Decline in case rates of youth onset type 2 diabetes in year three of the COVID-19 pandemic.

OBJECTIVES: To determine changes in case rates of youth onset type 2 diabetes in the three years following the COVID-19 pandemic. METHODS: A single-center, retrospective medical record review was conducted for patients newly diagnosed with T2D between 3/1/18 and 2/28/23 at a pediatric tertiary care center. The number of patients referred to CHLA with a T2D diagnosis date between 3/1/2020 and 2/28/2023 was compared to historical rates between 3/1/2018 and 2/29/2020. χ2 or Fisher's exact test was used to compare categorical variables between each year and 2019. RESULTS: Compared to prepandemic baseline (3/1/19-2/29/20, 11.8±3.7 cases/month), there was a significant increase in new T2D monthly case rates in pandemic year 1 (3/1/20-2/28/21, 20.1±6.0 cases/month, 171 %, p=0.005) and pandemic year 2 (3/1/21-2/28/22, 25.9±8.9 cases/month, 221 %, p=0.002). Case rates declined in pandemic year 3 to 14.5±4.1 cases/month (3/1/22-2/28/23, p=0.43). Compared to prepandemic year 1, the frequency of DKA at diagnosis was higher in pandemic year 1 (13.3 vs. 5.0 %, p=0.009). The DKA rate in pandemic years 2 (6.8 %) and 3 (3.4 %) were comparable to prepandemic year 1 (p=0.53 and 0.58, respectively). CONCLUSIONS: Youth onset type 2 diabetes cases and DKA rates in year 3 of the pandemic have returned to prepandemic level.

Risk Factors for Hyperosmolar Hyperglycemic State in Pediatric Type 2 Diabetes.

Background: There is a paucity of data on the risk factors for the hyperosmolar hyperglycemic state (HHS) compared with diabetic ketoacidosis (DKA) in pediatric type 2 diabetes (T2D). Methods: We used the national Kids' Inpatient Database to identify pediatric admissions for DKA and HHS among those with T2D in the years 2006, 2009, 2012, and 2019. Admissions were identified using ICD codes. Those aged <9yo were excluded. We used descriptive statistics to summarize baseline characteristics and Chi-squared test and logistic regression to evaluate factors associated with admission for HHS compared with DKA in unadjusted and adjusted models. Results: We found 8,961 admissions for hyperglycemic emergencies in youth with T2D, of which 6% were due to HHS and 94% were for DKA. These admissions occurred mostly in youth 17-20 years old (64%) who were non-White (Black 31%, Hispanic 20%), with public insurance (49%) and from the lowest income quartile (42%). In adjusted models, there were increased odds for HHS compared to DKA in males (OR 1.77, 95% CI 1.42-2.21) and those of Black race compared to those of White race (OR 1.81, 95% CI 1.34-2.44). Admissions for HHS had 11.3-fold higher odds for major or extreme severity of illness and 5.0-fold higher odds for mortality. Conclusion: While DKA represents the most admissions for hyperglycemic emergencies among pediatric T2D, those admitted for HHS had higher severity of illness and mortality. Male gender and Black race were associated with HHS admission compared to DKA. Additional studies are needed to understand the drivers of these risk factors.

Association Between COVID-19 and Severity of Illness for Children With Hyperglycemic Crisis.

OBJECTIVES: Admissions to the ICU for children with hyperglycemic crisis (HGC, defined as diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, or hyperosmolar ketoacidosis) increased during the COVID-19 pandemic. We sought to identify if severity of illness for HGC also increased from prepandemic to pandemic years 1 and 2. METHODS: Retrospective study of children aged ≤18 years hospitalized in the Pediatric Health Information System for HGC. Pre-COVID-19 years were defined as March 2017-February 2020, COVID-19 year 1 as March 2020-February 2021, and COVID-19 year 2 as March 2021-February 2022. The primary outcome was ICU admission. Secondary outcomes included mortality, length of stay, cost, and use of neurologic therapies, mechanical ventilation, or vasoactive support. RESULTS: There were 46 425 HGC admissions to 42 hospitals, 20 045 (43.2%) of which were ICU admissions. In comparison with pre-COVID-19, children admitted in COVID-19 year 1 (odds ratio, 1.31 [95% confidence interval, 1.25-1.38], P < .0001) and year 2 (odds ratio, 1.17 [95% confidence interval, 1.11-1.22], P < .0001) had a higher odds of ICU admission in multivariable modeling after controlling for confounding variables. Severity of illness was higher during COVID-19 years when considering secondary outcomes, although these associations were not consistent across outcomes and year. There was no difference in mortality. CONCLUSIONS: Children with HGC had a higher severity of illness during the pandemic which was sustained over 2 years. Reduction in social distancing and evolving variants of SARS-CoV-2 over the 2 years of the pandemic did not significantly alter the relationship between HGC and higher requirement for ICU care.

Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP-1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatric type 2 diabetes and the mechanism of action of GLP-1RAs as it pertains to physiological pathways relevant for type 2 diabetes, obesity and their related comorbidities. The outcomes of paediatric trials evaluating liraglutide, exenatide, semaglutide and dulaglutide in paediatric type 2 diabetes and obesity will be closely examined, including differences compared with adult studies. Finally, potential barriers and strategies to expanding GLP-1RA access in adolescents will be discussed. Future studies are needed to determine if the cardio-and renal-protective benefits of GLP-1RAs apply to youth-onset type 2 diabetes.

Youth-onset type 2 diabetes mellitus: an urgent challenge.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes.

BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).

Making Diabetes Electronic Medical Record Data Actionable: Promoting Benchmarking and Population Health Improvement Using the T1D Exchange Quality Improvement Portal.

This article describes how the T1D Exchange Quality Improvement Collaborative leverages an innovative web platform, the QI Portal, to gather and store electronic medical record (EMR) data to promote benchmarking and population health improvement in a type 1 diabetes learning health system. The authors explain the value of the QI Portal, the process for mapping center-level data from EMRs using standardized data specifications, and the QI Portal's unique features for advancing population health.

Spike in Diabetic Ketoacidosis Rates in Pediatric Type 2 Diabetes During the COVID-19 Pandemic.

OBJECTIVE: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) on the incidence of new-onset type 2 diabetes and diabetic ketoacidosis (DKA) is unclear. It is unknown whether the coincidence of DKA noted in adult patients with type 2 diabetes is an issue for youth during the coronavirus disease 2019 pandemic. RESEARCH DESIGN AND METHODS: A retrospective single-center medical record review was conducted in a large, urban children's hospital of pediatric subjects presenting with new-onset type 2 diabetes between March and August of 2018 to 2020. RESULTS: The proportion of subjects presenting with new-onset type 2 diabetes in DKA dramatically increased in 2020 (9% in 2018, 3% in 2019, and 20% in 2020, P = 0.029). CONCLUSIONS: In 2020, youth with new-onset type 2 diabetes had a greater incidence of DKA at presentation than previously observed. Future studies should examine the impact of SARS-CoV2 exposure on the presentation of type 2 diabetes in all age-groups to inform better patient care.

Glycemic control in youth-onset type 2 diabetes correlates with weight loss.

OBJECTIVE: To identify risk factors for glycemic failure in youth with type 2 diabetes (T2D). METHODS: A retrospective review of HbA1c, anthropomorphic measures, medication records, and laboratory studies was performed using registry data from a dedicated pediatric T2D clinic. Latent profile analysis (LPA) was performed to model longitudinal trajectory of HbA1c over 5 years. RESULTS: The registry includes 229 youth with T2D, of whom 80% self-identify as Latinx. The odds ratio (OR) for uncontrolled diabetes 5 years after diagnosis correlated with diagnostic HbA1c, with OR of 2.41 if HbA1c at diagnosis >8.5% (sensitivity 68%, specificity 54%, P = .015). LPA modeling identified three HbA1c profiles: (a) mean HbA1c <8% throughout the 5 years, (b) persistent elevation of mean HbA1c >9%, and (c) mean HbA1c of 12% at diagnosis, rapid decline to 6.4% by 4 to 6 months, and increase to 11% by 18 months. Our analysis of medication regimen showed that, amongst patients treated with metformin, the addition of multiple daily injections (MDI) did not improve HbA1c compared to those on basal insulin. Finally, weight loss over the 1 year after diagnosis correlated with improvement in HbA1c in both subjects prescribed metformin monotherapy, as well as insulin-containing regimen. CONCLUSION: Youth with T2D exhibit distinct HbA1c profiles. Patients with diagnostic HbA1c >8.5% are at high risk for glycemic failure, irrespective of short-term improvement in HbA1c. Weight management has the potential to improve short-term HbA1c outcome in youth with T2D. Additional studies are needed to determine the role of medication adherence on glycemic control.

Nur77 deletion impairs muscle growth during developmental myogenesis and muscle regeneration in mice.

Muscle atrophy is a prevalent condition in illness and aging. Identifying novel pathways that control muscle mass may lead to therapeutic advancement. We previously identified Nur77 as a transcriptional regulator of glycolysis in skeletal muscle. More recently, we showed that Nur77 expression also controls myofiber size in mice. It was unknown, however, whether Nur77's regulation of muscle size begins during developmental myogenesis or only in adulthood. To determine the importance of Nur77 throughout muscle growth, we examined myofiber size at E18.5, 3 weeks postnatal age, and in young adult mice. Using the global Nur77-/- mice, we showed that Nur77 deficiency reduced myofiber size as early as E18.5. The reduction in myofiber size became more pronounced by 3 weeks of age. We observed comparable reduction in myofiber size in young myofiber-specific Nur77-knockout mice. These findings suggest that Nur77's effect on muscle growth is intrinsic to its expression in differentiating myofibers, and not dependent on its expression in myogenic stem cells. To determine the importance of Nur77 expression in muscle accretion in mature mice, we generated an inducible-, muscle-specific, Nur77-deficient mouse model. We demonstrated that tamoxifen-induced deletion of Nur77 in 3-month-old mice reduced myofiber size. This change was accompanied by increased activity of Smad2 and FoxO3, two negative regulators of muscle mass. The role of Nur77 in muscle growth was further elaborated in the cardiotoxin-induced muscle regeneration model. Compared to wildtype mice, regenerated myofibers were smaller in Nur77-/- mice. However, when normalized to saline-injected muscle, the recovery of sarcoplasmic area was comparable between Nur77-/- and wildtype mice. These findings suggest that Nur77 deficiency compromises myofiber growth, but not the regenerative capacity of myogenic progenitor cells. Collectively, the findings presented here demonstrate Nur77 as an important regulator of muscle growth both during prenatal and postnatal myogenesis.

