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.

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.

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.

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.

Treatment of Gestational Diabetes Mellitus and Maternal Risk of Diabetes After Pregnancy.

OBJECTIVE: To compare postpartum glucose tolerance between women treated for gestational diabetes mellitus (GDM) and those not treated. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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 ß-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). CONCLUSIONS: Treating GDM lowers birth weight but does not disrupt the association between gestational glycemia and maternal prediabetes/diabetes after pregnancy.

Glycemic Index Versus Wheat Fiber on Arterial Wall Damage in Diabetes: A Randomized Controlled Trial.

OBJECTIVE: High cereal fiber and low-glycemic index (GI) diets are associated with reduced cardiovascular disease (CVD) risk in cohort studies. Clinical trial evidence on event incidence is lacking. Therefore, to make trial outcomes more directly relevant to CVD, we compared the effect on carotid plaque development in diabetes of a low-GI diet versus a whole-grain wheat-fiber diet. RESEARCH DESIGN AND METHODS: The study randomized 169 men and women with well-controlled type 2 diabetes to counseling on a low GI-diet or whole-grain wheat-fiber diet for 3 years. Change in carotid vessel wall volume (VWV) (prespecified primary end point) was assessed by MRI as an indication of arterial damage. RESULTS: Of 169 randomized participants, 134 completed the study. No treatment differences were seen in VWV. However, on the whole-grain wheat-fiber diet, VWV increased significantly from baseline, 23 mm3 (95% CI 4, 41; P = 0.016), but not on the low-GI diet, 8 mm3 (95% CI -10, 26; P = 0.381). The low-GI diet resulted in preservation of renal function, as estimated glomerular filtration rate, compared with the reduction following the wheat-fiber diet. HbA1c was modestly reduced over the first 9 months in the intention-to-treat analysis and extended with greater compliance to 15 months in the per-protocol analysis. CONCLUSIONS: Since the low-GI diet was similar to the whole-grain wheat-fiber diet recommended for cardiovascular risk reduction, the low-GI diet may also be effective for CVD risk reduction.

Treating Gestational Diabetes Reduces Birth Weight but Does Not Affect Infant Adiposity Across the 1st Year of Life.

OBJECTIVE: The continuum of maternal glycemia in pregnancy shows continuous associations with both 1) neonatal birth weight at delivery and 2) subsequent adiposity later in childhood. While treating gestational diabetes mellitus (GDM) can lower birth weight and thereby disrupt the former association, it is unclear if such treatment reduces childhood adiposity. Thus, we sought to compare anthropometry across the 1st year of life between infants born to women who were treated for GDM and those with lesser degrees of gestational dysglycemia (untreated). RESEARCH DESIGN AND METHODS: Anthropometric measurements were performed at 3 months and 12 months of life in 567 infants born to women comprising the following four gestational glucose tolerance groups: 1) women with normoglycemia on both glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy; 2) women with an abnormal GCT but normal OGTT; 3) those with mild gestational impaired glucose tolerance; and 4) women treated for GDM. RESULTS: Birth weight progressively increased across the three untreated groups but was lowest in women treated for GDM (P = 0.0004). Similarly, women treated for GDM had the lowest rate of macrosomia (P = 0.02). Conversely, however, there were no differences among the four groups in weight z score, length z score, weight-for-length z score, or BMI z score at either 3 months or 12 months (all P values = NS). Similarly, there were no differences among the groups in triceps/biceps/subscapular/suprailiac skinfold thickness or sum of skinfolds at either 3 months or 12 months (all P values = NS). CONCLUSIONS: Despite reducing birth weight and macrosomia, the treatment of GDM does not have analogous effects on infant adiposity across the 1st year of life.

Polymorphisms in the stearoyl-CoA desaturase gene modify blood glucose response to dietary oils varying in MUFA content in adults with obesity.

Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.

Assessments of right ventricular strain using cardiac magnetic resonance imaging following kidney transplantation.

