United States

Absorption of ultraviolet B (UVB) radiation by the B ring of 7-dehydrocholesterol (7-DHC) leads to the transformation of 7-DHC to previtamin D₃, which after absorption of additional UVB isomerizes to tachysterol₃ (T₃) and lumisterol3 (L₃). Previously we demonstrated that CYP11A1 can hydroxylate the side chain of vitamin D₃ (D₃), 7-DHC and L₃. Similarly CYP27A1 can hydroxylate the side chain of L₃ to biologically active hydroxyderivatives. In a continuation of these studies, we report that CYP11A1 and CYP27A1 hydroxylate T₃ to 20S(OH)T₃ and 25(OH)T₃, respectively, plus minor unidentified hydroxyderivatives. Both 20S(OH)T₃ and 25(OH)T₃were detected in the human epidermis and serum. T₃ was also detected in human serum and was present at a concentration of 7.3±2.5 ng/ml. 20S(OH)T₃ and 25(OH)T₃ inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D3 . They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR-coupled GFP (VDR-GFP) from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay revealed marked activation of AhR by 20S(OH)T₃, a smaller effect by 25(OH)T3 and only minimal activation by T₃. The T₃ hydroxyderivatives showed high affinity binding to the ligand binding domain (LBD) of the liver X receptor (LXR) α and β, and to the peroxisome proliferator-activated receptor γ (PPARg) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs and PPARγ revealed high docking scores for 20S(OH)T₃ and 25(OH)T₃, comparable to their previously characterized ligands. The scores for binding to the non-genomic site of the VDR were very low indicating a lack of interaction with hydroxy-T₃ ligands. In conclusion, we have identified 20S(OH)T₃ and 25(OH)T₃ in the human epidermis and serum, identified CYP enzymes responsible for their production, demonstrated phenotypic effects on skin cells, and identified VDR, AhR, LXRs and PPARγ, and possibly RORs, as their genomic receptor targets. Thus CYP11A1, aside from its role in steroidogenesis, not only metabolizes vitamin D₃, 7-DHC and L₃ to biologically active metabolites, but also activates T₃ to biologically active 20S(OH)T₃. Similarly, CYP27A1, previously reported to act on L₃, D₃ and 7DHC, also activates T₃ via hydroxylation at C25. We believe that these novel findings open new areas for future studies on the role of active forms of T₃, not only in the skin, but also in systemic physiology and pathology.

ENDO 2022

Metabolic activation of tachysterol to biologically active hydroxyderivatives that act on VDR, AhR, LXRs and PPARγ receptors

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

technical paper

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Anti-inflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.

Disrupting a Key H-bond Network Drives Glucocorticoid Receptor Gene Suppression Without Off-target Gene Activation for Duchenne Muscular Dystrophy Treatment

Background: Severe insulin resistance syndromes including lipodystrophy and pathogenic variants in the insulin receptor (INSR) lead to diabetes that is challenging to control. Oral antidiabetic agents have been used to control hyperglycemia, however the efficacy of these treatments has not been studied systematically. This study explores safety and efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2i) in these patients.
Methods: This was a retrospective chart-review assessing safety (N=31) and efficacy (N=18) of SGLT2i use in patients with clinically or genetically confirmed diagnosis of lipodystrophy or INSR pathogenic variants at our institute. Efficacy outcomes included HbA1c, insulin dose, C-peptide, fasting insulin and 24-hour urine glucose at 12 months and throughout follow-up from 2 to 24 months. Glycemic parameters were analyzed as change from baseline (prior to SGLT2i) adjusted for baseline values after 12 months of SGLT2i and across all timepoints using linear mixed models with post-hoc Dunnett-adjusted comparison of each time point compared to baseline.  For HbA1c, additional models were conducted including change in insulin dose as a covariate.
Results: HbA1c did not significantly change after 1 year of SGLT2i (baseline 9.5±2.5 [80.3±27.7]; 12 months 8.8±2.3% [72.6±25.3 mmol/mol]; p=0.093), or across all time points (p=0.11). However, most patients (83%) were taking insulin, and SGLT2i treatment led to 35% reduction in total daily dose of insulin after 12 months (baseline 186 [100,1010]; 12 months 120 [75,260] units/day; p=0.07) and across all visits (p=0.035), which may have mitigated the reduction in HbA1c. Reduction in HbA1c was significant after adjustment for changes in insulin dose over time (p=0.0498). No significant change was noted in C-peptide, however fasting insulin decreased after 12 months (p=0.021) and across all visits (p=0.005). Urinary glucose excretion increased greater than 5-fold after 12 months of SGLT2i, to over 80 grams per day after 1 year (p=0.04). Adverse effects occurring in >1 subject included hypoglycemia, fungal infections, and extremity pain.
Conclusions: SGLT2i reduced insulin dose, insulinemia, and insulin dose-adjusted HbA1c in patients with severe insulin resistance, with a similar safety profile compared to type 2 diabetes. SGLT2i use may lead to overall better glycemic control and should be considered as part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.

