1. INTRODUCTION:

Diabetes mellitus (DM) is a group of metabolic diseases characterized by elevated glucose level resulting from defects in insulin secretion or action^1,2. DM is a major global health problem affecting approximately 537 million people according to International Diabetes Federation (2021). By 2045, this number is expected to increase to 784 million. Approximately 90-95% of these cases are type 2 diabetes mellitus (T2DM)³. DM is a devastating disease⁴.

The estimated 5-year mortality rate in patients with T2DM is calculated as 18.9%. Diabetic complications, mainly cardiovascular diseases^5,6, neuropathy⁷, retinopathy⁸ and nephropathy⁷ with subsequent amputation⁹, usually lead to death¹⁰.

C-reactive protein (CRP) is a representative acute phase inflammation response protein. It is mainly synthesized in the liver, stimulated by inflammatory cytokines such as interleukin-6 (IL-6), and has a half-life of up to 19 hours¹¹. With the advancement of technology, a high sensitivity (Hs)-CRP assessment method was developed, enabling the measurement of CRP with high precision even at low concentration, or mild elevation such as that seen in chronic inflammation¹².

Subclinical inflammation has been observed in patients with T2DM. Inflammation has recently been suggested to be a crucial factor contributing to the development of T2DM. This systemic and subclinical inflammatory process is characterized by elevated circulating levels of inflammatory parameters, including CRP or Hs-CRP and inflammatory cytokines¹³. Some studies have examined the relationship between glycated haemoglobin (HbA_1c) and Hs-CRP in diabetic patients but the results were inconclusive¹⁴. Chronic CRP elevation may also have biologic effects on endothelial function, coagulation, fibrinolysis, oxidation of low-density lipoproteins (LDL), and atherosclerotic plaque stability¹⁵. Many studies have suggested that higher CRP levels are associated with increased risk of cardiovascular events such as coronary heart disease (CHD)¹⁶. The American Heart Association (AHA) has established that cardiovascular risk is dependent on Hs-CRP levels¹⁷. It is well known that HBA_1c levels reflects the average glycaemic control over the previous 3 months. Studies also showed that HBA_1C concentration elevation was an independent factor in the increase of cardiovascular risk¹⁸. The aim of this study was to evaluate the association between Hs-CRP level and both glycaemic control and CHD in Syrian type 2 diabetes mellitus (T2DM) patients.

2. MATERIALS AND METHODS:

A cross-sectional study was conducted between September 2018 and July 2019. The study population included one hundred and eight subjects (N=108). Randomly selected patients and healthy controls were seen at Diabetes Centre and the outpatient clinic of the cardiology department at Tishreen University Hospital in Latakia, Syria. Four groups were formed: Group 1 (diabetic individuals without CHD, N=29), Group 2 (non-diabetic individuals with CHD, N=25), Group 3 (diabetic individuals with CHD, N=29), and Group 4 (healthy controls, N=25). The exclusion criteria included type 1 diabetes mellitus, active liver or kidney diseases, chronic pancreatitis, gastrointestinal diseases, recent infectious diseases, endocrine disorders, and autoimmune diseases.

After providing written informed consent, needed information, such as age and gender, were collected for study participants. All subjects were clinically examined, and body parameters, including height and weight, were measured without shoes and/or cap. Body mass index (BMI) was expressed as weight/height squared (Kg/m²). Seven millilitres of venous blood were collected from all subjects. Two millilitres of each sample were placed in vacationer tubes containing EDTA to be used in measuring HbA_1c level by fast ion-exchange resin separation method¹⁹. The other 5ml of blood were placed in plain tubes and centrifuged to obtain serum, which was used to measure the levels of Hs-CRP by turbidimetry assay.

Statistical analysis was carried out using Statistical Package for Social Sciences (SPSS, version 25). Results were shown as mean±SD. Analysis of variance (ANOVA) was used for comparison among groups. When ANOVA was significant, post-hoc LSD test (least significant difference) was used for the comparison between sub-groups. Person correlation test was used to correlate between Hs-CRP and BMI, HBA_1C, age, and sex. Adjusted logistic regression was performed using elevated Hs-CRP as the response and HBA_1C, BMI, age, sex as the predictors. Probability (P) value was considered statistically significant when it was less than 0.05.

