Postpartum weight retention and the early evolution of cardiovascular risk over the first 5 years after pregnancy.

BACKGROUND: The cumulative effect of postpartum weight retention from each pregnancy in a woman's life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy. METHODS: In this prospective observational cohort study, 330 women (mean age 35.7 ± 4.3 years, mean pre-pregnancy body mass index 25.2 ± 4.8 kg/m2, 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n = 100), weight gain 0-6% (n = 110), and weight gain ≥ 6% (n = 120). RESULTS: At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0-6% to weight gain ≥ 6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p = 0.001), HDL (p = 0.02), LDL (p = 0.01), apolipoprotein-B (p = 0.003), Matsuda index (p < 0.0001), HOMA-IR (p < 0.0001), fasting glucose (p = 0.07), and CRP (p = 0.01). Moreover, on logistic regression analyses, weight gain ≥ 6% emerged as an independent predictor of pre-diabetes/diabetes at 5-years (adjusted OR = 3.40, 95%CI: 1.63-7.09). CONCLUSION: Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women.

Gestational diabetes: One size does not fit all-an observational study of maternal and neonatal outcomes by maternal glucose profile.

OBJECTIVES: To examine obstetrical and neonatal outcomes across maternal glucose profiles at the population level and to explore insulin sensitivity and beta-cell function across profiles in an independent, well-phenotyped cohort for potential pathophysiologic explanation. RESEARCH DESIGN AND METHODS: Observational cohort study of all pregnancies with gestational diabetes screening between October 2008 and December 2018 resulting in live singleton birth in Alberta, Canada (n = 436,773) were categorized into seven maternal glucose profiles: (1) normal 50 g-glucose challenge test (nGCT), (2) normal 75-g OGTT (nOGTT), (3) isolated elevated 1 h post-load glucose (ePLPG1), (4) isolated elevated 2 h post-load glucose (ePLPG2), (5) elevated 1 and 2 h post-load glucose (ePLPG12), (6) isolated elevated FPG (eFPG), and (7) elevated FPG + elevated 1-h and/or 2-h PLG (Combined). Primary outcomes were large for gestational age (LGA) and neonatal intensive care unit (NICU) admission rates. An independent observational cohort of 1451 women was examined for measures of beta-cell function (ISSI-2, insulinogenic index/HOMA-IR) and insulin sensitivity/resistance (Matsuda index, HOMA-IR) by similar maternal glucose profiles. RESULTS: Pregnancies with elevated FPG, either isolated or combined, had higher adverse events and lower insulin sensitivity. The combination of elevated FPG + elevated 1-h and/or 2-h PLG had the highest rates of LGA(20.9%), NICU admissions (14.7%), and lowest insulin sensitivity as measured by Matsuda index and HOMA-IR, and beta-cell function as measured by ISSI-2 and Insulinogenic index/HOMA-IR. CONCLUSIONS: Elevated fasting plasma glucose, either alone or combined with post-load glucose elevation is associated with worse outcomes than isolated post-load glucose elevation, possibly due to higher degrees of insulin resistance. Future work is needed to better understand these differences, and explore whether tailored treatment of GDM can improve neonatal outcomes.

Gestational diabetes in twin pregnancies-a pathology requiring treatment or a benign physiological adaptation?