Although kidney transplantation (KT) has been shown to ameliorate adverse left ventricular (LV) remodelling associated with end stage kidney disease, its effects on the right ventricle have not been well studied. Recently, strain imaging has been shown to be a sensitive measure of early subclinical myocardial dysfunction. Using cardiac magnetic resonance imaging (MRI), we examined the effects of KT on right ventricular (RV) strain parameters. In a cohort of 81 patients (39 patients underwent KT and 42 patients remained on dialysis as control group), cardiac MRI studies were obtained at baseline and at 1 year follow-up. There were no significant differences in RV strain values between the groups at baseline. After 1 year, RV strain values did not significantly change in patients who received KT, and changes in RV strain over 1 year were not significantly different between the KT and the dialysis groups. Given the previously demonstrated improvement in LV strain post-KT, the current study suggests that RV and LV remodelling post-KT may have different mechanisms. Further studies elucidating the effects of KT on RV remodelling are needed.

The Increase in Paraoxonase 1 Is Associated With Decrease in Left Ventricular Volume in Kidney Transplant Recipients.

Background: Patients on dialysis have impaired cardiac function, in part due to increased fluid volume and ventricular stress. Restored kidney function through transplantation reduces left ventricular volume in both systole and diastole. We previously reported that the decrease in NT-proB-type natriuretic peptide (NT-proBNP) was associated with a decrease in adiponectin. Paraoxonase 1 (PON1) has been inversely associated with cardiovascular outcomes. We now report the association of changes in PON1 with changes in left ventricular volume and left ventricular mass after kidney transplantation. Design: Patients on dialysis were assessed at baseline and 12 months after kidney transplantation (n = 38). A comparison group of patients on dialysis who were not expected to receive a transplant in the next 24 months were studied (n = 43) to determine if the change of PON1 with kidney transplantation achieved a significance greater than that due to biologic variation. Left ventricular volume and mass were determined by cardiac magnetic resonance imaging. PON1 was measured by arylesterase activity and by mass. Results: PON1 mass and activity were not different between the groups at baseline. Both PON1 mass and activity were increased post-kidney transplantation (p < 0.0001 for change). The change in PON1 mass (p = 0.0062) and PON1 arylesterase activity (p = 0.0254) were inversely correlated with the change in NT-proBNP for patients receiving a kidney transplant. However, only the change in the PON1 mass, and not the change in PON1 arylesterase, was inversely correlated with the change in left ventricular volume (ml/m2.7) (p = 0.0146 and 0.0114 for diastolic and systolic, respectively) and with the change in hemoglobin (p = 0.0042). Conclusion: Both PON1 mass and arylesterase activity are increased by kidney transplantation. The increase in PON1 mass is consistent with a novel relationship to the increase in hemoglobin and decrease in left ventricular volume and NT-proBNP seen when kidney function is restored.

Subtypes of gestational diabetes and future risk of pre-diabetes or diabetes.

BACKGROUND: Recent studies have suggested that gestational diabetes (GDM) is a heterogeneous condition with distinct subtypes determined by whether the predominant metabolic abnormality is impaired insulin sensitivity or deficient insulin secretion. However, it is not known if the elevated future risk of pre-diabetes/diabetes associated with GDM varies according to these subtypes. Thus, we sought to evaluate maternal metabolic function in the 1st year postpartum in relation to GDM subtypes. METHODS: In this prospective cohort study conducted in Toronto, Canada, 613 women underwent GDM screening by oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at both 3-months and 12-months postpartum between 09/2003 and 03/2016. The antepartum OGTT identified 3 groups of women: GDM with predominant sensitivity defect (GDM-sensitivity), GDM with predominant secretion defect (GDM-secretion), and non-GDM. FINDINGS: Antepartum findings persisted after pregnancy, with lower insulin sensitivity in GDM-sensitivity (Matsuda index; HOMA-IR) and lower insulin secretion in GDM-secretion (Stumvoll first-phase; insulinogenic index (IGI)) at both 3-months and 12-months (all p<0.005). Beta-cell compensation (Insulin Secretion-Sensitivity Index-2; IGI/HOMA-IR) was lower in both GDM subtypes compared to non-GDM (all p<0.0005) but did not differ between GDM-sensitivity and GDM-secretion. Similarly, both subtypes exhibited higher post-challenge glycemia on OGTT at 3-months and 12-months than non-GDM (all p<0.0005) but did not differ from one another. The prevalence of pre-diabetes/diabetes was higher in both GDM-sensitivity (30.9%; 95%CI: 21.7-41.2) and GDM-secretion (27.6%; 16.7-40.9) than in non-GDM (10.4%; 7.7-13.6) at 12-months (both p<0.005), with no difference between GDM subtypes (p = 0.75). INTERPRETATION: Beta-cell dysfunction, glycemia and incident pre-diabetes/diabetes do not vary between GDM subtypes in the 1st year postpartum. FUNDING: Canadian Institutes of Health Research; Diabetes Canada.