Clinical Effects of Sodium Glucose Transporter Type 2 Inhibitors in Patients with Severe Insulin Resistance

Introduction: Outpatient consultations comprise the majority of referrals in endocrinology. Patients with diabetes require constant follow-up and medication adjustments to achieve optimal glycemic targets. The COVID-19 pandemic made interruption and delays in healthcare delivery inevitable. This placed a great strain on monitoring patients with diabetes, placing greater importance on patient self-management. Telemedicine was introduced in our country to bridge the gap between physician and patient that was created by community quarantines and travel restrictions. However, our country was not ready for telemedicine as it has never been used in our healthcare system. This caused apprehension among doctors and patients as not everyone was technologically adept to understand the system. However, as months went by, telemedicine was eventually accepted as a "new normal" way of seeking medical care.
Objective: To determine if there is a difference in patient's self-care activities before and after using telemedicine using the Diabetes Self-Management Questionnaire (DSMQ)
Methodology: A descriptive cross-sectional study of patients with type 2 diabetes mellitus who consulted via telemedicine using different available platforms were included. Patients were asked to accomplish the Diabetes Self-Management Questionnaire (DSMQ) as a measure of self-care activities before and after the use of telemedicine. Clinical profile and glycemic control before and after telemedicine were secondary outcomes. With the goal of improving and tailoring telemedicine for our countrymen, patient satisfaction and opinions regarding telemedicine (i.e, accessibility, ease of use, areas to improve on) were also assessed using a patient satisfaction survey.
Results: Fifty-five patients were included in the study. An improvement in self-care practices was demonstrated by significantly higher mean DSMQ scores after telemedicine consultations (6.79 + 1.33 to 7.32 + 1.21, p = 0.0015), with dietary control and physical activity subscales obtaining the highest scores. There was a statistically significant reduction in HbA1c on follow up (8.37 + 2.31 to 7.31 + 1.36; p < 0.00001). In terms of clinical profile, majority of patients had poorly controlled diabetes at baseline. Those with well-controlled diabetes (n = 14) at baseline remained to have good control while the proportion of those with poorly controlled diabetes (n = 34) showed improvement on follow up (p = 0.0045). Most patients were highly satisfied with telemedicine experience and were likely to recommend it to others and avail of the service in the future.
Conclusion: As far as we know, there has been no previously published study in our country regarding telemedicine and its effect on diabetes management. This paper showed that the use of telemedicine by patients with type 2 diabetes mellitus significantly improved both self-care practices and glycemic control. These findings, together with the positive responses in patient satisfaction, may deem it necessary that telemedicine be mainstreamed as part of diabetes care in our country.