There is level-1 evidence that screening for and treating gestational diabetes in singleton pregnancies reduce maternal and neonatal morbidity. However, similar data for gestational diabetes in twin pregnancies are currently lacking. Consequently, the current approach for the diagnosis and management of gestational diabetes in twin pregnancies is based on the same diagnostic criteria and glycemic targets used in singleton pregnancies. However, twin pregnancies have unique physiological characteristics, and many of the typical gestational diabetes-related complications are less relevant for twin pregnancies. These differences raise the question of whether the greater increase in insulin resistance observed in twin pregnancies (which is often diagnosed as diet-treated gestational diabetes) should be considered physiological and potentially beneficial in which case alternative criteria should be used for the diagnosis of gestational diabetes in twin pregnancies. In this review, we summarize the most up-to-date evidence on the epidemiology, pathophysiology, and clinical consequences of gestational diabetes in twin pregnancies and review the available data on twin-specific screening and diagnostic criteria for gestational diabetes. Although twin pregnancies are associated with a higher incidence of diet-treated gestational diabetes, diet-treated gestational diabetes in twin pregnancies is less likely to be associated with adverse outcomes and accelerated fetal growth than in singleton pregnancies and may reduce the risk for intrauterine growth restriction. In addition, there is currently no evidence that treatment of diet-treated gestational diabetes in twin pregnancies improves outcomes, whereas preliminary data suggest that strict glycemic control in such cases might increase the risk for intrauterine growth restriction. Overall, these findings provide support to the hypothesis that the greater transient increase in insulin resistance observed in twin pregnancies is merely a physiological exaggeration of the normal increase in insulin resistance observed in singleton pregnancies (that is meant to support 2 fetuses) rather than a pathology that requires treatment. These data illustrate the need to develop twin-specific screening and diagnostic criteria for gestational diabetes to avoid overdiagnosis of gestational diabetes and to reduce the risks associated with overtreatment of diet-treated gestational diabetes in twin pregnancies. Although data on twin-specific screening and diagnostic criteria are presently scarce, preliminary data suggest that the optimal screening and diagnostic criteria in twin pregnancies are higher than those currently used in singleton pregnancies.

Impact of the diagnosis of gestational diabetes on maternal physical activity after pregnancy.

AIM: The diagnosis of gestational diabetes (GDM) identifies women who are at future risk of developing type 2 diabetes. However, it is unclear if diagnosing GDM thus motivates women to increase physical activity after pregnancy or if this medicalization has the opposite effect of decreasing activity, possibly reflecting assumption of a sick role. We thus sought to evaluate the impact of diagnosing GDM on changes in maternal physical activity after pregnancy. METHODS: In this prospective cohort study, physical activity patterns were assessed by the Baecke questionnaire for the year before pregnancy and the first year postpartum in 405 white women comprising the following three gestational glucose tolerance groups: (a) those who did not have GDM (non-GDM; n = 247), (b) women with undiagnosed GDM (n = 46) and (c) those diagnosed with GDM (n = 112). RESULTS: In the year before pregnancy, mean adjusted total physical activity progressively decreased from non-GDM to undiagnosed GDM to diagnosed GDM (p = .067). Conversely, at 1 year postpartum, total physical activity was highest in those who had been diagnosed with GDM (p = .02). Compared with non-GDM, diagnosed GDM predicted an increase in total physical activity from pre-pregnancy to 1 year postpartum (t = 2.3, p = .02) whereas undiagnosed GDM predicted a concurrent decrease in leisure-time activity (t = -2.74, p = .006). Accordingly, the mean adjusted increase in body mass index from pre-pregnancy to 1 year postpartum was lowest in those with diagnosed GDM (0.26 ± 0.25 kg/m2 ), highest in undiagnosed GDM (1.23 ± 0.38 kg/m2 ) and intermediate in non-GDM (0.89 ± 0.22 kg/m2 ) (overall p = .04). CONCLUSION: Diagnosis of GDM leads to increased physical activity after pregnancy that may partially attenuate postpartum weight retention.

Antenatal glycemic management and postpartum cardiovascular disease risk screening.