3. RESULTS:

3.1. Main characteristics of study population:

Demographic characteristics and laboratory findings of the study population are presented in Table 1. There was no significant difference among all four groups in term of age, and gender. However, we found significant difference in BMI, Hs-CRP, and HBA_1Clevels among the groups.

Table1: Clinical and laboratory characteristics of patients and healthy control subjects

Variable	T2DM (+) CHD (-)	T2DM (-) CHD (+)	T2DM (+) CHD (+)	T2DM (-) CHD (-)	P value
Variable	Group 1 (N=29)	Group 2 (N=25)	Group 3 (N=29)	Group 4 (N=25)	P value
Age (year)	58.41 ± 8.24	57.24 ± 8.27	59.65 ± 5.94	56.4 ± 6.75	0.395
Male	16 (55.2%)	14 (56%)	14 (48.3%)	15 (60%)	0.858
Female	(44.8%)13	11 (44%)	15 (51.7%)	10 (40%)	0.858
BMI (Kg/m2)	28.84 ± 4.30	24.62 ± 3.66	28.84 ± 4.98	23.90 ± 3.51	<0.0001
Hb_A1c%	8.86 ± 2.58	5.62 ± 0.34	8.52 ± 1.98	4.65 ± 0.21	<0.0001
Hs-CRP (mg/l)	0.78± 2.29	2.56 ± 0.45	5.23 ± 1.56	0.16 ± 0.04	<0.0001

We further analyzed the differences between each two groups in terms of Hs-CRP, BMI, and HBA_1C using LSD sup-group analysis. Results are summarized in Table 2.

Table 2: Results of all sub-group analysis with post-hoc LSD test

Groups	Mean ± SD	Groups	Mean ± SD	P value
Hs-CRP (mg/l)
T2DM (+) CHD (+)	5.23 ± 1.56	T2DM (+) CHD (-)	0.78± 2.29	<0.0001
T2DM (+) CHD (+)	5.23 ± 1.56	T2DM (-) CHD (+)	2.56 ± 0.45	<0.0001
T2DM (+) CHD (+)	5.23 ± 1.56	T2DM (-) CHD (-)	0.16 ± 0.04	<0.0001
T2DM (+) CHD (-)	0.78± 2.29	T2DM (-) CHD (+)	2.56 ± 0.45	0.287
T2DM (+) CHD (-)	0.78± 2.29	T2DM (-) CHD (-)	0.16 ± 0.04	<0.0001
T2DM (-) CHD (+)	2.56 ± 0.45	T2DM (-) CHD (-)	0.16 ± 0.04	<0.0001
BMI (kg/m2)
T2DM (+) CHD (+)	28.84 ± 4.98	T2DM (+) CHD (-)	28.84 ± 4.30	0.999
T2DM (+) CHD (+)	28.84 ± 4.98	T2DM (-) CHD (+)	24.62 ± 3.66	<0.0001
T2DM (+) CHD (+)	28.84 ± 4.98	T2DM (-) CHD (-)	23.90 ± 3.51	<0.0001
T2DM (+) CHD (-)	28.84 ± 4.30	T2DM (-) CHD (+)	24.62 ± 3.66	<0.0001
T2DM (+) CHD (-)	28.84 ± 4.30	T2DM (-) CHD (-)	23.90 ± 3.51	<0.0001
T2DM (-) CHD (+)	24.62 ± 3.66	T2DM (-) CHD (-)	23.90 ± 3.51	0.548
HBA1C%
T2DM (+) CHD (+)	8.52 ± 1.98	T2DM (+) CHD (-)	8.86 ± 2.58	0.456
T2DM (+) CHD (+)	8.52 ± 1.98	T2DM (-) CHD (+)	5.62 ± 0.34	<0.0001
T2DM (+) CHD (+)	8.52 ± 1.98	T2DM (-) CHD (-)	4.65 ± 0.21	<0.0001
T2DM (+) CHD (-)	8.86 ± 2.58	T2DM (-) CHD (+)	5.62 ± 0.34	<0.0001
T2DM (+) CHD (-)	8.86 ± 2.58	T2DM (-) CHD (-)	4.65 ± 0.21	<0.0001
T2DM (-) CHD (+)	5.62 ± 0.34	T2DM (-) CHD (-)	4.65 ± 0.21	0.048