Adipose Tissue Insulin Resistance Is Longitudinally Associated With Adipose Tissue Dysfunction, Circulating Lipids, and Dysglycemia: The PROMISE Cohort.

OBJECTIVE: To determine the association of adipose tissue insulin resistance with longitudinal changes in biomarkers of adipose tissue function, circulating lipids, and dysglycemia. RESEARCH DESIGN AND METHODS: Adults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort had up to four assessments over 9 years (n = 468). Adipose tissue insulin resistance was determined using a novel validated index, Adipo-IR, calculated as the product of fasting insulin and nonesterified fatty acids measured at baseline. Fasting serum was used to measure biomarkers of adipose tissue function (adiponectin and soluble CD163 [sCD163]), circulating lipids (total cholesterol, HDL, LDL, triglyceride [TG]), and systemic inflammation (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes at follow-up. Generalized estimating equation (GEE) models were used to assess the relationship of Adipo-IR with longitudinal outcomes. RESULTS: GEE analyses showed that elevated Adipo-IR was longitudinally associated with adipose tissue dysfunction (adiponectin -4.20% [95% CI -6.40 to -1.95]; sCD163 4.36% [1.73-7.06], HDL -3.87% [-5.15 to -2.57], TG 9.26% [5.01-13.69]). Adipo-IR was associated with increased risk of incident dysglycemia (odds ratio 1.59 [95% CI 1.09-2.31] per SD increase). Associations remained significant after adjustment for waist circumference and surrogate indices for insulin resistance. There were no significant longitudinal associations of Adipo-IR with IL-6, TNF-α, total cholesterol, or LDL. CONCLUSIONS: Our findings demonstrate that adipose tissue insulin resistance is prospectively associated with adipose tissue function, HDL, TG, and incident dysglycemia.

The association of soluble CD163, a novel biomarker of macrophage activation, with type 2 diabetes mellitus and its underlying physiological disorders: A systematic review.

This systematic review investigates the association of sCD163, a novel biomarker of macrophage activation, with type 2 diabetes mellitus (T2DM), insulin resistance, and beta-cell dysfunction. Sixteen studies (seven cross-sectional, two case-control, one nested case-control, three prospective cohort, and three experimental) were identified. Most studies demonstrated that elevated sCD163 concentrations were associated with increased insulin resistance. Cross-sectional, case-control, and nested case-control studies showed higher sCD163 in subjects with T2DM compared with healthy individuals. An 18-year follow-up prospective cohort study showed that elevated baseline sCD163 was a strong predictor of T2DM incidence. Prospective cohort studies demonstrated that baseline measures and longitudinal changes in sCD163 were positively associated with insulin resistance; however, associations with beta-cell function were inconsistent. Two experimental studies evaluated the relationship of sCD163 with T2DM and HOMA-IR after weight-reducing interventions. After very low-calorie diet treatments, sCD163 concentration declined significantly in patients with T2DM but was not associated with insulin resistance. Bariatric surgery did not significantly impact sCD163 levels. In a double-blind randomized controlled trial, resveratrol supplementation significantly reduced circulating sCD163 in T2DM patients. Current studies demonstrate the potential utility of sCD163 as an early biomarker of T2DM risk and highlight a potential mechanism linking obesity with T2DM onset.

Cardiac MRI assessment of the right ventricle pre-and post-kidney transplant.