OBJECTIVE: This study aims to evaluate the cardiovascular disease (CVD) risk profiles of patients referred to the maternal health clinic (MHC) with a history of gestational diabetes (GDM). METHODS: Eligible patients had their MHC appointment at 6 months postpartum between November 2011 and May 2022 and experienced GDM in their most recent pregnancy. Included participants were then divided into subgroups comparing methods of glycemic control: diet-controlled GDM and insulin-controlled GDM. Additionally, the MHC recruited 47 patients who have not experienced a complication in pregnancy to act as a comparator group in research studies. Demographics, medical and pregnancy history, and CVD risk scores were compared between the three groups. RESULTS: 344 patients with GDM were included in the analysis; 165 insulin-controlled and 179 diet-controlled. When measuring the median 30 year Framingham risk score based on both BMI and lipids, there was a significant stepwise increase seen from the unexposed group, the diet-controlled GDM, and the insulin-controlled groups, respectively (all P < 0.05). The presence of metabolic syndrome showed a stepwise increase in prevalence when comparing the unexposed group, diet exposure group, and the insulin exposure group, respectively (16.7%, 21.5%, 44.8%; P < 0.05). CONCLUSION: Our findings reinforce the prevalence of maternal CVD risk among GDM-diagnosed patients in the postpartum period and the necessity for screening. More specifically, our findings show how CVD risk may differ based on required interventions for glycemic control throughout pregnancy. Future research should aim to compare a more diverse patient population to optimize the generalizability of glycemic control-specific CVD outcomes.

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following 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.

The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes.

OBJECTIVE: Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM. METHODS: In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry. RESULTS: At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout. CONCLUSION: Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02194595.

Glycemic control and neonatal outcomes in twin pregnancies with gestational diabetes mellitus.

BACKGROUND: Preliminary data suggest that strict glycemic control in twin pregnancies with gestational diabetes mellitus may not improve outcomes but might increase the risk of fetal growth restriction. OBJECTIVE: This study aimed to investigate the association of maternal glycemic control with the risk of gestational diabetes mellitus-related complications and small for gestational age in twin pregnancies complicated by gestational diabetes mellitus. STUDY DESIGN: This was a retrospective cohort study of all patients with a twin pregnancy complicated by gestational diabetes mellitus in a single tertiary center between 2011 and 2020, and a matched control group of patients with a twin pregnancy without gestational diabetes mellitus in a 1:3 ratio. The exposure was the level of glycemic control, described as the proportion of fasting, postprandial, and overall glucose values within target. Good glycemic control was defined as a proportion of values within target above the 50th percentile. The first coprimary outcome was a composite variable of neonatal morbidity, defined as at least 1 of the following: birthweight >90th centile for gestational age, hypoglycemia requiring treatment, jaundice requiring phototherapy, birth trauma, or admission to the neonatal intensive care unit at term. A second coprimary outcome was small for gestational age, defined as birthweight <10th centile or <3rd centile for gestational age. Associations between the level of glycemic control and the study outcomes were estimated using logistic regression analysis and were expressed as adjusted odds ratio with 95% confidence interval. RESULTS: A total of 105 patients with gestational diabetes mellitus in a twin pregnancy met the study criteria. The overall rate of the primary outcome was 32.4% (34/105), and the overall proportion of pregnancies with a small for gestational age newborn at birth was 43.8% (46/105). Good glycemic control was not associated with a reduction in the risk of composite neonatal morbidity when compared with suboptimal glycemic control (32.1% vs 32.7%; adjusted odds ratio, 2.06 [95% confidence interval, 0.77-5.49]). However, good glycemic control was associated with higher odds of small for gestational age compared with nongestational diabetes mellitus pregnancies, especially in the subgroup of diet-treated gestational diabetes mellitus (65.5% vs 34.0%, respectively; adjusted odds ratio, 4.17 [95% confidence interval, 1.74-10.01] for small for gestational age <10th centile; and 24.1% vs 7.0%, respectively; adjusted odds ratio, 3.97 [95% confidence interval, 1.42-11.10] for small for gestational age <3rd centile). In contrast, the rate of small for gestational age in gestational diabetes mellitus pregnancies with suboptimal control was not considerably different when compared with non-gestational diabetes mellitus pregnancies. In addition, in cases of diet-treated gestational diabetes mellitus, good glycemic control was associated with a left-shift of the distribution of birthweight centiles, whereas the distribution of birthweight centiles among gestational diabetes mellitus pregnancies with suboptimal control was similar to that of nongestational diabetes mellitus pregnancies. CONCLUSION: In patients with gestational diabetes mellitus in a twin pregnancy, good glycemic control is not associated with a reduction in the risk of gestational diabetes mellitus-related complications but may increase the risk of a small for gestational age newborn in the subgroup of patients with mild (diet-treated) gestational diabetes mellitus. These findings further question whether the gestational diabetes mellitus glycemic targets used in singleton pregnancies also apply to twin pregnancies and support the concern that applying the same diagnostic criteria and glycemic targets in twin pregnancies may result in overdiagnosis and overtreatment of gestational diabetes mellitus and potential neonatal harm.

