United States

Introduction-Prediabetes is defined as Hba1c 5.7% - 6.4%, with an intermediate metabolic state and includes impaired glucose tolerance and impaired fasting glucose due to insulin resistance. While Type 2 Diabetes Mellitus is a well-established risk factor for cardiovascular disease, the possible link between Prediabetes and risk of Myocardial infarction (MI) has become a focus of interest in recent years. We wanted to evaluate if Prediabetes is independently associated with increased risk for MI.
Methods-We included adult patients admitted to teaching hospitals with a primary or secondary diagnosis of &quot;acute myocardial infarction&quot; from the National inpatient sample of 2016, 2017, and 2018. We created three separate multivariate logistic regression models with outcomes as MI, Percutaneous intervention (PCI), and CABG (Coronary artery bypass grafting).
Results-A total of 1,794,149 (95% CI 1,753,742-1,834,556) weighted hospitalizations with MI were included. Out of the 1.79 million patients with MI, 1% had Prediabetes. Prediabetes was greatly associated with increased odds for MI (OR 1.41, 95% CI 1.35-1.47, P=0.000). After adjusting for age, sex, race, family history of MI, dyslipidemia, hypertension, Diabetes, nicotine dependence, and obesity, Prediabetes was significantly associated with increased odds of MI (OR 1.25, 95% CI 1.20-1.31, P=0.000), increased odds of PCI (OR 1.45, 95% CI 1.37-1.53, P=0.000) and increased odds of CABG (OR 1.95, 95% CI 1.77-2.16, P=0.000).
Discussion- Our study shows that Prediabetes may be an independent risk factor for MI despite adjusting for the well-established risk factors. Coronary interventions such as PCI and CABG were highly associated with Prediabetes, suggesting macrovascular CAD. This growing evidence indicates the need to identify patients with Prediabetes and aggressively manage their cardiovascular risk factors to prevent MI. Although Prediabetes is commonly missed during coding and adds a limitation to this study, we would highlight that the association of Prediabetes with Myocardial Infarction, PCI, and CABG is a significant addition to the literature. Our study serves as a wake-up call for clinicians and patients to shift the focus to preventing Prediabetes and not just Diabetes. Our findings reinforce the importance of early recognition by screening and early intervention of Prediabetes by lifestyle changes and/or medications to decrease the risk of cardiovascular events.

ENDO 2022

Prediabetes is a Risk Factor for Myocardial Infarction-A National Inpatient Sample Study

**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. 

Introduction-Prediabetes is defined as Hba1c 5.7% - 6.4%, with an intermediate metabolic state and includes impaired glucose tolerance and impaired fasting glucose due to insulin resistance. While Type 2 Diabetes Mellitus is a well-established risk factor for cardiovascular disease, the possible link between Prediabetes and risk of Myocardial infarction (MI) has become a focus of interest in recent years. We wanted to evaluate if Prediabetes is independently associated with increased risk for MI.
Methods-We included adult patients admitted to teaching hospitals with a primary or secondary diagnosis of "acute myocardial infarction" from the National inpatient sample of 2016, 2017, and 2018. We created three separate multivariate logistic regression models with outcomes as MI, Percutaneous intervention (PCI), and CABG (Coronary artery bypass grafting).
Results-A total of 1,794,149 (95% CI 1,753,742-1,834,556) weighted hospitalizations with MI were included. Out of the 1.79 million patients with MI, 1% had Prediabetes. Prediabetes was greatly associated with increased odds for MI (OR 1.41, 95% CI 1.35-1.47, P=0.000). After adjusting for age, sex, race, family history of MI, dyslipidemia, hypertension, Diabetes, nicotine dependence, and obesity, Prediabetes was significantly associated with increased odds of MI (OR 1.25, 95% CI 1.20-1.31, P=0.000), increased odds of PCI (OR 1.45, 95% CI 1.37-1.53, P=0.000) and increased odds of CABG (OR 1.95, 95% CI 1.77-2.16, P=0.000).
Discussion- Our study shows that Prediabetes may be an independent risk factor for MI despite adjusting for the well-established risk factors. Coronary interventions such as PCI and CABG were highly associated with Prediabetes, suggesting macrovascular CAD. This growing evidence indicates the need to identify patients with Prediabetes and aggressively manage their cardiovascular risk factors to prevent MI. Although Prediabetes is commonly missed during coding and adds a limitation to this study, we would highlight that the association of Prediabetes with Myocardial Infarction, PCI, and CABG is a significant addition to the literature. Our study serves as a wake-up call for clinicians and patients to shift the focus to preventing Prediabetes and not just Diabetes. Our findings reinforce the importance of early recognition by screening and early intervention of Prediabetes by lifestyle changes and/or medications to decrease the risk of cardiovascular events.