The Effect of Telemedicine on the Self-Care Activities of Patients with Type 2 Diabetes Mellitus and Patient Satisfaction during the COVID-19 Pandemic at the University of Santo Tomas Hospital

Background
The Endocrine Society recommends preconception counseling be provided to all women with DM who are considering pregnancy; the ADA recommends counseling women of childbearing age with DM on the importance of tight pregnancy glycemic control and appropriate use of contraception at pubertal onset. However, only 25% of women receive contraception and preconception counseling (PCC). As most studies are retrospective chart reviews, what is cited may not reflect the PCC offered.
Methods
Physicians and advanced care providers (n=97) at one institution were surveyed on their behaviors in offering and documenting PCC provided to women with T1DM and T2DM.
Women with T1DM and T2DM (n=15) receiving care at the same institution were contacted after a recent endocrine visit and surveyed on the PCC they received. A retrospective chart review examined how the women's perception of the PCC provided correlated with documentation.
Additionally, similar surveys were distributed to women aged 18 to 50 via diabetes groups on a social media platform (n=202).
Results
Overall, 37% of providers reported offering PCC < 5% of the time; PCPs and pediatric endocrinologists were least likely to offer PCC (p<0.01 between all groups). The majority of OBGYNs and endocrinologists shared PCC up to 25% of the time (p >0.05).
Providers were most likely to educate on or prescribe contraception. Half said they document counseling >75% of the time.
Of all the women surveyed (n=217), 89% had T1DM, 91% were White and the average HbA1c was in the 6.6%-6.9% range. 59% of women reported previous pregnancies and 6.9% were pregnant. There was no difference in HbA1cs for those planning or considering pregnancy and those who were not (HbA1c 7% v 6.7%, p >0.05 in chart review survey; HbA1c 6.6-6.9% in both groups in social media survey, p >0.05).
55% reported receiving PCC in the past, most likely from their endocrinologist or OBGYN.
The most frequently reported forms of contraception were OCPs (22%) followed by barrier contraception (18%)–generally with other methods—followed by no form of contraception (15%).
In the chart review survey (n=15), none were currently pregnant but 13% were planning pregnancy in the next year and 47% were unsure of their plans. Two reported PCC was discussed at their most recent visit; one reported receiving PCC at the penultimate visit. Of these three visits, PCC was documented twice. Topics commonly discussed were glycemic targets, preconception planning, and contraception.
Conclusion
This study suggests the rates of lifetime PCC are higher than described and lower reported rates may be related to deficiencies in documentation. However, the small size of the chart review survey limits the ability to draw definitive conclusions. This study may also be limited by self-selection bias and over-representation of White patients among survey respondents.

Providing Contraception and Preconception Counseling to Women with Diabetes: Health Care Provider Behaviors and Patient Perception

Prevalence of Fournier's Gangrene in T2DM Treated with Oral Antiglycemic Medications

Prevalence of Fournier’s Gangrene in T2DM Treated with Oral Antiglycemic Medications

