In this prospective research, we observed that the prevalence of IFG or diabetes increased as the levels of SAG increased independent of risk factors such as age, sex, BMI, SBP, DBP, HDL, LDL, AST, ALT, potassium and albumin. The results of the ROC curve indicated that the SAG level had predictive ability for the development of IFG or diabetes. In addition, the percentage of subjects progressing to IFG or diabetes increased as SAG increased.
Serum anion gap indicates the gap between undetermined cations and anions. This refers to the concentration of fixed acids in plasma, which is a normal used and easily gained laboratory parameter of acid-base imbalance[13]. The elevation of SAG is generally caused by the overproduction of organic acid anions and/or the concomitant and proportionate reduction in the anion excretions, while changes in the equivalents of potassium, calcium, phosphorus and total proteins are unusual causes[14]. It has been reported that lactate and ketoanions accounted for 62% of the increments in SAG[15].
In recent years, many researchs have revealed that elevated SAG is closely related to poor prognosis in various diseases, including acute and chronic kidney injury[8, 16], sepsis[17], acute pesticide poisoning[18], and coronary artery disease[19]. In a large study, it was shown that increased SAG may be of prognostic significance, as higher levels of AG were associated with hypertension[10].
In our research, men are more likely suffering from IFG or diabetes than women. Individuals with elevated SAG, both men and women, had a high probability of suffering from IFG. Poorer compliance and management in men with diabetes along with differences in the biological response to hyperglycemia and other risk factors between sexes[20, 21] may explain these findings. Obesity is a strong predictor of an increasing risk factor for adults T2DM[22, 23] and probably promote the development of diabetes[24]. Here, we show the participants in the upper tertiles of serum anion gaps had higher levels of weight and BMI, and these findings are consistent with previous studies. Lower HDL and higher LDL were also found in individuals with higher SAG. In recent studies, a high prevalence of IFG was significantly and independently related to increased LDL-C levels and low HDL-C levels[25, 26]. Dyslipidemia in this population indicates that obesity can affect the secretion of insulin and also may cause insulin resistance, which may explain this association[25].
Subjects with higher SAG had significantly higher SBP and DBP, and it was found in other studies that in prediabetic hypertensive patients, blood pressure control is less satisfactory than in nondiabetic patients[27, 28]. Furthermore, our study found that ALT, AST and albumin were higher as the SAG level increased. Previous studies also indicated a significant association between these parameters and IFG/DM[29, 30] because liver dysfunction related to chronic hepatitis or liver cirrhosis results in glucose intolerance[31].
In our study, the AUC of SAG was 0.623, suggested that the ability of SAG to discriminate IFG or diabetes was poor. This may be limited by our sample size. However, the NPV value was 95.7%, which suggested the predictive value for the absence of development of IFG or diabetes is great. The optimum cutoff value of SAG for predicting progression to IFG or diabetes was 13.76 mmol/L. This means that SAG above a certain level is harmful. We can see that the optimum cutoff value matches closely with the upper tertiles of the SAG level.
Although the precise mechanism underlying the association between SAG and IFG or diabetes risk has not been fully expounded, it may be related to insulin resistance, as a previous study has shown that high SAG was related to insulin resistance[10]. Ions play a very important role in maintaining homeostasis and regulating the electrical activities of pancreatic β-cells[32]. The Ca2+ influx and the depolarization of β-cells are caused by closure of ATP-sensitive potassium channels, which result in insulin granule exocytosis and insulin secretion[33]. SAG is related to several ion concentrations, so it may influence the occurrence of IFG through ions. The exact mechanism is still unclear and awaits further investigation and clarification.
However, the present study had three limitations. First, the sample size was small due to the withdrawal of the study halfway, and some participants did not undergo serological examinations. Thus, the number of patients who has a final diagnosis of IFG or type 2 diabetes was small, which may cause deviations in the results. Second, the study population was collected from one single clinical center, which may raise the possibility that the observed outcomes were specific to this peculiar patient population. Third, our adjustment for confounding variables may have been incomplete, including the consumption of medications and dietary variables that may influence blood glucose and the SAG level. However, we believe that these limitations do not bias the results of our study.
In a word, our study found that elevated SAG had higher odds of progressing to IFG or diabetes. Thus, possible proposals to encourage the general population to maintain normal SAG levels through diet or other methods may reduce the risk of developing IFG or diabetes. Controlling SAG at a relatively lower level may aid in the prevention of IFG or diabetes. Of course, large-scale, multicenter researches are necessary to confirm our results. Additional studies are required to discovery the exact underlying mechanism.