Beta-cell dysfunction is the primary contributor to the early postpartum diabetes among Chinese women with history of gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a glucose intolerance of varying severity with onset or first recognition during pregnancy.¹ The prevalence of GDM is about 1%–14% of all pregnancies, depending upon the ethnic background of the study population and the detection method for GDM.^2,3 It has been identified that GDM women are at higher risk of future development of diabetes.^4,5 Reported data have shown that GDM women have a 17% to 60% risk of developing type 2 diabetes within 5–16 years after pregnancy.^2,5-7 Insulin resistance and defective insulin secretion are present in pregnant women with GDM and are reverted after delivery in order to maintain normal glucose tolerance.^8,9 However, some of the GDM women fail to return to normal glucose regulation (NGR) or develop early postpartum diabetes soon after delivery.¹⁰ Little is known about the underlying mechanism. The aim of this study was to identify the population with early postpartum abnormal glucose regulation (AGR) among Chinese women with history of GDM, and to investigate the possible risk predictors.

Participants
A total of 186 women diagnosed with GDM during May 2005 to April 2006 in the prenatal clinic at the First Affiliated Hospitals of Sun Yat-sen University participated in this study. All those 186 women were recruited at 6–8 weeks after delivery and a 75 g oral glucose tolerance test (OGTT) were performed. Women were considered to be in AGR group (n=52) if plasmic blood glucose values exceeded the following limits: ≥6.1 mmol/L (fasting) before OGTT, or ≥7.8 mmol/L 120 minutes after glucose load, otherwise were considered to be in NGR group (n=132). Those with AGR (n=52) were given lifestyle intervention therapy, including: diet and physical activities and another 75 g OGTT was performed in 6–12 months. Insulin levels were also checked at each point of the OGTT. High-sensitivity C-reactive protein (HsCRP) and lipid concentration were measured as well at the same time.

Demographic data of each participant that included the age, duration of gestation, medical history (gravidity; parity; previous diagnosis of GDM, and family history of DM), anthropometric data (body mass index (BMI) at the first pregnancy visit, pre-pregnant BMI, height, weight, weight gain during pregnancy, blood pressure, and waist circumference after delivery), prenatal care (date of prenatal visit, insulin use during the affected pregnancy, and complications of pregnancy) were recorded. Diabetes and GDM were diagnosed with the World Health Organization (WHO) (1999) criteria. Early postpartum AGR was confirmed if AGR did not reverted in 6 months after delivery.

The protocol for the study was performed according to clinical practice guidelines and approved by the local ethics committee and each participant signed informed consent. The information given by participants remained confidential.

Laboratory measurements
Blood samples were drawn from the medial cubital vein and serum was prepared according to standard methods. All measurements were performed in the central laboratory of the First Affiliated Hospital of Zhongshan University, China. Plasma glucose was measured with a glucose oxidase method. Plasma insulin concentrations were measured by radioimmunoassay. Plasma HsCRP was measured by a highly sensitive immunonephelometry method (intraassay CV, 4.8%). Total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) levels were measured by the enzymatic colorimetric method. LDL-cholesterol was calculated by Fridewald's formula. All samples were recovered by centrifugation and frozen at –20°C until analysis. The insulinogenic index, expressed as Dins30'/DBG30' ((30' insulin-fasting insulin)/(30'glucose-fasting glucose)), was calculated to present the first phase insulin secretion. The homeostasis model assessment index: homeostasis model assessment index (HOMA)-B (fasting plasma insulin (mU/L) ×20 / (fasting plasma glucose (mmol/L) – 3.5) for beta-cell function and HOMA-IR (fasting plasma insulin (mU/L) × fasting plasma glucose (mmol/L)/22.5) for insulin resistance were calculated.

Statistical analysis
All statistical analysis was performed using the SPSS 11.0 statistical package. Data are expressed as mean ± standard deviation (SD) or n (%). Differences between groups were compared using a two tailed Student's t test (quantitative data) or χ² test (qualitative data). Liner regression analysis was performed to examine the relationship between AGR and each factor, and multiple regression analysis to identify independent factors associated with early postpartum AGR. The odds ratios (ORs) are presented with a 95% confidence interval (CI). HOMA-B and HOMA-IR were log transformed for the analyses. P values of <0.05 were considered statistically significant.