Mean serum Hs-CRP level was 0.16±0.04mg/l in healthy subjects, 2.29±0.78mg/l in T2DM patients without CHD, 2.56±0.45 in non-diabetic subjects with CHD, and 5.23±1.56mg/l in T2DM patients with CHD. As expected, mean Hs-CRP level was higher in subject with CHD than healthy controls (p<0.0001). Interestingly, mean Hs-CRP was higher in T2DM patients with or without CHD compared to healthy subjects (p<0.0001, for both). On the contrary, mean Hs-CRP level of T2DM patients without CHD was not different from non-diabetic subject with CHD (p=0.287). Mean Hs-CRP level in T2DM patients with CHD was higher not only than T2DM patients without CHD (p<0.0001), but also than non-diabetic subjects with CHD (p<0.0001).

Mean BMI was higher in T2DM patients without CHD (28.84±4.30Kg/m²) than healthy controls (23.9±3.51 Kg/m²) (p<0.0001) and non-diabetic subjects with CHD (24.62±3.66Kg/m²) (p<0.0001). Furthermore, BMI in T2DM patients with CHD (28.84±4.98Kg/m²) was higher than healthy controls (p<0.0001) and non-diabetic subjects with CHD (p<0.0001).

When we compared the four groups in term of HBA_1C, we found that mean HBA_1Clevel was higher in T2DM patients without CHD (8.86±2.58%) than healthy controls (4.65±0.21%) (p<0.0001) and non-diabetic subjects with CHD (5.62±0.34%) (p<0.0001), as well as HBA_1C in T2DM patients with CHD (8.52±1.9%) was higher than healthy controls (p<0.0001) and non-diabetic subjects with CHD (p<0.0001). Interestingly, we also found that non-diabetic subjects with CHD had higher HBA_1C compared to healthy controls (p<0.05). However, there was no statistical difference between T2DM patients with or without CHD in HBA_1C levels (p>0.05).

3.2. Pearson’s correlation analysis of Hs-CRP and other risk variables in T2DM patients with or without CHD:

Pearson’s correlation analysis in T2DM without CHD group revealed that Hs-CRP has a strong positive correlation with HBA_1C (r=0.800, p<0.0001) (Figure 1A). Similarly, Hs-CRP levels were positively and significantly correlated with BMI (r=0.566, P=0.001) as shown in Figure 1B. In T2DM with CHD group, we also noticed, the presence of a strong correlation of Hs-CRP with both HBA_1C(r=0.781, p<0.0001) (Figure 1C), and BMI (r=0.489, p=0.007) (Figure 1D).

3.3. HBA_1Cas a predictor of Hs-CRP levels in T2DM patients

Hs-CRP level was evaluated as a dichotomous variable (elevated or not elevated) in T2DM patients. An elevated level of Hs-CRP was defined prospectively, using a cut-of >3mg/l, based on previous studies of cardiovascular disease²⁰.

Results of adjusted logistic regression analyses for T2DM patients using HBA_1c, age, gender, and BMI as continuous variables are shown in Table 3. We found that HbA_1c was a significant predictor of elevated Hs-CRP (1.774 OR 95% CI; 1.184- 2.658), which means that for every 1.0% increase in HbA_1c there was an 77% increase in the likelihood of having an elevated Hs-CRP.