technical paper

Persons with HIV (PWH) who are well-treated on antiretroviral therapies (ART) have a 1.5-2.0 fold increased risk of cardiovascular disease (CVD) compared to persons without HIV (PWOH). A unique cardiovascular phenotype is seen in HIV such that traditional cardiovascular risk factors alone to do not account for this excess CVD risk. Coronary microvascular dysfunction may promote subendocardial ischemia and cardiomyocyte injury and provide a potential underlying mechanism for the atherosclerotic and myocardial disease prevalent in HIV. We assessed coronary microvascular function among those with HIV, comparing to those without HIV and with diabetes (DM).
39 PWH with no known history of CVD or DM, required to be on stable ART and virologically controlled (HIV viral load <200 copies/mL), underwent coronary ¹³N-ammonia PET/CT to evaluate coronary flow reserve (CFR)—a measure of microvascular dysfunction calculated by the ratio of peak coronary flow during regadenoson stress to rest. CFR was corrected using the rate pressure product, which integrates resting blood pressure and heart rate. A 0.1 unit reduction in CFR is associated with a 8% increase in hazard of CV events. Comparisons of CFR were made to PWOH from a database of higher risk clinical referrals who were matched approximately 2: 1 based on demographics and traditional risk factors and to those with diabetes and no known history of CVD recruited as part of a prior study evaluating CFR. Overall group comparisons for CFR were analyzed with the Wilcoxon/Kruskal-Wallis test, and if significant, the Mann-Whitney U test was employed for two-group comparisons.
PWH(74% male, age 55±7years, BMI 32±6kg/m², duration HIV 20±8years, duration ART 16±7years, CD4+ count 801±333cells/ul) were similar to PWOH(n=69, 74% male, age 55±8years, BMI 32±6kg/m²) and persons with DM(n=63, 63% male, age 55±8years, BMI 32±5kg/m²). CFR was significantly different among groups: PWOH 2.76(2.37,3.36), PWH 2.47(1.92,2.93), DM 2.31(1.98,2.84), overall P=.003. CFR was significantly reduced when comparing to PWH to PWOH(P=.02) as was DM to PWOH(P=.001) and did not differ when comparing PWH to DM(P=.68). Total cholesterol 182(168,205)mg/dL, LDL 108(77,127)mg/dL, triglycerides 159(88,219)mg/dL, and current tobacco use 23% were overall significantly higher among PWH (overall P<.03 for each comparison). Controlling for group status (PWH vs. PWOH) and either total cholesterol or current tobacco use, only group status remained significantly and independently related to CFR (group status P=.02 and .01, respectively).
Subclinical coronary microvascular dysfunction is present among asymptomatic, chronically infected PWH on ART who demonstrate good immunological control. This study demonstrates for the first time CFR is reduced compared to higher risk PWOH and comparable to those with DM, regardless of traditional CVD risk factors, and further highlights well-treated HIV as a CVD-risk enhancing factor similar to diabetes. The implications of reduced CFR in HIV warrants further investigation.