Total 52 of those 186 women (28.0%) enrolled in the study were found to stay in AGR on the basis of 75 g OGTT at 6-8 weeks after delivery. This included, 1 impaired fasting glucose (IFG), 46 intolerance glucose test (IGT) and 5 diabetes (DM). After 6-12 months lifestyle intervention treatment 40 of those 52 women had a second OGTT. Seventeen of the 40 women (45.2%) remained in AGR (12 IGT, 4 DM and 1 IFG) while 23 recovered to NGR. The reasons for women not to attend the second visit are moving, change of job or unwillingness to return.

Risk factors for prediction of AGR at 6-8 weeks postpartum
The clinical characteristics of the women with NGR and with AGR at 6-8 weeks after delivery were reported in Table 1. On the whole, the two groups were similar at age at delivery, gravidity, parity, pre-pregnancy BMI, weight gain over pregnancy, age ≥35 years, blood pressure and their family history of DM. As compared with the NGT women, the AGT women had a significant higher glucose value in the 50 g challenge glucose test (P <0.001), a higher fasting glucose value (P <0.05) and 75 g OGTT 2 hours glucose value (P <0.05) during pregnancy. The ratios of pre-pregnancy BMI ≥25 kg/m² (P <0.05) and the prenatal insulin use were also higher (P <0.05) in the AGT than in NGT group.

Regressive analysis identified the fasting glucose value and 2 hours postprandial glucose value during pregnancy, prenatal insulin use, pre-pregnancy BMI ≥25 kg/m² as significant contributors to the AGR at 6–8 weeks after delivery. By multivariate analysis, when pregravid maternal weight, fasting glucose level, postprandial glucose level and insulin requirements were included as independent variables and AGR as the dependent variable, a significant contribution to postpartum AGR risk in GDM women was observed for pre-pregnancy BMI ≥25 kg/m², fasting glucose level ≥5.6 mmol/L and 75 g OGTT 2 hours glucose level ≥11.1 mmol/L during pregnancy. The insulin requirement was no longer a significant contributor in this analysis (Table 2).

Characteristics of women with and without AGR at 6–12 months after delivery and risk factors
Forty of the women with AGR at 6–8 weeks after delivery had a second test in 6–12 months (40/52, 75%). Seventeen of them (12 IGT, 4 DM, and 1 IFG) remained in AGR and 23 recovered to NGR. Compare to those who reverted to NGR, women with consistent AGR had significantly higher 75 g OGTT 2 hours glucose levels. No differences between these two groups were observed in age, BMI, waist circumference, blood pressure, family history of DM, complications of pregnancy or ratio of age ≥ 35 years. Serum HsCRP, HOMA-IR and lipid concentrations were similar in these two groups. There is a significantly lower fasting insulin concentration as well as Dins30'/DBG30' in AGR than in NGR, indicating a dysfunction of first phase insulin secretion of beta-cells in women with AGR, while the HOMA-B was also lower in AGR than in NGR (Table 3). Using age, BMI, waist circumference, lipid levels, HsCRP, Dins30'/DBG30' and HOMA-IR as independent variables and early postpartum AGR as the dependent variable, multivariate regressive analysis demonstrated that Dins30'/DBG30'≤1.05 is the only significant risk contributor to the consistent AGR after deliver (OR 2.801, P <0.001, 95% CI 0.104–1.363).