Baseline determinants of remission of type 2 diabetes in response to short-term insulin-based therapy: The pivotal role of beta-cell function.

AIM: To identify baseline determinants of diabetes remission in response to short-term insulin-based therapy. METHODS: In this study, adult patients with type 2 diabetes (T2D) of less than 7 years duration were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice-daily lispro, or (c) glargine + twice-daily exenatide, followed by 12 weeks of washout that enabled assessment of remission (defined as HbA1c < 6.5% after ≥ 3 months without glucose-lowering therapy). At baseline, 8 weeks and washout, beta-cell function was assessed with four measures: Insulin Secretion-Sensitivity Index-2 (ISSI-2), insulinogenic index/Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), ΔC-peptide0-120 /Δglucose0-120 × Matsuda and Δinsulin secretion rate (ISR)0-120 /Δgluc0-120 × Matsuda. RESULTS: Diabetes remission was achieved in 31 of 90 participants (34.4%). Compared with their peers, those who went on to remission had lower HbA1c (P < .001) and better beta-cell function at baseline (all four measures P ≤ .01). The non-remission and remission groups did not otherwise differ in baseline insulin sensitivity/resistance (Matsuda, HOMA-IR), body mass index, duration of diabetes, pretrial diabetes medications or allocated insulin-based therapy during the trial. On logistic regression analyses, each baseline measure of beta-cell function emerged as a significant predictor of remission (log ISSI-2: adjusted OR 4.41 [95% CI: 1.71-11.34]; log insulinogenic index/HOMA-IR: 2.21 [1.26-3.89]; log ΔC-peptide0-120 /Δglucose0-120 × Matsuda: 1.62 [1.00-2.64]; log ΔISR0-120 /Δgluc0-120 × Matsuda: 1.87 [1.09-3.23]). Similarly, higher baseline ISSI-2 tertile predicted longer time to glycaemic relapse after cessation of the insulin-based therapy (log-rank P = .029). CONCLUSION: Beta-cell function is the dominant baseline pathophysiological determinant of the likelihood of achieving remission of diabetes in response to short-term insulin-based therapy.

Mediating effect of vascular risk factors underlying the link between gestational diabetes and cardiovascular disease.