Coronary Microvascular Dysfunction is Present Among Well-Treated Asymptomatic Persons with HIV, Similar to Those with Diabetes

Introduction: Tirzepatide, the novel dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes, has been shown to reduce HbA1c and weight, with more patients achieving HbA1c ≤6.5%, compared to placebo and active comparators in the phase 3 SURPASS 1-5 studies. This analysis compared the percentage of patients treated with tirzepatide achieving a composite endpoint of HbA1c <6.5% without weight gain and hypoglycemia in these studies.Methods: We compared the proportion of participants achieving the composite endpoint between the tirzepatide (5, 10, or 15 mg) and respective comparator groups while patients were on treatment and without rescue medication. Missing data was imputed based on observed data in the same treatment arm from subjects who had their efficacy measure at the endpoint visit assessed after early discontinuation of study drug. End of treatment HbA1c and weight were evaluated at week 40 (SURPASS-1, 2, 5) and week 52 (SURPASS-3, 4). Weight gain was defined as a change from baseline in weight <0.1 kg. Hypoglycemia included blood glucose level <54 mg/dL with symptoms of hypoglycemia or severe hypoglycemia.Results: In SURPASS-1, 2, 3, 4, and 5 significantly more patients treated with tirzepatide achieved the composite endpoint compared to placebo or comparator (P≤0.002). As a monotherapy in SURPASS-1, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (75%, 78%, 83%, and 5%, respectively; all P<0.001). As add-on to metformin in SURPASS-2, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than semaglutide (67%, 77%, 83%, and 59%, respectively; P=0.002, P<0.001, P<0.001, respectively). When compared to basal insulin in SURPASS-3, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin degludec (63%, 76%, 82%, and 13%, respectively; all P<0.001). When added to 1-3 oral antihyperglycemics in SURPASS-4, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin glargine (56%, 68%, 75%, and 10%, respectively; all P<0.001). As an add-on to basal insulin in SURPASS-5, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (63%, 70%, 76%, and 8% respectively; all P<0.001).Conclusions: Significantly more patients treated with tirzepatide achieved a composite endpoint of HbA1c <6.5% without weight gain or hypoglycemia than those treated with placebo, semaglutide, insulin degludec, or insulin glargine in the phase 3 SURPASS program.

Achievement of HbA1c <6.5% without weight gain and hypoglycemia in people with type 2 diabetes treated with tirzepatide across the phase 3 SURPASS program

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN). Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM). Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction.
GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist. Pharmacodynamic studies demonstrated that GFB-024 protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN.
In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of GFB-024 in up to 56 healthy overweight and obese (BMI 25 – 40 kg/m2) participants.
A total of 38 subjects have completed 5 cohorts in the SAD, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects.
PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on four different in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested.
In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing.

Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus

IntroductionAdherence to lifestyle modifications can prevent diabetes; however, this poses a challenge for most individuals. CGM is an effective tool for glycemic control and lifestyle modifications in patients with diabetes on insulin therapy. We explored the impact of CGM use in individuals with prediabetes.HypothesisIndividuals using CGM in addition to diabetes education will show improved adherence to lifestyle modifications and greater reduction of HbA1c as compared to those receiving diabetes education alone.Design57 individuals with prediabetes were randomized to use CGM for 3 months along with diabetes education (CGM group) or receive diabetes education alone (EDU group). Food frequency (UKDDQ) and physical activity (IPAQ) questionnaires were completed by participants at the beginning and at the end of the study (6 months). Primary outcomes were lifestyle modifications and changes in HbA1c. Secondary outcomes were changes in weight and blood pressure.ResultsBoth groups reported an increase in healthy food choices; however, EDU group performed better (EDU: 12.4 vs 9.2, p<0.01, CGM: 10.6 vs 9.5, p 0.08). Unhealthy food choices were reduced in both groups. CGM group reported a greater increase in moderate physical activity levels (CGM: 230 vs 61 minutes/week, p 0.01, EDU: 78.5 vs 48 minutes/week, p 0.22). Vigorous physical activity was reported by more individuals in CGM group than EDU (35% vs 4%). Greater reduction in mean HbA1c was noted in CGM group (5.7 vs 5.9%, p 0.05) compared to EDU (5.8 vs 5.9%, p 0.01). 33% of participants in both groups had normalization of HbA1c at the end of study. CGM group had greater reduction in weight (3.5 vs 0.8 lb, p 0.1) and systolic BP (12 vs 2.4 mmHg, p 0.01) than EDU. Irrespective of group assignment, the study population had improvement in all outcomes despite the beginning of COVID-19 pandemic during 4th month of the study. Smaller number of participants in the CGM group reported negative impact of the pandemic on their lifestyle modifications than EDU (Diet: 68% vs 80%, Physical activity: 48% vs 64%). Majority of CGM group participants were able to maintain lifestyle changes after discontinuing CGM use (Diet: 72%, Physical activity: 84%). On comparing both interventions, 56% of CGM group participants felt CGM to be more helpful than education for lifestyle modifications, while 40% felt both interventions helped equally.ConclusionsCGM use in addition to diabetes education resulted in improvement in physical activity, food choices, HbA1c, weight, and BP in individuals with prediabetes. The significance of diabetes education was noted by greater improvement in food choices in EDU group. CGM can be an effective tool for diabetes prevention with lifestyle modifications in prediabetes. The long-term impact of CGM use and cost-benefit analysis in high-risk patients needs to be explored further.