Worsening renal function in chronic kidney disease correlates with worsening right ventricular (RV) systolic function. We evaluated the association between kidney transplantation (KT) and RV structure and systolic function, and the relationships between RV and left ventricular (LV) changes, blood pressure, and specific cardiac biomarkers, in patients with end-stage kidney disease using cardiac magnetic resonance imaging (CMR). In this prospective, multi-centre, cohort study, 39 adult patients on dialysis receiving KT and 42 patients eligible for, but not yet receiving KT, were recruited. CMR was performed at baseline, and repeated at 12 months. Among 81 patients (mean age 51 years, 30% female), RV end-diastolic volume index (RVEDVi), end-systolic volume index (RVESVi), mass index (RVMi), and ejection fraction (RVEF) did not change significantly within either the dialysis or KT group over 12 months (all p ≥ 0.10). There were no significant differences in the 12-month changes of these parameters between the dialysis and KT groups (all p ≥ 0.10). RVMI demonstrated positive correlations with NT-proBNP and systolic blood pressure, but not GDF-15, at baseline and at 12 months. Changes in RVEDVi, RVESVi, and RVEF were positively correlated with changes in LVEDVi, LVESVi, and LVEF, respectively over 12 months (Spearman r = 0.72, 0.52, and 0.41; all p < 0.001), but not mass index (Spearman r = 0.20, p = 0.078). In conclusion, there were no significant changes in RV mass, volumes, or systolic function 12 months after KT, as compared with continuation of dialysis. The associations between RV and LV remodeling may suggest similar underlying pathophysiologic mechanisms.

Evaluation of left atrial remodeling in kidney transplant patients using cardiac magnetic resonance imaging.

BACKGROUND: Increased left atrial (LA) size predicts cardiovascular events in patients with end-stage kidney disease. There is a paucity of data on LA changes after kidney transplantation (KT). Accordingly, we used cardiac magnetic resonance imaging (CMR) to evaluate LA remodeling after KT, and examined its relationship with left ventricular (LV) measurements, blood pressure and cardiac biomarkers. METHODS: In this prospective multi-center cohort study, 39 pre-transplant dialysis patients underwent KT and 42 eligible transplant recipients remained on dialysis. CMR, blood pressure and serum measurements for N-terminal pro b-type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), and growth differentiation factor-15 (GDF-15) were performed at baseline and 12 months. RESULTS: After 12 months, there were no significant changes in LA end-systolic volume index, LA end-diastolic volume index, or LA ejection fraction (LAEF) within the KT or dialysis group; changes over time did not differ between the 2 groups (all p > 0.25). At baseline and over 12 months, LA volumes and LAEF positively correlated with LV volumes and mass while LAEF positively correlated with LV function. Changes in LA volumes also positively correlated with NT-proBNP and systolic blood pressure (sBP) while LAEF negatively correlated with NT-proBNP. GDF-15 correlated with LA measurements at baseline but not in 12-month changes. hsCRP did not correlate with any LA measurements. CONCLUSIONS: LA volumes and function as measured by CMR did not change significantly over 12 months post-KT. There were significant associations between LA and LV remodeling, NT-proBNP and sBP, suggesting common underlying pathophysiological mechanisms.

The Macrophage Activation Marker Soluble CD163 is Longitudinally Associated With Insulin Sensitivity and ß-cell Function.

CONTEXT: Chronic inflammation arising from adipose tissue macrophage (ATM) activation may be central in type 2 diabetes etiology. Our objective was to assess the longitudinal associations of soluble CD163 (sCD163), a novel biomarker of ATM activation, with insulin sensitivity, ß-cell function, and dysglycemia in high-risk subjects. METHODS: Adults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 408). Levels of sCD163 were measured using fasting serum. Insulin sensitivity was assessed by HOMA2-%S and the Matsuda index (ISI). ß-cell function was determined by insulinogenic index (IGI) over HOMA-IR and insulin secretion-sensitivity index-2 (ISSI-2). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes. Generalized estimating equations (GEE) evaluated longitudinal associations of sCD163 with insulin sensitivity, ß-cell function, and incident dysglycemia adjusting for demographic and lifestyle covariates. Areas under receiver-operating-characteristic curve (AROC) tested whether sCD163 improved dysglycemia prediction in a clinical model. RESULTS: Longitudinal analyses showed significant inverse associations between sCD163 and insulin sensitivity (% difference per standard deviation increase of sCD163 for HOMA2-%S (ß = -7.01; 95% CI, -12.26 to -1.44) and ISI (ß = -7.60; 95% CI, -11.09 to -3.97) and ß-cell function (ISSI-2 (ß = -4.67; 95 %CI, -8.59 to -0.58) and IGI/HOMA-IR (ß = -8.75; 95% CI, -15.42 to -1.56)). Increased sCD163 was associated with greater risk for incident dysglycemia (odds ratio = 1.04; 95% CI, 1.02-1.06; P < 0.001). Adding sCD163 data to a model with clinical variables improved prediction of incident dysglycemia (AROC=0.6731 vs 0.638; P < 0.05). CONCLUSIONS: sCD163 was longitudinally associated with core disorders that precede the onset of type 2 diabetes.

