Background
Diabetes is one of the most important health problems around the world in the twenty-first century [
1]. The disease can cause damages in microvessels of multiple organs such as heart and kidney. Cardiovascular complications are the leading causes of death in patients with diabetes [
2]. Diabetic cardiomyopathy (DCM) is generally considered to be the manifestation of microvascular disease in the heart [
3]. The left ventricular (LV) diastolic dysfunction is the earliest functional change in DCM, and eventually progresses to heart failure with normal cardiac ejection fraction [
4]. Hyperglycaemia in patients with diabetes can have much detrimental impacts on the myocardium form lipotoxicity, mitochondrial dysfunction, abnormal substrate metabolism and impaired calcium handling [
5‐
7]. Glycosylated hemoglobin (HbA1c) can reflect the average level of glycemic control. The glycosylation occurs by the non-enzymatic reaction between glucose and N-terminal end of the β-chain of hemoglobin [
8]. An average of 1% reduction in mean HbA1c levels could reduce 37% microvascular complications [
9]. Glycosylated hemoglobin plays an important role in the assessment of the occurrence, development and prognosis of diabetic cardiovascular complications. The high incidence of diastolic dysfunction was found in asymptomatic diabetes correlating with HbA1c levels in Indian patients [
10].
Overweight and obesity have long been regarded as health risks associated with the type 2 diabetes [
11]. Overweight and obesity itself not only can lead to left ventricular dilatation, hypertrophy, impaired relaxation and diastolic dysfunction; but also can cause aggravated insulin resistance, increase the difficulty of blood glucose control and increase the risk of cardiovascular disease. BMI can reflect the level of weight control. Until now, there was no report to focus on interaction analysis of body mass index (BMI), HbA1c levels and LV diastolic dysfunction in patients with type2 diabetes in China; therefore we performed this investigation in a cohort of patients with type 2 diabetes in a region of South China.
Discussion
The incidence of type 2 diabetes has rapidly increased over recent decades and become one of leading public health problems in China. One third of patients with heart failure have diabetes. This is partly because all the major risk factors for heart failure can present in patients with type 2 diabetes such as obesity, hypertension, advanced age, sleep apnoea, dyslipidaemia, anemia, chronic kidney disease, and coronary heart disease [
15]. Hyperglycaemia is a risk factor for heart failure in persons with type 2 diabetes [
16]. Excess body weight, is also a major risk factor for cardiovascular disease [
17].
Understanding the relationships between BMI levels, HbA1c levels and LV diastolic dysfunction in the patients with type 2 diabetes will help clinicians to have appropriate management plans for the patients and reduce heart failure rates in patients. In this investigation, we had an in-depth analysis of the relationships among BMI, HbA1c and LV diastolic dysfunction of 925 type 2 diabetes patients in South China. We had found that the BMI was an independent risk factor to LV diastolic dysfunction, confirming previous reports from South Korea [
18], Australia and the Netherlands [
19], and USA [
20]. Chinese population was transformed from one of the leanest populations to have more than 200 million overweight or obese in its population [
21]. Our results of the independent role of BMI to LV diastolic dysfunction in type 2 diabetes indicates the importance of education of health diets, exercises to prevent the most common heart diseases in China.
