In this prospective study, 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, K+, and ALB levels. The results of the ROC curve indicated that SAG had the ability to predict 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 the levels of undetermined cations and anions. This refers to the concentration of fixed acids in the plasma, which is a normally used and easily determinable laboratory parameter signifying acid–base imbalance[13]. An increase in SAG is generally caused by the overproduction of organic acid anions and/or the concomitant and proportionate reduction in 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 the recent years, many studies have reported that increased 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, increased SAG was considered to be of prognostic significance, as higher levels of AG were associated with hypertension[10].
In our study, men were more likely to develop IFG or diabetes than women. Individuals with increased SAG, both men and women, had a high probability of developing 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 adult-onset T2DM[22, 23] and probably promote the development of diabetes[24]. Here we showed that the participants in the upper tertiles of serum anion gaps were overweight and had high BMI values, and these findings are consistent with those of previous studies. Lower HDL and higher LDL levels were also found in subjects with higher SAG. In a few recent studies, the 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 may also 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 levels were higher as the SAG increased. Previous studies also indicated a significant association between these parameters and the development of IFG/T2DM[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 SAG cannot be used to distinguish between IFG and diabetes. This observation may have been caused by our limited sample size. However, the NPV value was 95.7%, which suggested that the predictive value for the absence of development of IFG or diabetes is high. 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 matched closely with the upper tertiles of the SAG.
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 showed 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 depolarization of β-cells are caused by closure of ATP-sensitive potassium channels, which result in insulin granule exocytosis and secretion[33]. SAG is related to several ion concentrations, so it may affect the development 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 because of the abrupt withdrawal from the study by some of the participants and some participants did not undergo serological examinations. Thus, the number of patients who underwent IFG or T2DM diagnosis was small, which may have caused deviations in the results. Second, the study population was included from a single clinical center, which may lead to 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 affect blood glucose level and SAG. However, we believe that these limitations do not contribute to a bias in the results of our study.