GDM is a common disease among pregnant women. Most of the GDM women recover to normal glucose levels within 6 weeks after delivery. A diagnosis of impaired glucose regulation or DM is confirmed for those who maintain an abnormality for more than 6 months after delivery. Long-term follow-up studies have revealed that women with GDM do progress to diabetes at a relatively constant rate during the first 10 years after pregnancy.⁵ It has been reported that about 10% of patients have AGR soon after delivery.¹⁰ The ADA Expert Committee on the Diagnosis and Classification of Diabetes Mellitus recommends screening women with a history of GDM for type 2 diabetes 6 to 8 weeks after delivery and, if normal, at a minimum of 3-year intervals.¹¹ Unfortunately, screening rates for type 2 diabetes after delivery are low. There is evidence that many women with GDM are not being appropriately screened for type 2 diabetes in their postpartum period. Only one third underwent diabetes testing after delivery.^12-14 In the present study we have 186 women with a history of GDM who returned for their 6–8 weeks postpartum visit and detected an incidence of 28.0% AGR among those women, a risk that is much higher than that reported.⁵

Reported risk factors for postpartum diabetes include the detection of islet autoantibodies,^15,16 insulin treatment during pregnancy, maternal obesity and age at delivery.^2,17 Weight gain during pregnancy, relatively high glucose levels during pregnancy, family history of diabetes also correlate with increased risk of diabetes.^5,17,18 Few were concerned about the early postpartum AGR. We evaluate the possible risk predictors for the women maintained in AGR at 6–8 weeks after delivery and found that the AGR women had a higher glucose value in OGTT during pregnancy and more pre-pregnancy BMI ≥25 kg/m² and insulin requirement during pregnancy. With multivariate regression analysis we estimated that pre-pregnancy BMI ≥25 kg/m², fasting glucose ≥5.6 mmol/L and/or 2 hours glucose ≥11.1 mmol/L in 75 g OGTT during pregnancy are significant risk factors in our study group. However, the insulin requirement no longer had an influence on risk. It may be due to the low number of women who needed insulin treatment in our study group (1.5% in NGT, and 7.7% in AGT).

Some clinical trials have demonstrated that lifestyle interventions and administration of medicine could delay or prevent the development of type 2 diabetes in people with prediabetes or IGT.^19-21 We conducted a lifestyle intervention of the women with AGR at 6–8 weeks after delivery. Acarbose or metformine were used if fasting ≤6.1 mmol/L, and/or postprandial ≤7.8 mmol/L were not achieved. Within the one year follow-up, 23 of those 40 women returned to normal glucose tolerance while 17 still remained in AGR. For a better understanding of the factors contributing to consistent AGR, both groups were compared by their metabolic parameters, inflammatory statue, insulin resistance, and beta-cell function. There are no significant differences in BMI, WC, BP, lipid profile and HOMA-IR between the two groups, indicating that both groups can maintain a similar control of their metabolic situation and insulin sensitivity after lifestyle intervention. Inflammation is considered a factor in the pathogenesis of diabetes.^22,23 HsCRP, as an inflammatory marker that was thought to be a predictor for type 2 diabetes,^24-27 was also similar in these two groups. However, the fasting insulin concentration and the insuliogenic index presented as Δins30'/ΔBG30' were significantly lower in the AGR than in the NGR, as was the HOMA-B. By multivariate regression analysis it was also estimated that Δins30'/ΔBG30' ≤1.05 is a risk factor for the consistent AGR after delivery. The insuliogenic index presents the first phase insulin secretion function, indicating that, unlike most pathophysiologic process in type 2 diabetes, intrinsic beta-cell dysfunction rather than inflammation or insulin resistance is the predominant contributor to the early postpartum AGR in Chinese women with previous GDM.

Our data indicated that there is a much higher than reported incidence of AGR soon after delivery among Chinese GDM women. Most of them benefited from the lifestyle intervention therapy and returned to normal. Some of them remained in consistent AGR and developed early postpartum AGR. Beta-cell dysfunction is the factor that contributes to the early onset and consistent AGR after delivery in Chinese GDM women. A regular screening test, as well as an analysis of beta-cell function, is strongly recommended after delivery, especially for those with pre-pregnancy BMI ≥25 kg/m², fasting glucose ≥5.6 mmol/L and/or 2 hours glucose ≥11.1 mmol/L in 75 g OGTT during pregnancy.

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