, 2005) and MAU (30 mg/g Cr.) (Kanellis & Kang, 2005), could be predictive for both chronic microvascular and macrovascular complications in DM. We also demonstrated a linear regression equation that describes the association between the levels of uric acid and microalbuminuria to diabetic chronic vascular complications (CAD, CVD, DN, DR and PN) (Table 4).Thus, our data may be used as early signs in a general clinical practice for monitoring the levels of uric acid and microalbuminuria in order to control the metabolic abnormality in T2DM patients for prevention of chronic vascular complications. Because of the nature of the cross-sectional design of this study, there may be interference among the data. This could be influenced by the treatments of diabetes, hypertension, and dyslipidemia received by patients. Such ongoing treatments necessarily complicated analyses of the patients with DM, yet were essential for the patients. In our study, only a small number of our subjects that eventually developed cerebrovascular complications were observed (only 6% of the total number of subjects). This may affect the power of the statistical analysis of our study. Larger prospective trials and intervention studies are required to better assess the associations. In conclusion, we found that increase of both uric acid and microalbuminuria levels was significantly associated with the severity of the chronic vascular complications in the T2DM patients. We proposed that they may be useful as predictors for monitoring the chronic micro/macro-vascular complications in patients with type 2 diabetes. Regular measurements of uric acid and microalbuminuria
Table 4 Linear regression equations for the associations between uric acid level (Fig. 2A)/MAU (Fig. 2B), and complications. Linear regression equations for the association between uric acid level and complications
Linear regression equation for the association between MAU and complications
CAD: CVD: DN: DR: PN: CAD: CVD: DN: DR: PN:
y y y y y y y y y y
= = = = = = = = = =
0.046x 0.009x 0.084x 0.052x 0.040x 0.071x 0.015x 0.148x 0.097x 0.071x
− + − − − − − − − −
0.077; 0.007; 0.040; 0.032; 0.054; 0.196; 0.024; 0.341; 0.257; 0.208;
R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
= = = = = = = = = =
0.873 0.308 0.910 0.858 0.868 0.866 0.496 0.796 0.855 0.823
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Table 5 Levels of uric acid and microalbuminuria from ROC curve at sensitivities of 100%, 95% and 90%. Levels
Sensitivity
Cerebrovascular disease
Coronary arterial disease
Diabetic nephropathy
Diabetic retinopathy
Diabetic peripheral neuropathy
Uric acid (mg/dl)
100% 95% 90% 100% 95% 90%
4.1 5.0 5.4 15.5 38.2 38.9
4.2 4.8 5.3 8.6 39.8 46.8
3.1 4.5 5.2 31.3 38.9 43.7
3.1 4.8 5.2 3.3 42.7 46.8
4.1 4.8 5.3 15.3 46.8 49.4
Microalbuminuria (mg/g Cr.)
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