Table 3: Adjusted regression model to predict elevation of Hs-CRP (>3 mg/l)

P	95%CI Upper	95%CI Lower	Odds ratio	Factor
0.358	1.150	0.951	1.046	Age (years)
0.880	3.796	0.319	1.100	Sex
0.277	1.253	0.938	1.082	BMI (kg/m2)
0.005	2.658	1.184	1.774	HbA_1c %

DISCUSSION:

The current study confirms the presence of a low level of systemic inflammation in patients with T2DM. Hs-CRP was considered as a ˝non-traditional˝ risk factor of atherosclerosis²¹, it has been proven to be one of the strongest risk predictors of cardiovascular events²². Hs-CRP is proposed to be a more sensitive predictor of CHD events than LDL itself^23,24, as well as novel markers like lipoprotein-a, homocysteine, and apolipoprotein A1 and B^16,24. CRP may be directly involved in atherothrombogenic process, it is present in the vessel’s walls, where it induces expression of the adhesion molecules by endothelial cells and serves as a chemoattractant for monocytes. CRP facilitates native LDL entry into macrophages and is associated with endothelial cell dysfunction and progression of atherosclerosis, possibly by decreasing nitric oxide synthesis and many of other mechanisms²⁵.

The Hs-CRP level was significantly elevated in T2DM patients compared to healthy controls. This finding is consistent with previous studies^14,26. However, this result contradicts the findings reported by Lima et el. They did not observe any significant difference in Hs-CRP level between T2DM patients and healthy controls²⁷.

The second finding of our study is that mean Hs-CRP level in T2DM patients without CHD is similar to that of non-diabetic patients with CHD. T2DM Patients have 2- to 4-fold increased risk of CHD and a 4-fold increase in mortality from CHD^28,29. Haffner et el. Suggested that diabetic subjects had a risk of myocardial infarction as high as non-diabetic subjects with previous myocardial infarction³⁰. We deduced that patients with T2DM but without CHD exhibit a similar risk for coronary events as patients who have already suffered a CHD event but who are non-diabetic. Furthermore, several risk factors are relevant in both diseases, supporting the concept of a common soil hypothesis³¹. It is now recognized that all stages of the atherosclerotic process, i.e., the initiation, growth, and complication of the atherosclerotic plaque, are inflammatory responses to vascular injury, suggesting that atherosclerosis may be one of the pathological conditions of inflammation³². Our study demonstrated that T2DM subjects had a high risk for CHD and supported that diabetes mellitus is a CHD risk equivalent.

The third major finding of our study is that mean Hs-CRP level of T2DM patients with CHD was not only higher than non-diabetic subjects with CHD, but also higher than T2DM patients without CHD. These findings were proven by previous studies. Gustavsson et el showed that Hs-CRP levels were higher in T2DM with CHD than non-diabetic subjects with CHD³³. Moreover, Baig et el^. demonstrated that Hs-CRP levels were higher in T2DM subjects suffering from complications of diabetes like CHD than diabetic subjects without complications³⁴. In the same context, Bahceci et el. proved that Hs-CRP level in T2DM subjects with CHD was higher than both non-diabetic subjects with CHD and T2DM subjects without CHD³⁵. Thus, diabetes can cause an additional rise in Hs-CRP levels in subjects who are suffering from CHD. There is no doubt that diabetes mellitus is associated with a higher risk of mortality by coronary artery disease, and inflammatory factors may play a role in this increasing of mortality³⁰. Therefore, it is likely that Hs-CRP is an important key to explaining the high incidence of CHD in patients with type 2 diabetes.

Our study revealed that mean HBA_1C level in non-diabetic subjects with CHD was higher than healthy subjects. HbA_1c is currently considered as an independent risk factor for coronary artery disease (CAD). A higher level of HbA_1c and the presence of factors associated with ongoing atherosclerosis and extensive CAD are concomitantly contribute to the higher major adverse cardiovascular events (MACEs) incidence and long-term mortality³⁶. Cavero-Redondo et el. proved that HbA_1c is a reliable risk factor of all-cause and cardiovascular mortality in both diabetics and non-diabetics. They established optimal HbA_1c levels, for the lowest all-cause and cardiovascular mortality, ranging from 6.0% to 8.0% in people with diabetes and from 5.0% to 6.0% in those without diabetes¹⁸.

In the present study, in both T2DM with or without CHD groups, serum Hs-CRP levels were positively related to BMI and HBA_1C, which is supported by earlier studies^{14, 37-41}.

