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.

Omega-3 Polyunsaturated Fatty Acids with Adipose Tissue Inflammation: Longitudinal Analysis in the PROMISE Cohort.

OBJECTIVES: Although pre-clinical studies have shown a beneficial impact of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on adipose (AT) inflammation, the current literature from human studies is limited. Therefore, we aimed to evaluate the longitudinal associations of circulating levels of n-3 PUFAs with biomarkers of AT inflammation. METHODS: Longitudinal data from participants in the PROMISE cohort (n = 474) were used. AT inflammation was measured using circulating biomarkers at baseline and up to 2 follow-up visits. n-3 PUFAs were measured at baseline in four serum lipid fractions. Generalized estimating equations (GEE) analyses evaluated longitudinal associations between n-3 PUFAs and AT inflammation, adjusting for covariates. RESULTS: Fully adjusted GEE models indicated that higher baseline proportions of eicosapentaenoic acid (EPA), n-3 docosapentaenoic acid (n-3 DPA), and docosahexaenoic acid (DHA) in total serum were significantly inversely associated with longitudinal change in soluble CD163 (sCD163) (all p < 0.05). A significant positive association of n-3 DPA and DHA with longitudinal change in adiponectin (p < 0.05) was also observed. Generally consistent associations were observed between n-3 PUFAs and sCD163 and adiponectin in the four lipid fractions. CONCLUSIONS: These findings will add to the limited evidence on the potential role n-3 PUFAs have in the prevention and management of AT inflammation in humans and may help inform future interventions targeting chronic inflammation at the level of AT.

The impact of gestational diabetes on functional capacity of the infant gut microbiome is modest and transient.

Gestational diabetes mellitus (GDM) is a metabolic complication that manifests as hyperglycemia during the later stages of pregnancy. In high resource settings, careful management of GDM limits risk to the pregnancy, and hyperglycemia typically resolves after birth. At the same time, previous studies have revealed that the gut microbiome of infants born to mothers who experienced GDM exhibit reduced diversity and reduction in the abundance of several key taxa, including Lactobacillus. What is not known is what the functional consequences of these changes might be. In this case control study, we applied 16S rRNA sequence surveys and metatranscriptomics to profile the gut microbiome of 30 twelve-month-old infants - 16 from mothers with GDM, 14 from mothers without - to examine the impact of GDM during pregnancy. Relative to the mode of delivery and sex of the infant, maternal GDM status had a limited impact on the structure and function of the developing microbiome. While GDM samples were associated with a decrease in alpha diversity, we observed no effect on beta diversity and no differentially abundant taxa. Further, while the mode of delivery and sex of infant affected the expression of multiple bacterial pathways, much of the impact of GDM status on the function of the infant microbiome appears to be lost by twelve months of age. These data may indicate that, while mode of delivery appears to impact function and diversity for longer than anticipated, GDM may not have persistent effects on the function nor composition of the infant gut microbiome.

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.

Urinary Vitamin D Binding Protein: A Marker of Kidney Tubular Dysfunction in Patients at Risk for Type 2 Diabetes.

Context: Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective: Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods: Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results: Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 µg/mmol, 2.63 µg/mmol, and 2.48 µg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (ß = 30.67 and ß = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.

Future cardiometabolic implications of insulin hypersecretion in response to oral glucose: a prospective cohort study.