Hyperglycaemia has detrimental effects on the myocardium [
5]. It up-regulates renin-angiotensin-aldosterone system, increases oxidative stress [
22], promotes accumulation of glycation end-products and causes interstitial fibrosis in heart muscle [
23]. Hyperglycaemia has strong associations with myocardial lipotoxicity, mitochondrial dysfunction, abnormal substrate metabolism and impaired calcium handling [
6]. The HbA1c level is now recommended as a standard for testing and monitoring diabetes [
24]. Previous investigations from DCCT, ADVANCE and UKPDS showed that the risk of microangiopathy in patients with type 2 diabetes increased with the increase of HbA1c levels. The microangiopathy in these studies were mostly diabetic nephropathy, diabetic retinopathy and neuropathy [
25‐
27]. The relationship between HbA1c and LV diastolic dysfunction has been reported as contradiction. Giorda et al. found that HbA1c was significantly correlated with LV diastolic function in patients with type 2 diabetes [
28], Clarke et al. also found that LV diastolic dysfunction is inversely linked to glycemic control in T2DM patients [
29]. Noh et al. did not found that HbA1c increased risk of LV diastolic dysfunction in type 2 diabetes [
30]. The different results may be related to the different blood glucose control status of the included populations. In our present study, we did not found significant correlation between HbA1c level and LV diastolic dysfunction in patients with type 2 diabetes. Our results suggest that HbA1c effects on LV diastolic dysfunction may be affected by some other confounding factors. Obesity is becoming increasingly prominent, not only affecting cardiovascular health, but also leading to glucose and lipid metabolism disorder. Stratified analysis in our investigation found that HbA1c was statistically correlated with LV diastolic dysfunction only in the normal weight group, suggesting that obesity is an important confounding factor in the relationship between HbA1c and LV diastolic dysfunction. In the normal weight group, we found that the relationship between HbA1c and LV diastolic dysfunction was curvilinear correlation, and had a saturation threshold (10%). In a Scotland cohort study of 8683 patients with type 2 diabetes, both high and low HbA1c levels have been found to predict heart failure development forming a U-shaped relationship [
8]. It may suggest that under normal weight, proper glycemic control is beneficial to the improvement of heart function. When HbA1c is higher than a certain range (10%) or in overweight/obesity, glycemic control may no longer be the most important factor affecting LV diastolic dysfunction. More attention should be paid to the some other effects such as lipotoxicity on cardiac function. In a Western Indian study, the dyslipidemic obese subjects had significant linear association with HbA1c in type 2 diabetes subjects [
31]. A rise in obesity and dyslipidemia with increasing urbanization have led to various lifestyle related disorders like type 2 diabetes, cardiovascular disease (CVD) and metabolic syndrome. Among dyslipidemic subjects, increased LDL-C, TG and hypo-HDL are established markers for CAD risk. The other reason is that HbA1c-lowering is greater in populations with poor glycaemic control than in well controlled populations with the same degree of weight loss [
32]. The genetic background for type 2 diabetes may be different in South China and may be relevance to the complex phenotypes of HbA1c phenotypes of patients with type 2 diabetes. In overweight/obese group, analysis found the obesity paradox: increased HbA1c unexpectedly reduced the risk of diastolic dysfunction, which was similar to some previous obesity paradox studies [
33‐
35] . There may be some other unmeasured confounders not yet be excluded, or because obesity itself may be a risk factor for disease events, and stratification bias can amplify the effects of confounding factors. The specific causes still need to be further investigated.
In this study, it was found for the first time that BMI and HbA1C had significant interactions in influencing the left ventricular diastolic dysfunction, suggesting that the interaction of multiple factors should be considered in the management of cardiac complications in type 2 diabetes mellitus.
There were some limitations in this study. The current investigation applied the evaluation index using the E/A ratio in the echocardiogram, it did not investigate the state of the heart load; the HbA1c levels which represented glycemic control in this study, only corresponded to changes in blood glucose levels for nearly 3 months, while diabetes cardiomyopathy and obesity are metabolic diseases and the pathological processes that change gradually over a long period of time. Single HbA1c may not reflect the historical impact of hyperglycemia on diastolic dysfunction. The effects of some medications and other confounders such as blood pressure and blood lipids were not fully considered, these confounders are needed to further research in detail.
The current investigation provides clinical implication about the importance of weight control in patients with type 2 diabetes as higher BMI was clearly a risk of LV diastolic dysfunction. It also indicates monitoring both HbA1c levels and BMI levels could assist us for correctly predicting early heart function changes for the patients. The results can help clinicians for appropriate management of patients with type 2 diabetes.
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