There is a current understanding of type 1 diabetes (T1D) as being the result of a heterogeneous disease of whole pancreas. So far, descriptions of pancreas alterations suggested a global involvement of inflammation throughout the organ, characterized by abnormal age-specific patterns (i.e. > or <7 yo). In our DIATAG study, we thoroughly characterized pancreatic structure modifications in new-onset T1D patients and investigated whether these correlated with pancreatic functions during the first postdiagnosis year. Pediatric patients with new-onset T1D (n=31; 11.2±2.9 years) underwent abdominal MRI scan at diagnosis (i.e. 40±37 days postdiagnosis). Exocrine function (i.e. serum trypsinogen) and residual endocrine secretion estimates (i.e. fasten = CPEPBASAL, stimulated model = CPEPEST (1)) were evaluated on fasten blood tests at diagnosis (Δ) and Δ+3, +12 months, respectively. Clinical parameters of glucose homeostasis (i.e. A1C, insulin daily dose, insulin-dose adjusted A1c [IDAA1C]) were collected at Δ+3, +6, +9 and +12 months. We compared pancreas volumes (i.e. PV, PVHEAD, PVBODY, PVTAIL) and ratios (pancreas volume ratio [PVR] = PVHEAD/PVBODY+TAIL; pancreas index [PI] = PV/body weight) to retrospectively identify age-, BMI- and sex-matched controls (n=29). Compared to control group, T1D patients demonstrated a homogeneous (PVR, 1.39±0.7 vs 1.46±0.4, p>0.05) decrease of PI (0.6±0.2 vs 1.1±0.3 mL/kg, p<0.0001) independently of pancreatic subregion. Interestingly, prepubertal children with T1D (n=15) exhibited greater pancreas atrophy of both the body-tail (10±5.6 %, p<0.05) and head (7.2±3%, p<0.05) subregions compared to pubertal group (n=16; PI difference of mean, 0.64 vs 0.48 mL/kg). Next, we evaluated correlations between pancreatic volumes and functions during the natural evolution of T1D using multivariate and univariate linear regressions. PV and PI correlated moderately with exocrine function (trypsinogen; R=0.46, R=0.52, p<0.001) but not with residual endocrine function evaluated at Δ+3 months. Interestingly, we observed using topographical analysis that PVHEAD correlated with trypsinogen (R=0.5, p<0.001) but not with any endocrine estimates (p>0.05). PVTAIL positively correlated with CPEPEST and CPEPBASAL at Δ+3 months (R=0.55, p=0.002; R=0.47, p<0.01) and not with clinical parameters or trypsinogen (p>0.05). PVBODY did not correlate with any pancreatic function. Finally, we identified multivariate models that included PV and predicted pancreatic endocrine function at Δ+6 and +12 months (i.e. IDAA1C, HbA1C). MRI performed early after T1D onset helped us define specific pancreas alterations and demonstrate for the first time: (1) the increased pancreas atrophy in prepubertal children; (2) correlations between pancreatic subregion volumes and their respective residual functions early after diagnosis and (3) the improvement of endocrine function prediction models by adding PV estimates as predictors.
(1) Wentworth et al. 2019;62(1): 33–40

Deep Characterization of Pancreas Volume of New-Onset Type 1 Diabetes Patients Reveals Puberty-Specific Patterns and New Topographic Correlations with Pancreatic Functions.

Cardiovascular morbidity and mortality are high in persons with severe mental illness. Psychotropic medications, particularly second-generation antipsychotics (SGA), and also adverse health behaviors are mediators of adverse cardiometabolic health outcomes in persons with severe mental illness. Identifying and addressing specific risk factors early and aggressively is key to improving health outcomes in these patients; yet studies addressing the above problems are limited. We therefore evaluated 39 patients with schizophrenia, schizoaffective, or bipolar disorder on SGA in a comprehensive cardiometabolic, lifestyle, and mental health screening program. Data were analyzed using SPSS version 24. As previously reported, the majority of screened patients had prediabetes (PD) or diabetes mellitus (DM), 74% per oral Glucose Tolerance Testing (oGTT), 56% per HbA1c criteria. Pulse rates, insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR, and Matsuda) were significantly different between patients classified as normal or with PD/DM, using either oGTT or HbA1c criteria. However, patients with PD/DM per HbA1c, but not oGTT criterium, also had higher waist/hip ratios (p=0.01), triglyceride (p=0.01) and hsCRP levels (p=0.04) as well as lower HDL levels (p=0.04). We then determined whether dietary habits (by UK Diabetes and Diet Questionnaire, UKDDQ), mood (by Patient Health Questionnaire, PHQ-9) and/or physical activity (average daily step count) were associated with unfavorable, and potentially modifiable cardiometabolic biomarkers (fasting, 2h-oGTT plasma glucose, serum insulin, triglycerides, HDL, LDL, HbA1c, hsCRP and adiponectin). We find that fasting plasma glucose and triglyceride levels significantly correlated with UKDDQ scores (fasting plasma glucose: r=0.34, p=0.03, fasting triglyceride levels: r=0.37, p=0.02); a trend was observed for higher insulin resistance indices (HOMA IR) being associated with higher UKDDQ scores (r=0.31, p=0.06). We also confirm a strong negative correlation of the average daily step count with hsCRP levels (r=-0.62, p<0.0001). PHQ-9 scores negatively correlated with adiponectin levels (r=-0.475, p<0.005). Altogether, in our patient population with severe mental illness on SGA, unhealthy diet habits, low physical activity, and symptoms of depression were associated with higher fasting glucose and triglycerides, higher hsCRP and lower adiponectin levels, all of which may potentially contribute to adverse cardiometabolic outcomes. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk patient population.