Impact of Continuous Glucose Monitoring (CGM) on Lifestyle Modifications in Individuals with Prediabetes

Post-bariatric hypoglycemia (PBH) is a rare disease characterized by recurrent episodes of severe, symptomatic hyperinsulinemic hypoglycemia (HH). The predominant form occurs after Roux-en-Y gastric bypass (RYGB). However, severe cases also present after other upper-gastrointestinal procedures. The mechanisms mediating PBH have long been debated, though a critical role for excessive postprandial secretion of glucagon-like peptide-1 (GLP-1) has been established. Avexitide (exendin 9-39) is a first-in-class GLP-1 receptor antagonist in development for treatment of PBH. Prior studies with avexitide administration have shown normalization of postprandial insulin concentrations and reductions in the occurrence of symptomatic hypoglycemia. In the Phase 2 multicenter PREVENT trial, avexitide administered to post-RYGB patients at a total daily dose of 60 mg [30mg twice daily (BID) or 60mg once daily (QD)] for 28 days was well-tolerated and demonstrated significant reductions in the rates of hypoglycemia, symptoms, and percent time in hypoglycemia. Based on the favorable safety and tolerability profile and dose-response relationship observed, we sought to evaluate whether higher doses of avexitide may further enhance the pharmacodynamic response. In addition, we sought to extend the evaluation to patients with HH after vertical sleeve gastrectomy, esophagectomy, gastrectomy or Nissen fundoplication. In this Phase 2b, open label, cross over study (NCT04652479), eligible patients included males and females (>18 years of age; BMI ≤40 kg/m²) with a history of recurrent hypoglycemia refractory to medical nutrition therapy (MNT) and exhibiting at least two severe hypoglycemia events while adhering to MNT over a 14-day period. Metabolic and symptomatic parameters were assessed by self-monitoring of blood glucose (SMBG), e-Diary, and blinded continuous glucose monitor (CGM) during 14 days of MNT as compared to 14 days of MNT + avexitide administered by subcutaneous injection at a dose of 45mg BID and 90mg QD in crossover design and random order, for a total of 28-days of treatment. An interim analysis (mixed-effect model) at ~50% completion was conducted (n=8). The primary and secondary endpoints were met with statistical significance. Compared with MNT alone, avexitide 45mg BID and 90mg QD reduced the rate of Level 1 hypoglycemia (SMBG<70 mg/dL) by 66% (p=0.022) and 74% (p=0.010); Level 2 hypoglycemia (SMBG <54 mg/dL) by 70% (p=0.003) and 93% (p=0.001); and Level 3 hypoglycemia (severe event characterized by altered mental and/or physical function requiring assistance) by 77% (p=0.002) and 93% (p=0.001), respectively. Objective assessment by blinded CGM corroborated SMBG/e-Diary results, demonstrating significant reductions in the rates of hypoglycemia and improvements in percent time in hypoglycemia. Responses were comparable across surgical subtypes. Greater improvements were consistently observed with once daily (90 mg QD) than twice daily (45 mg BID) dosing and exceeded those reported in the PREVENT trial. Avexitide was well-tolerated, with no serious adverse events. Complete study results will be presented.

Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery; Assessment of Novel Dosing Regimens in an Expanded Indication

Current markers of β-cell function poorly reflect glucose homeostasis after diabetes onset, mainly because of the lack of integration of parameters of insulin sensitivity and β-cell responsiveness to glucose. Recently, the widespread use of continuous glucose monitoring (CGM) helped stratify glucose control in patients with long-term diabetes in new clinically relevant glucotypes. In our DIATAG study, we investigated how CGM metrics may help to segregate patients with new-onset type 1 diabetes (T1D) entering or not in partial remission (PR). We collected data from 66 pediatric patients with T1D (10.4±4.7 yo) during the first year after diabetes onset (Δ). Clinical parameters (i.e. A1C, insulin daily dose, insulin-dose adjusted A1c [IDAA1C]) and CGM data were collected at Δ+3, +6, +9, +12 months (n=168, 57% remitters [IDAA1C <9]). A panel of 46 CGM metrics was calculated on an hourly and daily basis using iglu package (1). Using unsupervised hierarchical clustering based on daily CGM metrics and clinical parameters, we identified four clusters of glucose metrics that differed from each other (p<0.05). Cluster 1 was characterized by an increased glucose stability (coefficient of variation [CV] 32±5%) within time in target (TIT [63-140 mg/dL], 83±6%) with 9% of sensor values in 63-70 mg/dL range in the early morning period. Cluster 2 exhibited a progressive decrease of TIT (60±14%) and an increase of target above range (TAR [>180 mg/dL], 20±9%) especially during the day while target in range (TIR [70-180 mg/dL]) was nearly equivalent to Cluster 1 (80±8%). Notably, CV remained low (32±5%) with little time spent below range (TBR [<70 mg/dL], 5±2%). Cluster 3 demonstrated a net increase of CV during all the nycthemere (46±7%) concomitantly to an increase of TBR (14±7%). Interestingly, TIT and TAR remained close to values from Cluster 2 (55±11%; 23±10%). Finally, Cluster 4 demonstrated major hyperglycemias (TAR, 55±13%) with increased CV (47±9%) and decreased TBR (8±6%). Interestingly, clustering allowed clinically relevant segregation of intermediate values of IDAA1C (i.e. 7.5-10) between Cluster 2 and Cluster 3, independently of the remission status. Moreover, participants at Δ+3 months distributed across all clusters (with respectively 38% in Cluster 1, 26% in Cluster 2, 29% in Cluster 3 and 7% in Cluster 4) highlighting the usefulness of CGM in characterizing disease heterogeneity from diabetes onset. In our study, a combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of T1D. 1. Broll et al, 2021;16(4): e0248560.

Identification of Four New Glucotypes during the First Year after Type 1 Diabetes Onset Using Continuous Glucose Monitoring Metrics

VC-02 combination product (PEC‑Direct) is a clinical-stage regenerative medicine therapy being developed for patients with type 1 diabetes and hypoglycemia unawareness intended to restore homeostatic glycemic control.  It is comprised of stem cell-derived pancreatic progenitors (PEC‑01) loaded into a macroencapsulation device that facilitates the in-growth of blood vessels into the device lumen, supporting the maturation and differentiation of the graft into hormone-positive islet cells comprising glucose‑responsive beta cells. Initial data from one patient (2021, Keymeulen) demonstrated clinically-relevant levels of stimulated C-peptide and corresponding improvements in glycemic control within six months after subcutaneous implantation. These improvements now include a time-in-range consistently >90% and a persistent HbA1C <7%.Enrollment of additional patients with negligible C‑peptide levels in the ongoing VC02‑101 study implanted with the same device configuration has now resulted in multiple patients demonstrating C-peptide levels ≥0.3 ng/mL.  All patients are challenged with a mixed-meal tolerance test at baseline and post‑implantation to detect and monitor increases in plasma C‑peptide levels.  In some cases, the increased C‑peptide levels are observed to occur as soon as two months post‑implant with subsequent increases resulting as the patients progress further into the treatment period as high as 0.4 ng/mL by five months with additional time points at longer periods of exposure pending.  This progressive rise in beta cell function is consistent with preclinical findings showing time-dependent differentiation of the pancreatic progenitors into beta cells and subsequent increases in beta cell mass.The increases in plasma C‑peptide levels also correlate with trends toward improved glycemic control parameters.  Relative to baseline levels, improvements are observed in time‑in‑range data captured from continuous glucose monitoring, as well as substantial decreases in HbA1C by as much as 1.5%.  These positive trends also correlate with decreases in the amount of exogenous insulin required by as much as 70%.  Importantly, these data and observations have been obtained at separate clinical sites involving different surgeons, indicating that the achievement of functional engraftment of PEC‑Direct is reproducible with proper product handling, surgical training, and patient compliance with an adjunctive immunosuppression regimen.  These data provide further proof‑of‑concept that continued optimization of PEC‑Direct can result in a functional cure for T1D.