Background: The cardiometabolic implications of postprandial hyperinsulinemia are unclear with recent studies suggesting both adverse and beneficial associations. We aimed to evaluate the longitudinal cardiometabolic implications of the post-challenge insulin secretory response over 4-years follow-up. Methods: In this prospective cohort study, conducted in Toronto (Ontario, Canada), women comprising the full range of antepartum glucose tolerance were recruited in pregnancy (at the time of glucose tolerance screening, late in the second trimester) to undergo cardiometabolic testing in the years thereafter. Participants underwent oral glucose tolerance tests (OGTT) at 1-year, 3-years, and 5-years postpartum, enabling serial assessment of cardiovascular risk factors, glucose tolerance, insulin sensitivity or resistance (Matsuda index, HOMA-IR), and beta-cell function-via Insulin Secretion-Sensitivity Index-2 (ISSI-2) and insulinogenic index/HOMA-IR (IGI/HOMA-IR). Baseline post-challenge insulinemia was assessed with the corrected insulin response (CIR) at 1-year. Cardiometabolic factors were compared between baseline CIR tertiles. Findings: Between Oct 23, 2003 and March 31, 2014, 306 women were enrolled. In this study population, there was progressive worsening of waist circumference (p = 0.016), HDL (p = 0.018), CRP (p = 0.006), and insulin sensitivity (p < 0.001) from the lowest to middle to highest tertile of CIR at 1-year. However, these adverse features were accompanied by progressively better beta-cell function (both p < 0.001), coupled with lower fasting and 2-h glucose on the OGTT (both p < 0.001). On adjusted longitudinal analyses, higher CIR tertile at 1-year was independently associated with (i) higher ISSI-2 and IGI/HOMA-IR and (ii) lower fasting and 2-h glucose at both 3-years and 5-years (all p < 0.001), but was not associated with BMI, waist, lipids, CRP or insulin sensitivity/resistance. The highest CIR tertile at 1-year predicted lower risk of pre-diabetes or diabetes at both 3-years (adjusted OR = 0.19; 95% CI 0.08-0.45) and 5-years (aOR = 0.18; 0.08-0.39), relative to the lowest tertile. Interpretation: A robust post-challenge insulin secretory response does not indicate adverse cardiometabolic health but, rather, portends favourable metabolic function in the years to come. Future long-term study of the implications of the post-challenge insulinemic response is warranted. Funding: Canadian Institutes of Health Research.

Thyroid allostasis in drug-free affective disorder patients.

AIM: To assess the thyroid allostasis in drug-free patients with affective disorder. METHODS: Patients with major depressive disorder or bipolar disorder as drug-free, defined as those without psychiatric drugs exposure for at least 4 months before admission, from a tertiary hospital were recruited in this cross-sectional study. The primary outcomes were "structure parameters of thyroid homeostasis", which include "thyroid's secretory capacity" (SPINA-GT), "sum step-up activity of deiodinases" (SPINA-GD), the ratio of total to free thyroxine and "thyroid homeostasis central set point" (TSH index and "thyroid feedback quantile-based index" [TFQI]), calculated by TSH and thyroid hormones measured at admission. A healthy population and non-affective psychiatric disorder (schizophrenia) from the same catchment area were recruited as two comparison groups. RESULTS: A total of 1263 cases of major depressive disorder, 1619 cases of bipolar disorder, 1186 cases of schizophrenia, and 162 healthy controls were included in the study. Compared to healthy control, GD and ratio of total to free thyroxine were lower in affective disorders. Bipolar with mania episode had higher GT than bipolar with depressive episode and major depressive disorder (median level at 3.70 vs. 3.04 and 3.03, respectively). Compared with healthy control, schizophrenia had higher TSH index and TFQI, but no increase in these parameters in major depressive disorder and bipolar disorder. CONCLUSION: Affective disorders have a unique profile of thyroid allostasis with impaired step-up deiodinase activity and reduced serum protein binding of thyroid hormones, but no change in thyroid homeostasis central set point. Mania episode may be associated with higher thyroid secretory capacity.

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.

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.

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.

Contemporary Clinical Perspectives on Targeting Remission of Type 2 Diabetes.

It has long been known that some patients with type 2 diabetes (T2DM) can experience sustained metabolic improvement to near-normal levels of glycemia either spontaneously or after medical intervention. Now recognized as remission of diabetes, this intriguing state is currently more feasible than ever before due to profound advances in metabolic surgery, pharmacologic therapy, and regimens of lifestyle modification. This enhanced capacity to induce remission has revealed new pathophysiologic insights, including the presence of a reversible component of the pancreatic beta-cell dysfunction that otherwise drives the chronic progressive nature of T2DM. In doing so, it has changed the therapeutic landscape by offering new potential management objectives and considerations for patients and providers. However, the excitement around these developments must also be tempered by the sobering realities of our current understanding of remission, including the recognition that this condition may not be permanent (resulting in glycemic relapse over time) and that beta-cell function may not be normalized in the setting of remission. These limitations highlight both the many gaps in our current understanding of remission and the caution with which clinical discussions must be handled for clear patient-directed communication of the pros and cons of targeting this outcome in practice. In this mini-review, we consider this rapidly growing literature, including its implications and its limitations, and thereby seek to provide objective balanced perspectives on targeting remission of T2DM in current clinical care.