Poor Diet Habits, Depression and Low Physical Activity Correlate with Cardiometabolic Risk Markers in Persons with Severe Mental Illness on Second-Generation Antipsychotic Medications.

Aims: Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-known risk factor for nephrolithiasis. Recently in an observational study of patients with T2D, use of sodium-glucose transport protein 2 (SGLT2) inhibitors as glucose lowering agents was associated with a 49% lower risk of nephrolithiasis when compared with use of glucagon like peptide 1 (GLP-1) receptor agonists. We examined, prospectively, the association between renal stone disease and the use of the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials.
Methods: Pooled data from 15,081 patients with T2D treated with empagliflozin (10,177) or placebo (4,904) from 20 phase I-IV randomized, placebo-controlled trials including the large cardiovascular outcome trial, EMPA-REG OUTCOME, were included in this analysis. Incident urinary tract stone events were captured using a pre-defined collection of MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, calculus bladder, calculus urinary, calculus urethral, and nephrocalcinosis (MedDRA version 22.1). A sensitivity analysis used a narrower definition by excluding the terms renal colic and nephrocalcinosis. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated using the relative risk estimate stratified by study.
Results: The median exposure to study drug was 543 (placebo) and 549 (empagliflozin 10 or 25 mg) days We found that a total of 183 patients experienced an incident urolithiasis during follow-up (79 in placebo, 104 in pooled empagliflozin) yielding annual incidence rates of 1.01 versus 0.63 events per 100 patient years in placebo and empagliflozin, respectively. All but one event occurred in patients with no prior history of urinary tract stones. The IRR was 0.64 (95% CI 0.48, 0.86), in favor of empagliflozin. In the sensitivity analysis, now restricted to nephrolithiasis, ureterolithiasis, calculus bladder, calculus urinary, and calculus urethral, the results were similar (IRR, empagliflozin vs. placebo, 0.62 [95% CI 0.45, 0.85]).
Conclusion: As compared to placebo, use of empagliflozin was associated with an approximate 40% reduction in the risk of urolithiasis in patients with T2D. Alterations in lithogenic profile of the urine (including dilutional effects) of potential stone formers after SGLT2 inhibition may explain this finding. Based on these initial observations, mechanistic studies to elucidate the mediator(s) of this seemingly protective effect and dedicated randomized prospective clinical trials appear warranted in patients with renal stone disease. As with follow-up SGLT2 inhibitor investigations conducted in patients with heart failure and chronic kidney disease, such trials should include individuals who do not have T2D.

