Venkatesan, Nanditha

Background: Increasing maternal body mass index (BMI) represents a risk factor for Gestational Diabetes Mellitus (GDM) and adverse obstetrical and perinatal outcomes. Objective: To stratify clinical outcomes for pregnancies affected by GDM according to maternal BMI. Methods: Retrospective cohort study including individuals ≥18 years of age who were diagnosed with GDM from 2018 to 2022. Universal GDM screening was employed with a 50 g oral glucose challenge test ± a 100 g oral glucose tolerance test. Maternal demographics, preexisting medical conditions, and selected obstetric and neonatal morbidities were evaluated. Results: A total of 2193 pregnancies in 2110 women affected by GDM were identified. This included 506 (23.0%) with normal baseline maternal BMI, 596 (27.2%) with overweight, and 1091 (49.7%) with obese BMI. Adverse maternal outcomes were more frequent in the obese compared to overweight or normal BMI categories (cesarean delivery: normal 26.9% vs. overweight 28.5% vs. obese 40.9%; p < 0.001; hypertensive disorders of pregnancy: normal 8.7% vs. overweight 12.1% vs. obese 16.8%; p < 0.001). Postpartum glucose intolerance was higher in women with obesity (normal 7.3% vs. overweight 5.9% vs. obese 14.9%; p < 0.001). Infants born to mothers with obesity had higher birthweights (normal 3.3 kg vs. overweight 3.4 kg vs. obese 3.5 kg; p < 0.001), were more likely to have neonatal hypoglycemia (normal 29.4% vs. overweight 24.3% vs. obese 41.9%; p < 0.001) and require intensive care unit admission (normal 8.1% vs. overweight 5.9% vs. obese 11.9%; p < 0.001). Conclusions: Patients with GDM and baseline BMI in the obese range experienced the highest rate of adverse outcomes, while those with overweight BMI had similar outcomes to individuals who had normal BMI at baseline.

Background: Immune cell–driven inflammation is a key mediator of metabolic dysfunction–associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P 1 ) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver. Methods: The LyzMCre approach was used to generate myeloid cell–specific knockout mice, termed S1pr1 MKO . Littermate S1pr1 loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol–fed S1pr1 MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol–fed S1pr1 MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator–activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1 MKO consistent with attenuated MASH in mice. Conclusions: Deletion of S1P 1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

Abstract Disclosure: M. Moazzami: None. N. Venkatesan: None. K.S. Rajagopalan: None. A.V. Vella: None. A. Egan: None. Gestational diabetes mellitus (GDM) affects approximately 10% of pregnancies, with rates almost doubling in minority subgroups. Higher body mass index (BMI) is a significant GDM risk factor, and BMI ≥ 25kg/m2 is often used as a criterion in risk factor-based screening programs. However, up to 60% of individuals with GDM have a normal BMI, and it is unclear if this offers protection against associated adverse outcomes. Furthermore, many prior studies fail to address the fact that those of Asian descent require a lower BMI cut-off, given their different distribution of body fat. Our study evaluated GDM pregnancy outcomes using BMI as a risk indicator. We compared individuals with BMIs &lt; 25 kg/m2, 25-30 kg/m2, and &gt; 30 kg/m2. For individuals that self-identified as Asian, we adjusted BMI categories: &lt;23 kg/m2 for normal weight, 23-30 kg/m2 for overweight, and &gt;30 kg/m2 for obese. We identified 2212 subjects diagnosed with GDM via universal screening and Carpenter and Coustan criteria at our institution from 2018 - 22. In total, 508 (23.0%) were normal weight, 611 (27.6%) overweight, and 1093 (49.4%) obese. The average maternal age was 31 years. Higher proportions identified as Hispanic and non-White race in overweight and obese categories. Maternal adverse outcomes were higher in obese compared to overweight or normal BMI categories (cesarian delivery: normal 26.7 v overweight 28.3 v obese 22.7%, p&lt;0.001; hypertensive disorders: normal 13.2 v overweight 12.5 v obese 22.7%, p &lt;0.001). Pharmacological therapy was required in 50% with obesity versus 24.8% in normal, and 28.7% in overweight categories (p&lt;0.001). While there were no differences in live birth rates across categories, infants born to mothers with obesity had a higher birthweight (normal 3.30 v overweight 3.38 v obese 3.45kg, p&lt;0.001) and were more likely to have neonatal hypoglycemia (normal 28.7 v overweight 25.5 v obese 43.8%, p&lt;0.001) and require intensive care unit admission (normal 8.4 v overweight 5.5 v obese 12.7%, p&lt;0.001). Attendance at postpartum glucose testing varied across BMI categories with lower attendance in mothers with obesity followed by normal weight BMI (normal 40.75 v overweight 45.99 v obese 36.2%, p&lt;0.001). Compared to overweight individuals, those with normal weight exhibited higher rates of postpartum glucose intolerance (12.4 v 6.9%, p =0.002). However, those with obesity had the highest rates of glucose intolerance (20.7%, p&lt;0.0002). Individuals with normal weight had the highest rates of breastfeeding (normal 95.9 v overweight 92.8 v obese 91.4% p=0.006). This study highlights the nuanced relationship between BMI and pregnancy outcomes in GDM. While maternal obesity was associated with the poorest outcomes, those with normal BMI were not protected compared to overweight individuals, and experience higher rates of postpartum glucose intolerance. Presentation: 6/2/2024