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.

Association of Serum Very-Long-Chain Saturated Fatty Acids With Changes in Insulin Sensitivity and ß-Cell Function: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort.

A unique group of circulating very-long-chain saturated fatty acids (VLCSFAs), including arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have been associated with a lower risk of type 2 diabetes, although associations with early metabolic risk phenotypes preceding type 2 diabetes have received limited study. We aimed to examine the associations of VLCSFAs with longitudinal changes in insulin sensitivity and ß-cell function in a cohort at risk for type 2 diabetes. VLCSFAs in the four main serum pools (phospholipid, triacylglycerol, cholesteryl ester, and nonesterified fatty acid) were extracted from fasting baseline samples (n = 467). Generalized estimating equations were used to determine the associations between VLCSFAs and changes over 9 years in validated indices of insulin sensitivity (HOMA2-%S [insulin sensitivity as percentage of normal population and ISI) and ß-cell function (insulinogenic index [IGI], IGI divided by HOMA-insulin resistance [IGI/IR], and insulin secretion sensitivity index 2 [ISSI-2]). Associations of VLCSFAs with outcomes were strongest in the triacylglycerol lipid pool: 20:0 was positively associated with both insulin sensitivity and ß-cell function (5.01% increase in HOMA2-%S and 4.01-6.28% increase in IGI/IR and ISSI-2 per SD increase in 20:0); 22:0 was positively associated with insulin sensitivity, with a 6.55% increase in HOMA2-%S and a 5.80% increase in ISI per SD increase in 22:0. Lastly, 24:0 was positively associated with insulin sensitivity and ß-cell function (7.94-8.45% increase in HOMA2-%S and ISI, and a 4.61-6.93% increase in IGI/IR and ISSI-2 per SD increase in 24:0). Fewer significant associations were observed in the cholesteryl ester and nonesterified pools. Overall, our results indicate positive longitudinal associations of VLCSFAs with insulin sensitivity and ß-cell function, especially within the triacylglycerol pool.

Incidence of Heart Failure Related to Co-Occurrence of Gestational Hypertensive Disorders and Gestational Diabetes.

BACKGROUND: The extent to which their co-occurrence of gestational hypertensive disorders (GHTD) and gestational diabetes mellitus (GDM) influences heart failure (HF) risk is unclear. OBJECTIVES: The purpose of this study was to characterize the risk of HF related to concomitant GHTD and GDM. METHODS: We conducted a population-based cohort study using the Ministry of Health and Long-Term Care of Ontario (Canada) health care administrative databases. We included women with a livebirth singleton delivery between July 1, 2007, and March 31, 2018, and excluded those with prepregnancy diabetes, hypertension, HF, or coronary artery disease. GDM, GHTD, peripartum cardiomyopathy (at index pregnancy) were identified using diagnosis coding. Incident HF was assessed from index pregnancy until March 31, 2020. We estimated associations of GDM and/or GHTD with peripartum cardiomyopathy and incident HF. RESULTS: Among 885,873 women (mean age: 30 years, 54,015 with isolated GDM, 43,750 with isolated GHTD, 4,960 with GDM and GHTD), there were 489 HF events over 8 years. Compared to no-GDM and no-GHTD, isolated GDM (adjusted hazard ratio [aHR]: 1.44; 95% CI: 1.02-2.04) and isolated GHTD (aHR: 1.65; 95% CI: 1.17-2.31) were associated with a higher risk of incident HF. The co-occurrence of GDM and GHTD was associated with a higher HF risk (aHR: 2.64; 95% CI: 1.24-5.61). GDM and GHTD increased the risk of peripartum cardiomyopathy (adjusted risk ratio [aRR]: 7.30; 95% CI: 6.92-7.58), similarly to isolated GHTD (aRR: 7.40; 95% CI: 7.23-7.58). CONCLUSIONS: The co-occurrence of GDM and GHTD was associated with a significantly high risk of incident HF.

