Type 2 diabetes is a chronic metabolic disorder characterized by persistent hyperglycemia (1). It has been associated with increased risk of cardiovascular comorbidities and microvascular complications including nephropathy, retinopathy and neuropathy (2). Diabetes-related nephropathy and retinopathy are common causes of chronic kidney diseases and non-congenital blindness worldwide (3). However, knowledge of this among Ghanaians remain extremely low with only 17.7% and 5.4% of diabetics having knowledge about such microvascular complications as retinopathy and nephropathy respectively (4). With a diabetes prevalence of 6%, higher than the continental average of 4.7% (5, 6), diabetes and its complications present an enormous socioeconomic and health burden for people in developing countries (7). Therefore, with the development and severity of diabetic complications being dependent on the duration of the disease and how early it is detected and managed (8), there’s then the need to identify early markers, which will not only monitor disease progression and prognosis soon after diagnosis, but also predict the onset of micro-vascular complications.

Sialic acid, also referred to as N-acetyl neuraminic acid, comprises the terminal component of oligosaccharide chains of several glycoproteins and glycolipids (9). Serum sialic acid concentration is a marker of the acute phase response and constitutes the terminal component of many acute phase proteins including α1-acid glycoprotein, haptoglobin, fibrinogen, transferrin and complement (10). Levels of serum sialic acid are increased in several pathologic conditions such as inflammation and malignancy (11). A cytokine-induced acute phase response has been hypothesized to play an integral role in the pathophysiology of Type 2 diabetes mellitus (T2DM) (12). Elevated levels of sialic acid predict individual features of metabolic syndrome such as hypertension and dyslipidaemia independently of body mass index (BMI) (13). This study was therefore focused on determining the association between sialic acid and known metabolic risk factors of T2DM in microvascular complications.

Diabetic nephropathy and retinopathy were more prevalent in the female diabetics (68.3%, 66.7% respectively) than the male diabetics (31.7%, 33.3% respectively). However, while most risk factor parameters such as fasting blood glucose, HbA1c, blood pressure (SBP/DBP), and serum inflammatory markers did not show any statistically significant difference between the sexes, female diabetics also reported significantly lower levels of HDL-C (P=0.018), and significantly higher levels of BMI, VAI and BAI (P = 0.021, 0.001, and 0.007 respectively) (Table 1).

SSA levels were elevated among all the diabetic study participants regardless of whether one was having any microvascular complications or not (Table 2). However, serum sialic acid was significantly elevated among diabetics with retinopathy compared with those with nephropathy, and without complications (p-value = 0.005). HbA1c levels differed among the three groups (p-value = 0.005; significantly lower among those with nephropathy but similar between retinopathy and without complications). Blood pressure showed a significant difference across the various groups. Waist circumference, waist-to-hip ratio, adiposity indices, CRP and BMI showed no statistically significant difference on comparison among the groups.

When adjusted for age, increasing SSA levels shows a significantly moderate association with decreasing levels of triglycerides (r= -5.74, p-value = 0.003) among diabetics with retinopathy. Also, BAI showed moderate negative correlation with SSA (r= -0.419, p-value= 0.037) (Table 3). In an ANCOVA analysis adjusting for BAI and TG levels (Figure 2), mean SSA levels significantly differed between diabetics with retinopathy compared with those without complications (p-value =0.004).

A multiple linear regression analysis (stepwise) revealed that a one-point increase in Triglyceride level was associated with a significant decrease in SSA levels (-113.82, 95%CI: -181.91 to -45.74). Thus, variations in TG levels explains 33.2% of variations in SSA levels among diabetic patients with retinopathy, as shown by the R² value in Table 4. However, these significant changes were not observed among diabetic patients without complications and those with nephropathy (p-value >0.05).

Retinopathy and nephropathy are the major micro-vascular complications that lead to blindness and end-stage renal disease in diabetics (16). Many studies have indicated that diabetic complications are mainly due to the chronic hyperglycaemia that exerts its health effects through several mechanisms such as hypertension, dyslipidaemia, platelet activation, and altered endothelial metabolism (17). This study was therefore conducted to determine the association between sialic acid and known metabolic risk factors in Type 2 Diabetic patients with and without microvascular complications. Among the total number of patients recruited in this study, 68 presented with micro-vascular complications of which 39.7% had developed retinopathy and 60.3% had developed nephropathy. However, 54.7% of the diabetic patients did not have any microvascular complications.

There was an increasing trend in concentrations of serum sialic acid (SSA) levels among the diabetics in this study. Patients who had developed retinopathy had the highest level of SSA, followed by those who had developed nephropathy with the least levels seen in those without any microvascular complications. These concentrations of SSA in this study were higher than concentrations from diabetics in several other studies (18, 19) which found significantly elevated sialic acid levels in patients compared to their controls. These differences may be due to differences in methods used to measure SSA, the health status of the participants as well as individual differences in the SSA levels. In T2DM in general, the circulating sialic acid concentration is elevated in comparison with nondiabetic subjects (3). The vascular endothelium is enriched with sialic acid moieties which are released into circulation when there is extensive microvascular damage in T2DM. A cytokine-induced acute phase response exacerbated by the diabetic process has also been implicated to cause elevations in levels of SSA (20). This finding thus confirms that sialic acid may prove to be a useful marker in patients with T2DM particularly those with complications.