Abstract Disclosure: S. Rolak: None. N. Venkatesan: None. R. Gregg Garcia: None. W.F. Young: None. I. Bancos: None. Background: Bilateral primary hyperaldosteronism (PA) is treated with mineralocorticoid receptor antagonist (MRA) therapy. However, the best way to monitor the success of MRA therapy is unclear. Aims: To compare the impact of curative adrenalectomy versus MRA therapy in patients with PA on plasma renin activity (PRA), renal function, and hypertension control. Methods: Single center retrospective study of patients with unilateral PA treated with adrenalectomy or bilateral PA treated with MRAs, 2017-2021. Patients underwent adrenal vein sampling to confirm laterality. Hypertension control was defined based on blood pressure measurements and the standardized hypertension daily dose (HDD). Minimum follow-up was defined as first nonsuppressed PRA or &gt;1 month from therapy. Results: Of 73 patients, 53 underwent unilateral adrenalectomy for unilateral PA (median age 57, range 25-71 years, 36% women) and 20 had bilateral PA treated with MRA (median age 49, range 30-70 years, 70% women). At baseline, when compared to the bilateral PA, patients with unilateral PA had higher plasma aldosterone concentrations (median 31 ng/dL vs 19 ng/dL, P= 0.001), similarly suppressed PRA, and similar estimated glomerular filtration rate (eGFR). Uncontrolled hypertension (&gt;130/90 mmHg) was seen in 40 (75%) of patients with unilateral PA and 14 (70%) patients with bilateral PA, despite a more intensive antihypertensive regimen in unilateral PA (median HDD 5, range 1-18 vs median HDD 3.5 in bilateral PA, range 0.5-9; P=0.016). Hypokalemia was present in 50 (94%) patients with unilateral PA and 15 (75%) in bilateral PA, P = 0.02.Following treatment, hyperkalemia developed in 10 (19%) patients post-adrenalectomy and in 2 (10%) patients treated with MRAs, P = 0.36. At a median follow up of 108 days, 24 (45%) patients treated with adrenalectomy and 16 (80%) patients treated with MRAs demonstrated PRA &gt;1.5 ng/mL/hr, P = 0.008. eGFR decreased by at least 10 points in 15 (30%) patients treated with adrenalectomy vs in 11 (59%) patients treated with MRAs (P=0.033). Post-adrenalectomy, antihypertensive management lessened by a median of 2.5 HDD, while HDD increased in patients treated with MRAs by a median of 1.25, P&lt;0.0001. Hypertension control improved, with a mean decrease in systolic blood pressure of -11 mmHg (95%CI -16.5-(-5.5)) without between group differences. Diastolic blood pressure decreased by a mean of -4.7 mmHg (95%CI -8.7-(-0.7)) in the adrenalectomy group but did not change in those treated with MRAs. Conclusions: Following curative adrenalectomy in unilateral PA, more than half of patients continue to have suppressed PRA. Despite less severe PA at baseline, patients treated with MRAs, as compared to those treated with adrenalectomy, demonstrate a higher prevalence of non-suppressed PRA, lower eGFR, similar hypertension control, and a more intense antihypertensive regimen during follow up. Presentation: Thursday, June 15, 2023