Association of cumulative social risk and gestational diabetes mellitus in the US, 2007-2018.

AIMS: Little is known regarding the association of multiple social risk factors and gestational diabetes mellitus (GDM). METHODS: We analyzed the 2007-2018 National Health and Nutrition Examination Surveys including 10,439 women aged ≥20 years (8 % with history of GDM). We created a cumulative social risk score (CSR) by adding scores assigned to each of the following: race/ethnicity, citizenship status and country of birth, education, and family income (score of 0 used as reference group). Using logistic regression, we assessed the associations of individual social risk factors (education, income, race/ethnicity and citizenship status) and CSR score with GDM, adjusting for age, parity, insurance status, care access, smoking, diet, physical activity, and body mass index. RESULTS: Among individual social risk factors, being a non-U.S. citizen (OR:1.51, 95% CI: 1.06-2.15) or belonging to a minority racial/ethnic group (OR:1.30, 95% CI: 1.04-1.59) was significantly associated with a greater odds of GDM. When examining the combined effects of social risk factors, a CSR score ≥3 was associated with an increased odds of GDM (OR:1.64, 95% CI: 1.22-2.1). CONCLUSIONS: Women with a greater burden of social risk factors are more likely to have GDM, thus should be the focus of interventions to prevent and treat GDM.

Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes.

In early type 2 diabetes, the strategy of "induction" with short-term intensive insulin therapy followed by "maintenance" with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin.ClinicalTrials.Gov NCT02192424.

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.

The Glucose Challenge Test in Pregnancy Identifies Future Risk of Diabetes.

CONTEXT: Women with gestational diabetes (GDM) have an increased future risk of type 2 diabetes but, in practice, their recommended postpartum glucose tolerance testing is often missed or substituted with measurement of A1c instead. OBJECTIVE: We hypothesized that the antenatal screening glucose challenge test (GCT) should predict future diabetes risk and, if so, would have thresholds that identify the same degree of risk as the diagnosis of prediabetes on postpartum measurement of A1c. METHODS: With population-based administrative databases, we identified all women in Ontario, Canada, who had a GCT in pregnancy with delivery between January 2007 and December 2017, followed by measurement of A1c and fasting glucose within 2 years postpartum (n = 141 858, including 19 034 with GDM). Women were followed over a median of 3.5 years for the development of diabetes. RESULTS: Under the assumption of a linear exposure effect, the 1-hour post-challenge glucose concentration on the GCT was associated with an increased likelihood of developing diabetes (hazard ratio 1.39; 95% CI, 1.38-1.40). A GCT threshold of 8.0 mmol/L predicted the same 5-year risk of diabetes (6.0%; 95% CI, 5.8-6.2) as postpartum A1c 5.7% (identifying prediabetes). Moreover, in women with GDM, a GCT threshold of 9.8 mmol/L equaled prediabetes on postpartum A1c in predicting a 5-year risk of diabetes of 16.5% (14.8-18.2). CONCLUSION: The GCT offers predictive capacity for future diabetes in pregnant women. In women with GDM, this insight could identify those at highest risk of diabetes, toward whom postpartum screening efforts should be most strongly directed.

Effects of vaginal microbiota transfer on the neurodevelopment and microbiome of cesarean-born infants: A blinded randomized controlled trial.

The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome. Sixty-eight cesarean-delivered infants were randomly assigned a VMT or saline gauze intervention immediately after delivery in a triple-blind manner (ChiCTR2000031326). Adverse events were not significantly different between the two groups. Infant neurodevelopment, as measured by the Ages and Stages Questionnaire (ASQ-3) score at 6 months, was significantly higher with VMT than saline. VMT significantly accelerated gut microbiota maturation and regulated levels of certain fecal metabolites and metabolic functions, including carbohydrate, energy, and amino acid metabolisms, within 42 days after birth. Overall, VMT is likely safe and may partially normalize neurodevelopment and the fecal microbiome in cesarean-delivered infants.