Empagliflozin and the risk of nephrolithiasis

Background: Patients with gestational diabetes mellitus (GDM) have an increased risk of developing type 2 diabetes mellitus (T2DM) after delivery and are encouraged to practice behaviors, such as healthy nutrition, physical activity and weight loss to attenuate future risk of T2DM. GDM has been shown to significantly increase the risk for post-partum depressive symptoms, which can impair a woman's ability to engage in and adhere to diabetes prevention efforts. To further inform the development and adapation of lifestyle interventions to prevent T2DM, we sought to identify factors associated with depressive symptoms in the early postpartum period among women with recent GDM.
Methods: Participants are from the baseline cohort of the Balance after Baby Intervention study, a two-year randomized clinical trial of a lifestyle intervention for women with recent history GDM conducted in Boston, MA and Denver, CO between 2016-2019. Prior to randomization, a study visit was scheduled at approximately 6 weeks post-partum. At this visit, weight and height were measured for determination of BMI. We administered the Edinburgh Postpartum Depression Scale (EPDS) and Perceived Stress Scale (PSS-10). We used an EPDS score of ≥9 as depressive symptoms and a PSS score of ≥14 as moderate to high perceived stress. We collected self-reported pre-pregnancy weight, and reviewed medical records to obtain medical history, including GDM diagnosis, mode of delivery, gestational weight gain and insulin use during pregnancy. We conducted bivariate analyses to identify predictors of postpartum depressive symptoms, then modeled the odds of post-partum depressive symptoms using multivariate logistic regression.
Results: Our study included 181 women (mean age, SD 32.6 ± 5.3 years, 51.4% White/14.4% Black/33.7% Latinx, mean pre-pregnancy BMI 29.8 ± 6.0 kg/m²). 19% of women scored ≥9 on EPDS and 53% of women scored ≥14 on PSS at the post-partum visit. Variables included in the bivariate analysis were age, Black/Latinx-identifying, college completion, perceived stress, primiparity, having a partner, pre-pregnancy BMI, gestational weight gain, C-section, insulin use during pregnancy, breastfeeding, 1st GDM pregnancy, exceeding IOM weight gain guidelines and income level. Of those variables, the best fit multivariate model with the lowest Akaike information criterion (AIC) included perceived stress, C-section and 1st GDM pregnancy. Using this model, the regression analysis showed that only perceived stress (4.5 OR, 95% CI [2.6-7.7], p was predictive of post-partum depressive symptoms. Conclusion: Perceived stress was predictive of post-partum depressive symptoms in women with recent GDM. Addressing perceived stress in the early post-partum period may be an important target for development or adaptations of future lifestyle interventions to prevent T2DM in women with recent GDM.

Predictors of Postpartum Depressive Symptoms in Women with Recent GDM

Central estrogen signaling in the medial basal hypothalamus (MBH) coordinates energy expenditure, food intake, and reproduction, as well as skeletal homeostasis. Prior work from our lab found that estrogen signaling via Estrogen Receptor alpha (ERa) in the arcuate (ARC) nucleus normally restrains bone formation in female mice only. We asked if the high bone mass in the Esr1Nkx2-1Cre mouse model, which ablates ERa in the MBH, is maintained or deteriorates with chronic overnutrition, as this is known to increase bone frailty in humans. To carry out this study, Esr1Nkx2-1Cre mutant female mice were fed HFD (Research Diets, D12492, 60% fat) or chow (SCD, 5058; LabDiet, 4% fat) for 17 weeks beginning at 10 weeks of age and housed at 22C. Although neither cohort gained significant weight on HFD nor exhibited marked changes in other metabolic parameters (%fat, GTT, ITT, etc.), this dietary challenge reversed and normalized the high bone mass in mutant females. Specifically, the ratio of BV/TV in the distal femur decreased dramatically from 36% to 6%, as measured by 3D-microcomputed tomography (micro-CT); cortical bone also decreased similarly. For comparison, control females fed HFD showed a non-significant decrease in bone mass (4.9% to 3.9% BV/TV). Unexpectedly, the large drop in bone mass in Ers1Nkx2-1Cre females fed HFD was uncoupled from an increase in bone marrow adipose tissue (BMAT). In contrast, control cohorts showed a marked 9-fold increase in BMAT following HFD. Thus, the high bone mass in mutant Ers1Nkx2-1Cre females, which persists in aged and estrogen-depleted females, quickly disintegrates with a dietary challenge. Recent RNA-Seq data from microdissected ARC tissue reveals several secreted factors that are dramatically elevated in mutant females but drop 10-20-fold after HFD. Current studies are underway to ask if these candidate factors from the ARC impact bone mass or the osteogenic capacity of skeletal stem cells. Our findings are in stark contrast to the notion that dietary excess reduces bone health by increasing bone fat at the expense of osteogenesis. Instead, based on our model, we posit that dietary excess directly determines dynamic bone remodeling by acting on the brain.

Metabolic activation of tachysterol to biologically active hydroxyderivatives that act on VDR, AhR, LXRs and PPARγ receptors

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Disrupting a Key H-bond Network Drives Glucocorticoid Receptor Gene Suppression Without Off-target Gene Activation for Duchenne Muscular Dystrophy Treatment

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