Each Degree of Glucose Intolerance in Pregnancy Predicts Distinct Trajectories of β-Cell Function, Insulin Sensitivity, and Glycemia in the First 3 Years Postpartum

Abstract

OBJECTIVEGlucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes mellitus (T2DM) that is proportional to the severity of antepartum dysglycemia (i.e., highest in women with gestational diabetes mellitus [GDM], followed by those with milder dysglycemia). However, the pathophysiologic changes driving this risk are not known. Thus, we evaluated the longitudinal changes in b-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum after gestational dysglycemia. RESEARCH DESIGN AND METHODSA total of 337 women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at 3 months, 1 year, and 3 years postpartum. The antepartum GCT/OGTT identified four gestational glucose tolerance groups: GDM (n = 105); gestational impaired glucose tolerance (GIGT; n = 60); abnormal GCT, followed by normal glucose tolerance (NGT) on the OGTT (abnormal GCT NGT; n = 96); and normal GCT with NGT (n = 76). RESULTSAt each of 3 months, 1 year, and 3 years postpartum, the prevalence of glucose intolerance increased from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all P < 0.001), whereas b-cell function, assessed by the Insulin SecretionSensitivity Index-2 (ISSI-2), and insulin sensitivity (Matsuda index), progressively decreased across the groups (all P < 0.002). Each group predicted distinct trajectories of ISSI-2, Matsuda index, and fasting and 2-h glucose (all P < 0.001). Notably, GDM, GIGT, and abnormal GCT NGT predicted varying rates of declining b-cell function and insulin sensitivity, as well as rising glycemia, compared with normal GCT NGT. CONCLUSIONSEach degree of gestational glucose intolerance predicts distinct trajectories of b-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum that drive their differential risk of future T2DM.

Delayed timing of post-challenge peak blood glucose predicts declining beta cell function and worsening glucose tolerance over time: insight from the first year postpartum

“…However, owing to their time-consuming nature, clamp studies would have been difficult to complete on two occasions in the first year postpartum in 532 new mothers. Moreover, it should be noted that ISSI-2 and the Matsuda Index are validated measures that have been widely used in previous studies [11,[14][15][16][17][18][19][20][21]. Finally, the clinical application of the time to peak glucose is limited by the requirement for a multisample OGTT.…”

“…First, the study population consisted of a large cohort of young women reflecting a broad range of future diabetic risk, who were evaluated by OGTT at two points in time (3 and 12 months postpartum). Second, the range of future diabetic risk within this cohort has previously been shown to manifest in differential changes in beta cell function, insulin sensitivity and glycaemia within this period of observation [20], leading to differential rates of prediabetes and diabetes in the years thereafter [21]. Third, the women comprising this cohort experienced the full range of changes in peak glucose during this time, from an unchanged peak at either 30 min or ≥60 min, to shifts to either an earlier or later time point.…”

“…Beta cell function was assessed for each OGTT using the Insulin Secretion-Sensitivity Index-2 (ISSI-2), a validated measure of beta cell function that is analogous to the disposition index obtained from the IVGTT [15,16]. ISSI-2 has been directly validated against the disposition index from the IVGTT, with which it exhibits a stronger correlation than do other OGTT-derived measures of beta cell function [16], and it has been used to measure beta cell function in several previous studies, including both clinical trials [17,18] and observational studies [11,[19][20][21]. ISSI-2 is defined as the product of (1) insulin secretion measured by the ratio of AUC ins to AUC gluc , and (2) insulin sensitivity measured by the Matsuda Index [15,16].…”

The Insulin-Like Growth Factor Axis: A New Player in Gestational Diabetes Mellitus?

“…Importantly, although this clinical presentation arises in response to the physiologic stress test posed by pregnancy, affected women have chronic b-cell dysfunction and insulin resistance that is readily apparent in the years thereafter and that contributes to their elevated lifetime risk of T2D (5,6). Moreover, it is now recognized that metabolic dysfunction actually long precedes the development of GDM, leading to the recent emergence of a host of markers that may enable the early identification of at-risk women in first trimester and even prior to pregnancy (7)(8)(9)(10)(11) (Fig.…”

“…As women with GDM have chronic insulin resistance, they exhibit many associated features (e.g., dyslipidemia, adipokine dysregulation, inflammation) that differ from their peers but that are not necessarily related to the b-cell dysfunction that underlies the development of GDM (2,5). Indeed, although IGF-I, IGFBP-2, and IGF-I/IGFBP-3 at 10-14 weeks' gestation correlated with HOMA of insulin resistance at 15-26 weeks, their relationships with b-cell function are not known.…”