Discussion
Our study has a unique opportunity to reveal the impact of FPG variability in the prepregnancy period on the risk of GDM in the primipara with baseline normal fasting glucose level. Women in the highest quartile of FPG-VIM had an 22% increased risk for GDM even after adjusting for risk factors including mean FPG, and these associations were consistent in all indices of FPG variability such as FPG-CV, FPG-SD, and FPG-ASV. In particular, there was a 48% increase in the risk for GDM requiring insulin treatment in women in the highest quartile of FPG-VIM. The association between high FPG variability and the risk of GDM was intensified in the obese and aged more than 35 years women.
The prevalence of pre-diabetes and T2DM is more than 30% in women of reproductive-age.18 However, healthy young women have less chances of being diagnosed with diabetes or impaired glucose tolerance. Although the physiologic process of GDM is complicated,19 the main pathology of GDM is an aggravation of pre-existing insulin resistance which is not compensated by insulin secretion.20 GDM causes various complications both in the mother and fetus, and the incidence of these complications can be reduced with treatment; hence, timely diagnosis is important. However, GDM is diagnosed at 24–28 weeks of gestational age using glucose loading test, which allows a very limited time to reverse the adverse outcome of hyperglycemia. A simple and cost-effective strategy for the early risk stratification of GDM is required.
Long-term glycemic variability using visit-to-visit FPG or HbA1C is a marker of glycemic homeostasis.9 Glycemic variability has been widely studied in patients with T2DM. Increased glycemic variability correlates with diabetic polyneuropathy, retinopathy, and cardiovascular autonomic neuropathy in patients with diabetes.12 13 21 A meta-analysis including eight studies reported that increased FPG variability resulted in increased all-cause mortality in diabetes (HRs: 1.28, 95% CI 1.12 to 1.46).13 Recently, the impact of glycemic variability in the general population was also highlighted. Akirov et al22 reported that increased glycemic variability is associated with longer hospitalization and increased short-term and long-term mortality irrespective of underlying diabetes. Furthermore, Oka et al23 demonstrated that higher glycemic variability was associated with more severe myocardial damage after percutaneous coronary intervention in non-diabetic patients with ST-segment elevation myocardial infarction. In the CARDIA study, adults aged 18–30 years without diabetes were followed up to 30 years, and elevated FPG variability was associated with the development of T2DM, CVD, and all-cause mortality.15 Our study is the first to demonstrate that increased FPG variability in prepregnancy was associated with the risk of GDM in the primipara with normal fasting glucose level even after adjusting other risk factors. Although FPG variability is affected by the mean glucose level,24 the association between FPG variability and GDM was consistent even after adjusting the mean FPG. Interestingly, the association of FPG variability was strengthened in insulin-treated GDM rather than in those without insulin treatment. Insulin treatment during pregnancy is the strongest risk factor for the development of T2DM;25 thus, prepregnancy FPG variability is an important risk factor for GDM and also for future glycemic derangement.
The possible pathophysiologic mechanisms connecting FPG variability and GDM could be oxidative stress and β-cell dysfunction. A previous study showed that glycemic variability measured by continuous glucose monitoring is associated with oxidative stress.26 Monnier et al10 demonstrated that a marker of oxidative stress was significantly elevated in patients with high glycemic variability than in those with sustained hyperglycemia. Increased glucose excursion promotes proinflammatory cytokines by oxidative stress and contributes to the development of diabetes.27 In addition, intermittent hyperglycemia could induce mitochondrial superoxide overproduction and reduce adiponectin secretion.28 Lower adiponectin has been a well-known marker of reduced glucose sensitivity.29 Previous study demonstrated that lower adiponectin levels before pregnancy are associated with GDM.30 Besides oxidative stress, insulin secretory β-cell function is important in the pathology of GDM. Glycemic variability causes apoptosis of pancreatic β-cell,31 which may result in the deterioration of glycemic control and subsequent progression of diabetes. At 24–28 weeks gestation, glycemic variability correlates with impaired early-phase insulin secretion, which is higher in hyperglycemic women than in normoglycemic women.32 On the contrary, glycemic instability itself might be a marker of an β-cell dysfunction in at-risk individuals prior to the onset of diabetes. Women with normal glucose tolerance with a history of GDM showed elevated glycemic variability with low islet β-cell function index.33 A recent study reported that Koreans had smaller pancreatic volume and lower β-cell function than age and BMI matched Caucasians.34 East Asians have limited capacity for insulin secretion.35 Hence, glycemic variability, which suggests impaired insulin secretion, can be a more useful indicator for GDM in Asian women than in women belonging to another ethnic group. Furthermore, in our study, the association between high FPG variability and the risk of GDM was strengthened in the obese women and those aged more than 35 years, which are the well-known risk factors for GDM. Therefore, the early risk stratification of GDM using prepregnancy FPG variability might be clinically valuable, especially among obese, older, and Asian women.
Our study has several limitations. First, this study is a retrospective case-control study; we could not find any causal relationship. Second, GDM women were defined as those classified using four or more GDM codes or have taken have taken insulin during pregnancy because the nationwide database had no data on HbA1C value and oral glucose tolerance test results. However, the prevalence of GDM according to our definition was 4.2%, which correspond to that reported in previous study.36 Finally, we did not consider dietary habits. Despite these limitations, our study has some strengths. It is the first to reveal the association between prepregnancy FPG variability and risk of GDM using large population-based data. In addition, to overcome the effect of the high mean glucose level in the risk of GDM, we adjusted the mean FPG level in full adjustment models.
Taken together, high glycemic variability was related to an increased risk of GDM, and the relation remained significant after the adjustment for other risk factors. GDM affects the mother and their offspring during the perinatal period and also the life-long period; however, there are no definite ways to regress GDM after diagnosis. Therefore, monitoring the longitudinal pattern of FPG level in women of reproductive age may be clinically important for the early detection of individuals with high risk for GDM. Further studies to examine the predictive power of FPG variability for the incidence of GDM should be conducted to validate these results.