BACKGROUND: Women with gestational diabetes (GDM) have an elevated lifetime incidence of cardiovascular disease (CVD), but the basis of this excess risk remains to be established. In this context, we hypothesized that chronic exposure to adverse cardiovascular risk factors may contribute to their elevated risk of CVD. We thus sought to quantify the determinants of CVD risk in women with a history of GDM by performing mediation analyses. METHODS: Women in Ontario, Canada, with a live-birth pregnancy between Jan 1998 and Dec 2017 (n=757,541) were followed for a median of 13.2 years and stratified into the following 4 groups: women with GDM who developed CVD (GDM+/CVD+); women without GDM who developed CVD (GDM-/CVD+); those with GDM but no CVD (GDM+/CVD-); and those with neither GDM nor CVD (GDM-/CVD-). Lipids (total cholesterol, LDL, HDL, triglycerides) and glycemic variables (A1c, fasting glucose) were measured between 4.3±3.0 and 4.8±3.4 times over follow-up. RESULTS: On successive measurements at a median of 4.8, 7.1, and 8.7 years postpartum, respectively, each lipid and glycemic measure progressively worsened from GDM-/CVD- to GDM+/CVD- to GDM-/CVD+ to GDM+/CVD+ (all p<0.0001). At each point in time, each of the lipid and glycemic measures was significantly worse in GDM+/CVD+ compared to GDM+/CVD- (all p<0.001). Moreover, among women who did not develop CVD, all lipid and glycemic measures were significantly worse in those with previous GDM (all p<0.001 for GDM+/CVD- vs GDM-/CVD-). Mediation analyses revealed that the dominant determinants of CVD risk in women with GDM were A1c (56.0% mediation, 95%CI 47.4-67.8) and fasting glucose (47.4%, 38.8-60.8), followed by HDL (25.2%, 21.3-30.7) and triglycerides (12.1%, 9.7-15.6). Upon exclusion of those who developed diabetes during follow-up, the key determinants were HDL (40.8%), fasting glucose (37.7%), A1c (28.6%), triglycerides (21.0%), and LDL (9.9%). CONCLUSIONS: Adverse glycemic and lipid measures mediate the elevated risk of CVD in women with previous GDM, with the impact of lipids particularly evident in those who do not develop diabetes. These findings thus identify potential targets for risk factor monitoring and ultimately early intervention towards the goal of primary prevention of CVD in this at-risk patient population.

The ongoing evolution of basal insulin therapy over 100 years and its promise for the future.

The evolution of basal insulin therapy over the past 100 years since the discovery of insulin is a testimony to the biomedical bench-to-bedside process, wherein incremental advances in the basic sciences are progressively translated over time into a series of enhancements in clinical care, each building upon the success of its predecessors. The emergence of recombinant DNA technology and the resultant biosynthesis of human insulin in the 1980s provided the critical capacity to bioengineer designer insulin analogues with pharmacokinetic and pharmacodynamic properties that can better mimic, although not fully replicate, the effects of endogenous insulin secretion. Through these efforts, basal insulin therapy has progressed over this time from first-generation analogues (glargine U-100, detemir) to second-generation analogues (glargine U-300, degludec) to ultra-long-acting formulations that are suitable for administration once weekly (icodec). Each iteration in this progression has represented a step closer towards the goal of replicating the continuous secretion of insulin that normally comprises the basal output of the pancreatic beta-cells between meals, during episodes of fasting and overnight. However, it may be that we may have reached the achievable limit in the context of an "open-loop" approach, such that only with the addition of closed loop control will we be able to achieve physiologic basal insulin replacement. In this review, we will examine the evolution of basal insulin therapy over the past 100 years and its implications for patient care and outcomes in current practice and the future.

Mirtazapine use may increase the risk of hypothyroxinaemia in patients affected by major depressive disorder.

AIMS: Hypothyroxinaemia could be easily neglected if attention is paid only to patients with elevated thyroid-stimulating hormone. We aimed to assess the association between mirtazapine use and hypothyroxinaemia in patients affected by major depressive disorder. METHODS: We conducted a retrospective cohort study in the Second Affiliated Hospital of Xinxiang Medical University between January 2016 and December 2018. Patients affected by major depression disorder and admitted to the hospital for treatment during the study period and who had thyroid tests at admission and after treatment were included. Mirtazapine use during hospitalization was the exposure measure and newly developed hypothyroxinaemia was as the primary outcome and structure parameters of thyroid homeostasis were the secondary outcomes of this study. Log-binomial model was used to estimate the association between mirtazapine use and hypothyroxinaemia, after adjusting for potential confounding factors. RESULTS: A total of 220 eligible patients were included in the final analysis. The incidence of hypothyroxinaemia in patients who used mirtazapine was higher (37.5%) than those patients who did not use (19.7%). The relative risk of developing hypothyroxinaemia was 1.70 (95% confidence interval: 1.21-2.43) for mirtazapine use, after adjusting for confounding factors. The degree of reduction in thyroid feedback quantile-based index in mirtazapine group was significantly greater than that in nonmirtazapine group. CONCLUSION: Mirtazapine use was associated with the increased risk of developing hypothyroxinaemia. The underlying mechanism may be involved the changed central set point of thyroid homeostasis, in which pituitary was in a possibly impaired sensitivity to the lower level of thyroid hormones.

