To compare postpartum glucose tolerance between women treated for gestational diabetes mellitus (GDM) and those not treated.
Metabolic testing was performed at 3 and 12 months postpartum in 599 women ...comprising the following gestational glucose tolerance groups: 1) normal glucose challenge test (GCT) and oral glucose tolerance test (OGTT) during pregnancy, 2) abnormal GCT with normal OGTT, 3) gestational impaired glucose tolerance, 4) mild untreated GDM, and 5) severe treated GDM.
Birth weight progressively increased across groups 1-4 before falling steeply in treated GDM (P < 0.0001). In contrast, at 3 and 12 months, insulin sensitivity and β-cell function progressively decreased across the five groups, mirrored by rising fasting and 2-h glucose (all P < 0.0001). Accordingly, prevalence of prediabetes/diabetes at 12 months increased in a stepwise manner across groups 1-5 (2.8%, 9.6%, 13.5%, 21.5%, and 32.6%, respectively; P < 0.0001).
Treating GDM lowers birth weight but does not disrupt the association between gestational glycemia and maternal prediabetes/diabetes after pregnancy.
The cumulative effect of postpartum weight retention from each pregnancy in a woman's life may contribute to her ultimate risk of diabetes and vascular disease. However, there is little direct ...evidence supporting this hypothesis. In this context, we sought to evaluate the cardiometabolic implications of patterns of postpartum weight change and the time course thereof in the first year after pregnancy.
Three hundred five women underwent cardiometabolic characterization at recruitment in pregnancy and at 3 and 12 months postpartum. Based on their respective weight changes between prepregnancy and 3 months postpartum (loss or gain) and between 3 and 12 months postpartum (loss or gain), participants were stratified into four groups: loss/loss, gain/loss, loss/gain, and gain/gain.
Most women (81.0%) had higher weight at 3 months postpartum compared with prepregnancy. Between 3 and 12 months, most women (74.4%) lost weight. At 3 months, there were modest differences between the four groups in mean adjusted LDL cholesterol (P = 0.01) and apolipoprotein-B (apoB; P = 0.02) but no significant differences in adjusted blood pressure, fasting and 2-h glucose, HDL, triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and C-reactive protein. By 12 months postpartum, however, clear gradients emerged, with mean adjusted diastolic blood pressure (P = 0.02), HOMA-IR (P = 0.0003), LDL (P = 0.001), and apoB (P < 0.0001) all progressively increasing from the loss/loss group to gain/loss to loss/gain to gain/gain. Similarly, at 12 months, mean adjusted adiponectin showed a stepwise decrease from loss/loss to gain/loss to loss/gain to gain/gain (P = 0.003).
An adverse cardiometabolic profile emerges as early as 1 year postpartum in women who do not lose weight between 3 and 12 months after delivery.
Retrospective analyses of perinatal databases have raised the intriguing possibility of an increased risk of gestational diabetes mellitus (GDM) in women carrying a male fetus, but it has been ...unclear if this was a spurious association. We thus sought to evaluate the relationship between fetal sex and maternal glucose metabolism in a well-characterized cohort of women reflecting the full spectrum of gestational glucose tolerance from normal to mildly abnormal to GDM.
A total of 1,074 pregnant women underwent metabolic characterization, including oral glucose tolerance test (OGTT), at mean 29.5 weeks' gestation. The prevalence of GDM, its pathophysiologic determinants (β-cell function and insulin sensitivity/resistance), and its clinical risk factors were compared between women carrying a female fetus (n = 534) and those carrying a male fetus (n = 540).
Women carrying a male fetus had lower mean adjusted β-cell function (insulinogenic index divided by HOMA of insulin resistance: 9.4 vs. 10.5, P = 0.007) and higher mean adjusted blood glucose at 30 min (P = 0.025), 1 h (P = 0.004), and 2 h (P = 0.02) during the OGTT, as compared with those carrying a female fetus. Furthermore, women carrying a male fetus had higher odds of developing GDM (odds ratio 1.39 95% CI 1.01-1.90). Indeed, male fetus further increased the relative risk of GDM conferred by the classic risk factors of maternal age >35 years and nonwhite ethnicity by 47 and 51%, respectively.