Diabetic patients with retinopathy had significantly higher SSA compared to those without any complications. This finding agrees with the study by Merat al (21)., and Crook et al. (22) but inconsistent with the study by Deepa et al. (23) who found no significant difference in serum sialic acid levels in diabetics with proliferative and non-proliferative retinopathy, non-retinopathic diabetics and non-diabetic patients. Again, unlike Prajna et al. (24) who observed significantly higher SSA among diabetics with nephropathy compared to patients without any complications, our results showed no significant difference between these category of diabetics. Khan et al. (25) in their study found significantly higher serum SSA levels in patients with retinopathy, nephropathy and coronary artery disease compared to diabetics who did not have complications. In this study, difference in SSA levels between patients who had developed retinopathy and those who had nephropathy did not reach statistical significance. Generally, sialic acid is bound to acute phase proteins with negligible free sialic acid in circulation. Thus, to explain further, the associations observed in this study, a study that evaluate free and bound SSA levels will be needed.

How, the likely explanation to these associations is that acute phase response and tissue injury caused by diabetic vascular complications is pronounced among patients with retinopathy. Sialic acid levels in plasma may be influenced by several factors including variations in the sialylation of apolipoproteins before their secretion into plasma; variations in the amount of sialic acid-containing apolipoproteins on lipoprotein in plasma; and modifications of the SSA on lipoprotein constituents following their secretion in plasma Crook et al. (22).

Hyperglycaemia is a significant stressor that has also been shown to cause chronic inflammation (12, 26). Elevated glucose levels could promote inflammation by increased oxidative stress (27), although the relationship between inflammation markers and glycaemic control is not been fully understood. SSA showed no significant relationship with HbA1c or FPG. This result is consistent with the findings of Lindberg et al. (28) who indicated that hyperglycaemia may be unlikely to have a major effect on the acute phase response in T2DM. Others studies (19, 24) have however found a significantly positive correlation between sialic acid, HbA1c and FPG.

Hypertension significantly impact the incidence and progression of cardiovascular events and microvascular complications (29). SBP was significantly higher in diabetic patients who had developed nephropathy than those with retinopathy in this current study. Aside CVDs, hypertension particularly magnifies risk of nephropathy which occurs in about 40% of diabetic patients (29). Population-based studies have shown that CVD mortality was 7.5 times greater among persons with T2DM and its risk was associated with elevated sialic acid levels (30, 31). Crook et al. (22) found significant association between total sialic acid and both SBP and DBP in their study although the relationship between the lipid-associated sialic acid levels and systolic pressure did not reach significance in T2DM. These findings are consistent with this study, where no significant association was observed between blood pressure and sialic acid.

Furthermore, there was no statistically significant difference in lipid parameters among the three categories of diabetic patients except for triglyceride levels, which showed a significant negative correlation with SSA levels among diabetics with retinopathy. Reports from other studies (32–34) have however indicated a significant correlation between sialic acid and TG, TC and LDL-C. Inconsistent with our findings, Crook et al. found no significant relationship between sialic acid and TG in diabetics with retinopathy (22).

Production of inflammatory mediators by visceral adipose tissue induces the release of acute-phase reactants in hepatocytes and endothelial cells (35). Elevated CRP levels have been associated with abdominal adiposity in some studies (36–40). Waist circumference, waist-to-hip ratio as well as BAI and VAI did not vary among the diabetic patients. However, while serum sialic acid showed a significantly inverse relationship with BAI among participants with retinopathy, it rather showed a non-significant positive correlation among those with nephropathy. In patients without any microvascular complications, SSA showed a significantly positive correlation with BAI.

The are some limitations which are vital when interpreting the findings of this study. First, the small sample size has a significant impact on the power, interpretation of the results and inconsistent findings with other studies. Second, the cross-sectional study design of the current study did not allow generalisation of our result in the general population, thus the utility of sialic acid estimation in early prediction and prevention of microvascular complication in diabetes. However, there were considerable number of studies that supported our study findings. Thus, a prospective cohort study with larger sample size, considering the measurement of bound and free sialic acid. in addition, to the routine analytes will be useful to evaluate this associations with precision.

Elevated serum sialic acid was associated with the presence nephropathic and retinopathic micro-vascular complications in type 2 diabetic patients. There was also direct association of HbA1c with elevation of SSA and CRP.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Committee of Human Research, Publications and Ethics, School of Medicine and Dentistry, KNUST, Kumasi. The patients/participants provided their written informed consent to participate in this study.

WO, AB, and CO designed the study. Research data collection and laboratory analysis was performed by AB and HA. The data analysis and interpretation were performed by HA, EA, EOA, and EAA. SA, HA, and AB wrote the manuscript. WO, CO, SA, EOA, and EA reviewed the manuscript. All authors read and approved the final manuscript.

This study did not receive funding from private, government or not-for-profit organization and was fully funded by authors.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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