Oxcarbazepine was associated with risks of newly developed hypothyroxinaemia and impaired central set point of thyroid homeostasis in schizophrenia patients.

AIMS: Hypothyroxinaemia might be easily ignored, because attention is typically paid to individuals with elevated thyroid stimulating hormone (TSH). In this study, we aimed to evaluate the association of oxcarbazepine use as adjuvant for treatment of schizophrenia with hypothyroxinaemia and central set point of thyroid homeostasis. METHODS: This retrospective cohort study was conducted in the Second Affiliated Hospital of Xinxiang Medical University. Inpatients with a diagnosis of schizophrenia admitted between January 2016 and October 2019 with normal thyroid function at admission were included. Oxcarbazepine use was the exposure measure. Newly developed hypothyroxinaemia was the primary outcome measure and parameters of thyroid homeostasis central set point as measured by TSH index and thyroid feedback quantile-based index (TFQI) were the secondary outcome measures. RESULTS: In total, 1207 eligible patients were included. The occurrence of hypothyroxinaemia in patients who received oxcarbazepine was higher (35/107, 32.7%) than in those patients who did not (152/1099, 13.8%), with adjusted relative risk of 2.24 and 95% confidence interval of 1.57 and 3.17. Oxcarbazepine use was associated with greater reduction in TSH index (adjusted ß -0.33 and 95% confidence interval -0.48, -0.19) and TFQI (adjusted ß -0.24 and 95% confidence interval -0.31, -0.16). CONCLUSION: Oxcarbazepine use was independently associated with increased risk of developing hypothyroxinaemia, and greater reduction in TSH index and TFQI, suggesting that impaired central set point of thyroid homeostasis might be involved in the mechanism of oxcarbazepine-induced hypothyroxinaemia.

The adverse cardiovascular risk factor profile of women with pre-eclampsia develops over time in the years before pregnancy.

OBJECTIVE: Women with a history of pre-eclampsia have an elevated lifetime risk of cardiovascular disease that may be partly attributed to an adverse cardiovascular risk factor profile, the etiology of which is unclear. Hypothesising that this adverse risk profile may begin to arise over time in the years before pregnancy, we sought to evaluate the pregravid changes over time in cardiovascular risk factors in women who go on to develop pre-eclampsia and those who do not. DESIGN: Retrospective cohort study using population-based administrative databases. SETTING: Ontario, Canada. POPULATION: All nulliparous women who had singleton pregnancies between January 2011 and December 2018. METHODS: All results for the following analytes between January 2008 and the start of pregnancy were identified: A1c, glucose, lipids, and transaminases. Mean values were compared between those with and without preeclampsia. The annual change for each analyte in the years before pregnancy was estimated using generalized estimating equations. MAIN OUTCOME MEASURE: Preeclampsia. RESULTS: The 156 278 women (of whom 3827 developed preeclampsia) had mean 4.0 ± 3.3 pregravid tests overall. The two most recent pregravid tests were performed at median 0.6 and 1.9 years before pregnancy, respectively. Women who developed pre-eclampsia had higher pregravid A1c, fasting glucose, random glucose, LDL-cholesterol, triglycerides, and ALT, and lower HDL-cholesterol, than their peers (all P < 0.0001). In the years before pregnancy, women who went on to develop pre-eclampsia had higher annual increases than their peers in triglycerides (13.8-fold higher; P = 0.0004) and random glucose (1.55-fold higher; P = 0.001), coupled with a greater annual decrease in HDL-cholesterol (9.7-fold higher; P = 0.002). During this time, fasting glucose increased in women who developed pre-eclampsia but decreased in their peers (P = 0.01). CONCLUSION: In women who develop pre-eclampsia, an adverse cardiovascular risk factor profile evolves over time in the years before pregnancy. TWEETABLE ABSTRACT: In women who develop pre-eclampsia, an adverse CV risk factor profile evolves in the years before pregnancy.