Male fetus is associated with poorer β-cell function, higher postprandial glycemia, and an increased risk of GDM in the mother. Thus, fetal sex potentially may influence maternal glucose metabolism in pregnancy.
There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some ...breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk.
We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided.
High-density lipoprotein-cholesterol (HDL-C) (P = .05) and apoA1 (P = .02) levels were positively associated with breast cancer risk (75(th) vs 25(th) percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P = .03) and apoB (P = .01) levels were negatively associated (75(th) vs 25(th) percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk.
These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination.
Context:
In patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 ...agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment.
Objective:
The purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM.
Design/Setting/Participants/Intervention:
In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ±1.9 years' duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks.
Main Outcome Measures:
The glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test.
Results:
As expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48-week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 ± 34.9 vs 65.4 ± 36.4 pg/mL · 2 hours, P = .04), 36 weeks (162.2 ± 27.9 vs 55.7 ± 30.4 pg/mL · 2 hours, P = .01), and 48 weeks (155.5 ± 26.5 vs 45.7 ± 27.0 pg/mL · 2 hours, P = .006).
Conclusion:
In contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM.
apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin ...resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women. Approach and Results: In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, apoB apolipoprotein B, and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79,
<0.0001) and weakly so with adiponectin (r=0.12,
=0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index (
=0.24), homeostasis model assessment of insulin resistance (
=0.08), or area under the glucose curve on the oral glucose tolerance test (
=0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before (
=0.67) and after covariate adjustment (
=0.78).
Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.
Aims/hypothesis
Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes ...but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk.
Methods
In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 ISSI-2, insulinogenic index IGI/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models.
Results
Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (
p
=0.03) and 2 h glucose (
p
<0.0001) than non-progressors, coupled with higher BMI (
p
=0.001), greater insulin resistance (both Matsuda index and HOMA-IR,
p
≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR,
p
≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both
p
<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance.
Conclusion/interpretation
Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.
Graphical Abstract
Background & Aims The intestine efficiently incorporates and rapidly secretes dietary fat as chylomicrons (lipoprotein particles comprising triglycerides, phospholipids, cholesterol, and proteins) ...that contain the apolipoprotein isoform apoB-48. The gut can store lipids for many hours after their ingestion, and release them in chylomicrons in response to oral glucose, sham feeding, or unidentified stimuli. The gut hormone glucagon-like peptide-2 (GLP-2) facilitates intestinal absorption of lipids, but its role in chylomicron secretion in human beings is unknown. Methods We performed a randomized, single-blind, cross-over study, with 2 study visits 4 weeks apart, to assess the effects of GLP-2 administration on triglyceride-rich lipoprotein (TRL) apoB-48 in 6 healthy men compared with placebo. Subjects underwent constant intraduodenal feeding, with a pancreatic clamp and primed constant infusion of deuterated leucine. In a separate randomized, single-blind, cross-over validation study, 6 additional healthy men ingested a high-fat meal containing retinyl palmitate and were given either GLP-2 or placebo 7 hours later with measurement of TRL triglyceride, TRL retinyl palmitate, and TRL apoB-48 levels. Results GLP-2 administration resulted in a rapid (within 30 minutes) and transient increase in the concentration of TRL apoB-48, compared with placebo ( P = .03). Mathematic modeling of stable isotope enrichment and the mass of the TRL apoB-48 suggested that the increase resulted from the release of stored, presynthesized apoB-48 from the gut. In the validation study, administration of GLP-2 at 7 hours after the meal, in the absence of additional food intake, robustly increased levels of TRL triglycerides ( P = .007), TRL retinyl palmitate ( P = .002), and TRL apoB-48 ( P = .04) compared with placebo. Conclusions Administration of GLP-2 to men causes the release of chylomicrons that comprise previously synthesized and stored apoB-48 and lipids. This transiently increases TRL apoB-48 levels compared with placebo. Clinical trials number at www.clinicaltrials.gov : NCT 01958775.
Glucose 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 β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum after gestational dysglycemia.
A 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).
At 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 β-cell function, assessed by the Insulin Secretion-Sensitivity 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 β-cell function and insulin sensitivity, as well as rising glycemia, compared with normal GCT NGT.
Each degree of gestational glucose intolerance predicts distinct trajectories of β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum that drive their differential risk of future T2DM.
PDF