Several mechanisms may link obesity and elevated concentration of Hs-CRP. Expression of tumour necrosis factor alfa (TNF-α) and circulating concentrations of TNF-α are increased in obesity⁴². TNF-α can stimulate the production of Hs-CRP, cause insulin resistance, and promote the production of macrophage migration inhibitory factor, a proinflammatory cytokine^43,44. Furthermore, serum concentrations of interleukin-6 (IL)-6, which also promotes the production of Hs-CRP, may be elevated in individuals who are obese⁴⁵. Insulin concentrations, which are often high in individuals with insulin resistance or in obese individuals, and glucagon concentrations, which are normal or elevated in obese individuals, are directly related to Hs-CRP production⁴⁶.

The association between elevated concentrations of Hs-CRP and poor glycaemic control (higher HBA_1C levels) could be explained by different mechanisms. Elevated blood glucose levels lead to higher levels of advanced glycation end products, which leads to activation of phagocytes, increased oxidative stress and increased transcription of IL-1, IL-6 and TNF-α which in turn leads to increased circulating Hs-CRP levels⁴⁷. Hs-CRP may cause insulin resistance by increasing insulin receptor substrate 1 (IRS-1) phosphorylation at Ser307 and Ser612 via JNK and ERK1/2, respectively, leading to impaired insulin stimulated glucose uptake, GLUT4 translocation, and glycogen synthesis mediated by the IRS-1/PI-3K/Akt/GSK-3 pathway⁴⁸. Decreased insulin sensitivity may lead to enhanced CRP expression by counteracting the physiological effect of insulin on hepatic acute-phase protein synthesis⁴⁹.

Due to the cross-sectional design of our study, we were unable to conclude a cause-effect relation, i.e., whether poor glycaemic control leads to inflammation or whether inflammation leads to higher glucose levels (or whether third factor influences both). Prospective studies are needed to access those answers. Whatever, the direction of causality, it would have important implications. If poor glycaemic control leads to inflammation, then better glycaemic control should lower inflammation and therefore lower the risk of cardiovascular complications. If inflammation leads to poor glycaemic control, then treatment of inflammation with NSAIDs or hydroxymethylglutaryl- CoA reductase inhibitors may help improve glycaemic control.

Results of adjusted logistic regression analyses showed that for every 1.0% increase in HbA_1c there was a 77% increase in the likelihood of having an elevated Hs-CRP. In similar way, King et el. Showed that for every 1.0% increase in HbA_1c there was a 20% increase in the likelihood of having an elevated CRP²⁰. Thus, HBA_1C levels could be useful to predict status of inflammation in T2DM patients.

Limitations of this study include the fact that much of the data were by self-report, including the diagnosis of diabetes, use of anti-inflammatory medications. However, self-report questions have shown good agreement with other measures in previous studies and have proved useful²⁰. In addition, there was a small number of participants in the study. However, many other studies included the same number or less^14,35,50. A further limitation of this study is that we were unable to control the use of thiazolidinedione drugs that can affect CRP levels⁵¹. Anyhow, such medications were not in common use at the time of the survey. Still, this study has shown that Hs-CRP levels correlate strongly with CHD and HBA_1Cin T2DM patients. A larger prospective multi centres study can actually find the role of Hs-CRP in Syrian diabetic patients and the necessity of its inclusion in daily clinical practice as a cost-effective risk marker.

CONCLUSIONS:

Hs-CRP elevation was strongly common in patients with type 2 diabetic patients; the highest Hs-CRP level was observed in T2DM patients with CHD. Therefore, our results have strongly supported the inclusion of inflammatory markers particularly Hs-CRP in the risk assessment of diabetic patients. Those with elevated levels of Hs-CRP should be managed aggressively to prevent the development or progression of cardiovascular disease. Furthermore, we observed significant positive correlations between Hs-CRP and HBA_1C which suggest a link between inflammation and glycaemic control in patients with T2DM.

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Received on 12.05.2022 Modified on 16.06.2022

Research J. Pharm. and Tech 2023; 16(1):193-199.

DOI: 10.52711/0974-360X.2023.00036