Folic Acid Supplementation in Early Pregnancy, Homocysteine Concentration, and Risk of Gestational Diabetes Mellitus.

We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.

Neighbourhood Walkability and Risk of Diabetes: Causal Relationship or Epidemiologic Association?

PURPOSE OF REVIEW: We aim to evaluate whether the current literature supports (i) a causal relationship between neighbourhood walkability and risk of diabetes or instead (ii) a strictly epidemiologic association. RECENT FINDINGS: Both cross-sectional and longitudinal studies have reported that neighbourhoods that are scored as having higher levels of walkability have lower rates of prevalent and incident diabetes, respectively. However, other studies have been inconclusive, with more nuanced findings suggesting that this association may be limited to particular demographic groups defined by age and socio-economics. Key factors limiting this literature include disparities in the measurement of walkability, the necessary reliance on observational study designs (recognizing the infeasibility of randomized controlled trials for addressing this question), and the difficulty of disentangling the potential concomitant effects of other components of the built environment. At this time, causality cannot be ascertained in the relationship between neighbourhood walkability and risk of diabetes.

Impact of pregnancy on the trajectories of cardiovascular risk factors in women with and without gestational diabetes.

AIMS: The elevated lifetime risk of cardiovascular disease in women who develop gestational diabetes mellitus (GDM) has been attributed to adverse life-course trajectories of cardiovascular risk factors that arise before pregnancy and continue thereafter. We hypothesized that pregnancy may differentially affect these trajectories in women who develop GDM and those who do not. MATERIALS AND METHODS: With population-based administrative databases, we identified all nulliparous women in Ontario, Canada, who had singleton pregnancies between January 2011 and December 2016 and ≥2 measurements of the following analytes both before and after pregnancy: glycated haemoglobin (HbA1c), glucose, lipids and transaminases. In total, 39 581 women (4373 with GDM) had 3.9 ± 3.4 tests before and 4.6 ± 5.4 tests after pregnancy. RESULTS: Both before and after pregnancy, women who developed GDM had higher HbA1c, fasting glucose, low-density lipoprotein (LDL)-cholesterol and triglycerides than their peers, with lower high-density lipoprotein (HDL)-cholesterol (all p < .0001). Before pregnancy, women who went on to GDM had higher annual increases than their peers did in HbA1c, fasting glucose and triglycerides (all p ≤ .01); lesser annual decrease in LDL (p = .0003); and greater annual decrease in HDL (p = .0006). Compared with pre-pregnancy, the postpartum differences in annual rates of change in HbA1c and fasting glucose were 6.9- and 3.3-fold higher, respectively, in women with GDM. Conversely, the respective postpartum differences in annual rates of change in triglycerides, LDL and HDL were 1.2, 1.6 and 0.3 times lower than before pregnancy. CONCLUSION: After pregnancy, differences in pregravid trajectories of glycaemic measures are amplified between women with GDM and their peers. In contrast, pregravid differences in lipid measures persist but do not differentially worsen after pregnancy.

Short-term intensive insulin as induction and maintenance therapy for the preservation of beta-cell function in early type 2 diabetes (RESET-IT Main): A 2-year randomized controlled trial.

AIM: To test the hypothesis that the addition of periodic courses of short-term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta-cell function following induction IIT. METHODS: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2-week courses of IIT every 3 months for 2 years. Beta-cell function was assessed by the Insulin Secretion Sensitivity Index-2 (ISSI-2) at an oral glucose tolerance test every 3 months. RESULTS: In both arms, induction IIT increased ISSI-2, improved whole-body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline-adjusted ISSI-2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline-adjusted difference -35 [95% CI: -66, -3]), with three additional beta-cell measures showing no significant differences. Baseline-adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years. CONCLUSION: Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta-cell function.