Changes Over Time in Uric Acid in Relation to Changes in Insulin Sensitivity, Beta-Cell Function, and Glycemia.

CONTEXT: Serum uric acid has been linked to risk of type 2 diabetes (T2DM), but debate persists as to whether it plays a causal role. Indeed, it is unclear if changes in uric acid relate to the pathophysiologic determinants of T2DM (insulin resistance, beta-cell dysfunction), as would be expected if causal. OBJECTIVE: To evaluate the impact of changes in uric acid over 2 years on changes in insulin sensitivity, beta-cell function, and glycemia in women with and without recent gestational diabetes (GDM), a model of the early natural history of T2DM. DESIGN/SETTING/PARTICIPANTS: At both 1 and 3 years postpartum, 299 women (96 with recent GDM) underwent uric acid measurement and oral glucose tolerance tests that enabled assessment of insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance [HOMA-IR]), beta-cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index/HOMA-IR [IGI/HOMA-IR]), and glucose tolerance. RESULTS: Women with recent GDM had higher serum uric acid than their peers at both 1 year (281 ± 69 vs 262 ± 58 µmol/L, P = 0.01) and 3 years postpartum (271 ± 59 vs 256 ± 55 µmol/L, P = 0.03), coupled with lower insulin sensitivity, poorer beta-cell function, and greater glycemia (all P < 0.05). However, on fully adjusted analyses, neither uric acid at 1 year nor its change from 1 to 3 years was independently associated with any of the following metabolic outcomes at 3 years postpartum: Matsuda index, HOMA-IR, ISSI-2, IGI/HOMA-IR, fasting glucose, 2-hour glucose, or glucose intolerance. CONCLUSION: Serum uric acid does not track with changes over time in insulin sensitivity, beta-cell function, or glycemia in women with recent GDM, providing evidence against causality in its association with diabetes.

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort.

Objective: To evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D). Research design and methods: Adults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (ICFASTING) and areas under the curve of C peptide-to-insulin (ICAUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC. Results: IC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in ICFASTING and ICAUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia. Conclusions: Our findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

Screening Glucose Challenge Test in Pregnancy Can Identify Women With an Adverse Postpartum Cardiovascular Risk Factor Profile: Implications for Cardiovascular Risk Reduction.

Background The 1-hour glucose challenge test (GCT) is routinely performed in pregnancy to screen for gestational diabetes mellitus. Remarkably, it has recently emerged that the GCT can also predict a woman's future risk of cardiovascular disease, although the mechanistic basis of this relationship is unclear. In this context we hypothesized that a higher GCT may identify women with an otherwise unrecognized adverse cardiovascular phenotype. Thus, we sought to evaluate the relationship between the antepartum GCT and subsequent postpartum cardiovascular risk factor profile. Methods and Results In this study 503 women completed a screening GCT in late second trimester and then underwent cardiometabolic characterization at 3 months postpartum, whereupon traditional (blood pressure, glucose, lipids) and nontraditional (apolipoprotein B, C-reactive protein, adiponectin) cardiovascular risk factors were compared across GCT tertiles. At 3 months postpartum, each of the following risk factors progressively worsened from the lowest to middle to highest GCT tertile: fasting glucose (P=0.0002), 2-hour glucose (P<0.0001), total cholesterol:high-density lipoprotein cholesterol (P=0.0004), high-density lipoprotein cholesterol (P=0.004), triglycerides (P=0.001), apolipoprotein B (P=0.001), and adiponectin (P=0.02). On multiple linear regression analyses, the GCT emerged as a significant independent predictor of higher fasting glucose (P=0.0006), 2-hour glucose (P<0.0001), total cholesterol: high-density lipoprotein cholesterol (P=0.0004), triglycerides (P=0.001), low-density lipoprotein cholesterol (P=0.01), and apolipoprotein B (P=0.004) and of lower high-density lipoprotein cholesterol (P=0.02) and adiponectin (P=0.0099). Moreover, these independent associations persisted after excluding women who had gestational diabetes mellitus. Conclusions The antepartum GCT can identify women with an adverse underlying cardiovascular risk factor phenotype.