HGI, an indicator used to assess the inter-individual variation of HbA1c, reflects the difference in the degree of hemoglobin glycosylation at a given plasma glucose level . In addition to being influenced by blood glucose concentrations, the individual differences of HbA1c may be also associated with biological factors that influence non-enzymatic protein glycation such as genetics, and the life cycle of red blood cells .Various studies have confirmed that there are consistent inconsistencies between HbA1c and other clinically used blood glucose homeostasis indicators, such as fructosamine and mean blood glucose [8,21,22]. An increasing amount of evidence shows that such inconsistencies may affect the accuracy of HbA1c in management of diabetes and its other applications. For instance, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial stated that interventions aimed solely at reducing HbA1c levels in diabetic patients did not reduce the incidence of cardiovascular events. Conversely, the risk of mortality increased in the intensive therapy group (target HbA1c<6%) compared to the standard treatment group (target HbA1c 7.0% to 7.9 %) . However, the hazards or benefits from intensive glycemic control could be identified by HGI subgroups, suggesting that HGI should also be considered in addition to HbA1c levels . Therefore, some researchers proposed that HGI may serve as an alternative marker for diseases management and prediction.
This study found that HGI serves as an independent risk factor in the onset of hypertension, regardless of HbA1c levels. Similarly, HGI was reported to be positively correlated with cardo-metabolic risk factors, independent of other glucose indexes, including HbA1c and post-load glucose concentrations . A ten-year prospective cohort survey in Korean demonstrated that baseline HGI was significantly associated with the incidence of cardiovascular disease even after controlling HbA1c levels . Overall, this strongly suggested that HGI may confer additional influences on cardiovascular diseases over other glucose measurements. In addition, this study used FPG rather than mean blood glucose to calculate the HGI for several reasons. First, it was indicated that HGI calculated by average total glucose had significantly high correlation with that by prebreakfast FPG only . Second, FPG is comparatively more common and easily available in daily practice, whereas mean blood glucose data is not easily accessible and inconvenient to ascertain. Furthermore, a number of past studies have used FPG to calculate HGI, and demonstrated that it was an efficient and powerful indicator reflecting variation of HbA1c and may be used to predict related outcomes of diabetes [26,27].
The pathophysiological mechanisms that increase the HGI leads to an increased risk of hypertension, which are currently not fully understood. Enhanced HGI levels were more highly sensitivity to protein glycosylation and had increased accumulation of AGEs [29,30]. The concentration of AGEs taken from measuring skin intrinsic fluorescence was found to be significantly increased with the increase in HGI, suggesting that subjects with high HGI levels may have higher levels of AGEs than that of other populations . AGEs are intermediate products that respond to chronic hyperglycemia, which can alternate arterial stiffness and cause endothelial injury either directly or by binding to specific receptors to recognize AGEs modified proteins [32,33]. Compared to normotensive subjects, individuals suffering from hypertension had a significantly higher concentration of plasma AGEs . In spontaneously hypertensive rats, the levels of AGEs were shown to be elevated . Meanwhile, AGEs accumulation was shown to be closely related with night-systolic blood pressure, subclinical vascular atheromatosis and expected 10-year cardiovascular death risk in subjects with successful renal transplant . In addition, chronic inflammation was recognized to be involved in the development of hypertension . The National Health and Nutrition Examination Survey previously suggested that HGI was independently associated with inflammatory biomarkers including C-reactive protein (CRP), polymorphonuclear leukocytes, and monocytes . Following 6 weeks of low-AGEs diet intervention in diabetics, the concentrations of inflammatory markers such as high-sensitivity C-reactive protein and TNFα were significantly reduced . Meanwhile, serum AGE levels were reported to be significantly independent with the homeostasis model assessment of insulin resistance (HOMA-IR) index, suggesting that AGEs may trigger various pathologies via IR . Individuals with a high HGI displayed a higher degree of IR than those with a low HGI . An investigation using an animal model demonstrated that oral intake of AGEs impaired insulin uptake and induced insulin resistance by altering insulin receptor signal transduction .
The present study demonstrated that a remarkable interaction exists between HGI and family history of hypertension in regard to hypertension risk. Hypertension is the result of a combination of genetic and environmental factors, and family history of hypertension serves as an important marker for genetic factors, which is often used as a proxy indicator to analyze the association between genetic factors and hypertension. Numerous studies have indicated that having family history of hypertension is a considerable risk factor of hypertension. After analyzing the interactions between HGI and obesity on hypertension, all interactive indicators remained significant between HGI and abdominal obesity, however, only one index was significant in terms of HGI and general obesity. BMI may rapidly and easily assess the overall degree of obesity, but WC rather than BMI better reflects the accumulation of abdominal fat . Relevant studies have strongly suggested that abdominal obesity has a more substantial impact on cardiovascular diseases risk compared to general obesity. A seven-year cohort survey indicated that WC possessed a higher predictability in hypertension risk than BMI . Here, we found that WC, instead of BMI, was found to be significantly increased across HGI groups, suggesting that HGI and WC are closely related. The interaction of HGI and obesity may increase the occurrence of hypertension through co-owned mechanisms, such as inflammatory responses and insulin resistance [32,44]. Future research should further explore these interactive mechanisms, which may further elucidate the cause of hypertension.
Recently, several studies have been performed to analyze the practical applicability of HGI measurements. A cross-sectional study demonstrated that high HGI levels significantly increased the risk of coronary artery disease, stroke, and peripheral artery disease in individuals with an impaired glucose metabolism . The Kangbuk Samsung Health Study in Korean indicated that individuals with the highest HGI levels had a 1.722-fold risk of incident coronary artery calcium compared to the bottom group regardless of HbA1c levels . In type 2 diabetes HGI was proposed to be closely related with the severity of coronary heart disease, which contributed to cardiovascular risk stratification . In terms of ischemic stroke patients with type 2 diabetes, HGI was suggested to be an independent poor prognostic factor . Moreover, among nondiabetic individuals, a higher HGI was reported to be inde50pendently related with nonalcoholic fatty liver disease, chronic kidney disease, hepatic steatosis, and carotid intima-media thickness [26, 49-51]. Overall, substantial evidence has demonstrated the practical value of HGI in disease prediction and management.
The present study possesses some limitations. First, we cannot verify causality as this is a cross-sectional study, and prospective cohort studies should be done for further validation. Second, FPG and HbA1c were only measured once, however, it is common in epidemiological surveys. The day-to-day variations in blood glucose indicators levels were not considered. Third, the results did not generalize other ethnic groups as there were obvious ethnic differences in HbA1c levels [52,53]. Fourth, some other variables such as mental stress and daily salt intake were not collected, which might influence the associations observed in present study.