Dose-response association of acute-phase quetiapine treatment with risk of new-onset hypothyroidism in schizophrenia patients.

AIMS: To assess association between quetiapine treatment and risk of new-onset hypothyroidism in schizophrenia patients. METHODS: We conducted a retrospective cohort study in a tertiary hospital in China between January 2016 and December 2018. Schizophrenia patients with normal thyroid tests at admission were included. Hypothyroidism, which was defined as thyroid-stimulating hormone >4.20 mU/L and free thyroxine <12.00 pmol/L, or on L-thyroxine prescriptions, was the outcome measure, and quetiapine treatment between admission and subsequent thyroid test was the exposure measure of this study. Adjusted relative risks and 95% confidence intervals were used to assess the independent association of quetiapine treatment with risk of new-onset hypothyroidism. The dose-response association was further analysed by 3 quetiapine doses: low (≤<=0.2 g/d), medium (0.2-0.6 g/d), and high (>0.6 g/d). RESULTS: A total of 2022 eligible patients were included in the final analysis. Sixty patients (15.0%) in the quetiapine group developed hypothyroidism, while 56 patients (3.5%) in the nonquetiapine group developed hypothyroidism. Relative risk (95% confidence interval) of developing hypothyroidism for quetiapine use was 4.01 (2.86-5.64) after adjusting for several potential confounding factors. A strong dose-response association between quetiapine use and risk of developing hypothyroidism was observed: adjusted relative risks (95% confidence intervals) were 1.00 (0.25-2.59), 4.22 (2.80-6.25) and 5.62 (3.66-8.38), respectively, for low-, medium- and high-dose quetiapine, as compared with no quetiapine. CONCLUSION: Acute phase quetiapine treatment for schizophrenia patients was strongly associated with increased risk of developing new-onset hypothyroidism, with a clear dose-response association.

Changes in adiposity mediate the associations of diet quality with insulin sensitivity and beta-cell function.

BACKGROUND AND AIMS: To examine the mediating role of adiposity on the associations of diet quality with longitudinal changes in insulin sensitivity and beta-cell function. METHODS AND RESULTS: Adults at-risk for type 2 diabetes (T2D) in the PROMISE cohort had 4 assessments over 9 years (n = 442). Alternate Healthy Eating Index (AHEI) scores were used to assess diet quality. Generalized Estimating Equations (GEE) evaluated the associations between the AHEI and longitudinal changes in insulin sensitivity (HOMA2-%S and ISI) and beta-cell function (IGI/HOMA-IR and ISSI-2). The proportion of the mediating effect of waist circumference changes was estimated using the difference method. In the primary longitudinal analysis, AHEI was positively associated with insulin sensitivity and beta-cell function over time (% difference per standard deviation increase of AHEI for HOMA2-%S (ß = 11.0, 95%CI 5.43-17.0), ISI (ß = 10.4, 95%CI 4.35-16.8), IGI/HOMA-IR (ß = 7.12, 95%CI 0.98-13.6) and ISSI-2 (ß = 4.38, 95%CI 1.05-7.80), all p < 0.05). There was no significant association between AHEI and dysglycemia incidence (OR = 0.95, 95%CI 0.77-1.17). Adjustments for longitudinal changes in waist circumference substantially attenuated all associations of AHEI with insulin sensitivity and beta-cell function. Mediation analysis indicated that waist circumference mediated 73%, 70%, 83% and 81% of the association between AHEI and HOMA2-%S, ISI, IGI/HOMA-IR, and ISSI-2, respectively (all p < 0.01). CONCLUSION: In a Canadian population at-risk for T2D, AHEI score was positively associated with changes in insulin sensitivity and beta-cell function. These associations were substantially mediated by waist circumference, suggesting that changes in adiposity may represent an important pathway linking diet quality with risk phenotypes for T2D.