Further Clinical Evaluation of Stem Cell-Derived Islet Replacement Therapy (VC-02) Demonstrates Production of C-Peptide with Improvements in Glycemic Control Parameters in Multiple Patients with Type 1 Diabetes and Hypoglycemia Unawareness

The adrenal cortex and gonads are the two major endocrine hubs that participate in the hormonal regulation of vital aspects of mammalian homeostasis. Accordingly, their developmental aberrancies drive various congenital and adult-onset diseases. Lineage tracing studies in mice reveal that the adrenal cortex and gonads originate from a common progenitor, the adrenogonadal primordium. However, the specification pathways of the adrenal cortex and gonads and their lineage relationship remain poorly understood in humans. Here, we conduct the high resolution spatial and temporal lineage trajectory mapping of early human adrenal and gonadal lineages using single cell transcriptomics and histologic profiling on human embryos at 3-8 week post fertilization. We find that in humans, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to-mesenchymal-like transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages challenges the paradigm established in rodents and present evidence that the specification programs directing the formation of adrenal glands and gonads differ between rodents and humans. The molecular details of early lineage diversification of human adrenals and gonads will serve as both a framework for understanding the molecular pathology of human disorders.

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

Proper development and zonation of the adrenal cortex is intimately connected with its lifelong capacity to produce steroid hormones. Both adrenocortical development and homeostasis are mediated in part by paracrine WNT/β-catenin signaling, an essential pathway for zonal maintenance and aldosterone production. Patients harboring homozygous or compound heterozygous loss-of-function (LOF) mutations in the WNT ligand WNT2B present with congenital diarrhea and require parenteral nutrition. Despite evidence for euvolemia, WNT2B-null patients exhibit markedly elevated plasma renin levels with no corresponding increase in aldosterone, suggesting a primary adrenal defect in aldosterone synthesis. To test this hypothesis, we generated both global and conditional Wnt2b knockout mouse models. In the mouse adrenal, Wnt2b is expressed exclusively in the capsule, the outer compartment of mesenchymal cells that overlay and signal to the subcapsular zona glomerulosa (zG), the adrenocortical zone that harbors aldosterone-producing cells and critical long-term progenitor cells. Global loss of Wnt2b from early mouse development results in a near-complete absence of the histological zG. Moreover, Wnt2b-null mice exhibit significantly increased plasma renin but normal aldosterone levels compared to wild-type controls. These data suggest that WNT2B-null patients indeed have an adrenocortical phenotype caused by apparent zG hypofunction. To further define the mechanism(s) by which Wnt2b LOF leads to zG hypofunction, we temporally deleted Wnt2b in the adrenal capsule of adult mice. Wnt2b conditional knockout (cKO) adrenals exhibit a zG-restricted decrease in Wnt/β-catenin signaling as determined by decreased β-catenin activity and target gene expression. Moreover, Wnt2b cKO mice demonstrated a disorganized zG and disrupted adrenocortical zonation. To determine the contribution of WNT2B to aldosterone production, we administered a sodium-deficient diet to control and Wnt2b cKO mice to activate the renin-angiotensin-aldosterone system. Indeed, while control mice exhibited the expected increase in both plasma renin and aldosterone, Wnt2b cKO mice showed marked elevation of renin despite normal aldosterone compared to controls, consistent with hyperreninemic hypoaldosteronism. Together, our work supports a WNT2B-dependent mechanism for adrenal zG development and maintenance in mice and humans and provides relevant models to study the consequences of WNT2B deficiency within the zG.