The orphan nuclear receptor Nur77 is a determinant of myofiber size and muscle mass in mice.

We previously showed that the orphan nuclear receptor Nur77 (Nr4a1) plays an important role in the regulation of glucose homeostasis and oxidative metabolism in skeletal muscle. Here, we show using both gain- and loss-of-function models that Nur77 is also a regulator of muscle growth in mice. Transgenic expression of Nur77 in skeletal muscle in mice led to increases in myofiber size. Conversely, mice with global or muscle-specific deficiency in Nur77 exhibited reduced muscle mass and myofiber size. In contrast to Nur77 deficiency, deletion of the highly related nuclear receptor NOR1 (Nr4a3) had minimal effect on muscle mass and myofiber size. We further show that Nur77 mediates its effects on muscle size by orchestrating transcriptional programs that favor muscle growth, including the induction of insulin-like growth factor 1 (IGF1), as well as concomitant downregulation of growth-inhibitory genes, including myostatin, Fbxo32 (MAFbx), and Trim63 (MuRF1). Nur77-mediated increase in IGF1 led to activation of the Akt-mTOR-S6K cascade and the inhibition of FoxO3a activity. The dependence of Nur77 on IGF1 was recapitulated in primary myoblasts, establishing this as a cell-autonomous effect. Collectively, our findings identify Nur77 as a novel regulator of myofiber size and a potential transcriptional link between cellular metabolism and muscle growth.

Nkx6.1 regulates islet ß-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.

Loss of functional ß-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces ß-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates ß-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3) orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated ß-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in ß-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F transcription factor 1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including ubiquitin-conjugating enzyme E2C, resulting in degradation of the cell cycle inhibitor p21. These studies identify a unique bipartite pathway for activation of ß-cell proliferation, suggesting several unique targets for expansion of functional ß-cell mass.

The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis.

The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Here we characterize a novel LXR target gene, the lipopolysaccharide binding protein (LBP) gene. Surprisingly, the ability of LXRs to control LBP expression is cell-type specific, occurring in macrophages but not liver. Treatment of macrophages with oxysterols or loading with modified LDL induces LBP in an LXR-dependent manner, suggesting a potential role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies. After 18 weeks of Western diet feeding, atherosclerotic lesion burden was assessed revealing markedly smaller lesions in the LBP(-/-) recipients. Furthermore, loss of bone marrow LBP expression increased apoptosis in atherosclerotic lesions as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Supporting in vitro studies with isolated macrophages showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. The LBP gene is a macrophage-specific LXR target that promotes foam cell survival and atherogenesis.

Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation.

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.

Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice.

The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolism pathways. We previously demonstrated that NR4A nuclear receptors are highly induced in macrophages in response to inflammatory stimuli and modulate the expression of genes linked to inflammation in vitro. Here we used mouse genetic models to assess the impact of NR4A expression on atherosclerosis development and macrophage polarization. Transplantation of wild-type, Nur77⁻/⁻, or Nor1⁻/⁻ null hematopoetic precursors into LDL receptor (LDLR)⁻/⁻ recipient mice led to comparable development of atherosclerotic lesions after high-cholesterol diet. We also observed comparable induction of genes linked to M1 and M2 responses in wild-type and Nur77-null macrophages in response to lipopolysaccharides and interleukin (IL)-4, respectively. In contrast, activation of the nuclear receptor liver X receptor (LXR) strongly suppressed M1 responses, and ablation of signal transductor and activator of transcription 6 (STAT6) strongly suppressed M2 responses. Recent studies have suggested that alterations in levels of Ly6C(lo) monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6C(lo) monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice.

Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization.

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previously showed that Nur77, an orphan nuclear receptor of the NR4A family, regulates the expression of genes linked to glucose utilization. Here we demonstrate that expression of Nur77 in skeletal muscle also enhances mitochondrial function. We generated MCK-Nur77 transgenic mice that express wild-type Nur77 specifically in skeletal muscle. Nur77-overexpressing muscle had increased abundance of oxidative muscle fibers and mitochondrial DNA content. Transgenic muscle also exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Metabolomic analysis confirmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profile of fasting. Nur77 expression also improved the intrinsic respiratory capacity of isolated mitochondria, likely due to the increased abundance of complex I of the electron transport chain. These changes in mitochondrial metabolism translated to improved muscle contractile function ex vivo and improved cold tolerance in vivo. Our studies outline a novel role for Nur77 in the regulation of oxidative metabolism and mitochondrial activity in skeletal muscle.