WNT2B Deficiency Results in Hyperreninemic Hypoaldosteronism in Humans and Mice

Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a heterogeneous disease characterized by bilateral adrenal macronodules responsible for adrenal Cushing. To date, two genetic causes of PBMAH are known: germline inactivating variants of the tumor suppressor genes ARMC5 identified in 2013 (Assié, N Eng J Med 2013), responsible for 20 to 25% of index cases, and KDM1A, identified recently (Vaczlavik, GIM 2021; Chasseloup, Lancet D&E 2021), responsible for the rare presentation associated with food-dependent Cushing's syndrome (FDCS) due to aberrant expression of the GIP receptor (GIPR) in adrenocortical cells. Multiple other illegitimate receptors are known to be responsible for abnormal cortisol response to various physiological stimuli in PBMAH. A recent multiomic analysis, identified three distinct molecular PBMAH groups: G1 with ARMC5-mutated tumors, G2 with KDM1A-mutated tumors from FDCS patients, and G3 with no identified genetic cause at present. We aimed to identify specific expression profiles of illegitimate receptors in the three groups.
Methods: Based on the transcriptome data obtained by RNA sequencing (Illumina) of the tumors from 31 patients (G1/ARMC5, 16 patients; G2/KDM1A, 6 patients; G3, 9 patients), expression of the following genes, encoding potential illegitimate receptors, were compared: ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, AVPR1A, AVPR1B, AVPR2, GCGR, GIPR, HTR4, HTR7, LHCGR. Calculations were performed using R statistical software. The Bioconductor limma package was used to analyze mRNA differential expression.
Results: G1/ARMC5 tumors showed a relative overexpression of the vasopressin receptors AVPR1A and AVPR1B compared to the two other groups (fold-change [FC] =7.39, p<0.001 and 3.98, p<0.001, respectively) but a lower expression of AVPR2 (FC=0.43, p=0.015). G2/KDM1A tumors showed a dramatic overexpression of GIPR compared to the two other groups (FC=105.02, p<0.001) but also of the adrenergic receptors ADRA1D and ADRA2A (FC=2.93, p=0.027 and 9.99, p<0.001, respectively) and of the LH/hCG receptor (LHCGR) (FC=12.20, p<0.001). G3 tumors showed a slight overexpression of the adrenergic receptor ADRA1B (FC=3.49, p=0.001) and in few tumors ADRA1D, AVPR2 and LHCGR were highly expressed suggesting molecular heterogeneity in G3.
Conclusion: This study reveals specific expression profiles of illegitimate receptors related to the three molecular groups. ARMC5 tumors are associated with the overexpression of two vasopressin receptors, while, besides GIPR, KDM1A inactivation seems to drive the overexpression of the LH/hCG receptor, as previously suggested in patients with FDCS (Bertherat, JCE&M 2005), potentially responsible for Cushing's syndrome associated with pregnancy and menopause. These molecular patterns need to be corroborated by clinical data with a systematic testing of the aberrant cortisol responses. Additionally, further studies would be needed to investigate the clinical relevance and significance of moderate fold-changes in gene expression (e.g. <4).

Genetic Alterations of ARMC5 and KDM1A Are Associated With Different Expression Profiles of Illegitimate Receptors in Primary Bilateral Macronodular Adrenal Hyperplasia

Prediabetes is a Risk Factor for Myocardial Infarction-A National Inpatient Sample Study

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Coronary Microvascular Dysfunction is Present Among Well-Treated Asymptomatic Persons with HIV, Similar to Those with Diabetes

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