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1.
Pediatrics ; 151(1)2023 01 01.
Article in English | MEDLINE | ID: mdl-36827521

ABSTRACT

ABSTRACT: Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.


Subject(s)
Congenital Hypothyroidism , Infant, Newborn , Infant , Humans , Child , Child, Preschool , Thyroxine , Thyrotropin , Thyroid Function Tests , Neonatal Screening
2.
Pediatrics ; 151(1)2023 01 01.
Article in English | MEDLINE | ID: mdl-36827523

ABSTRACT

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.


Subject(s)
Congenital Hypothyroidism , Infant, Newborn , Infant , Humans , Child , Child, Preschool , Thyroxine , Thyrotropin , Thyroid Function Tests , Neonatal Screening
3.
Life Sci ; 315: 121385, 2023 Feb 15.
Article in English | MEDLINE | ID: mdl-36634865

ABSTRACT

Cadmium is a hazardous metal with multiple organ toxicity that causes great harm to human health. Cadmium enters the human body through occupational exposure, diet, drinking water, breathing, and smoking. Cadmium accumulation in the human body is associated with increased risk of developing obesity, cardiovascular disease, diabetes, and metabolic syndrome (MetS). Cadmium uptake is enhanced during pregnancy and can cross the placenta affecting placental development and function. Subsequently, cadmium can pass to fetus, gathering in multiple organs such as the liver and pancreas. Early-life cadmium exposure can induce hepatic oxidative stress and pancreatic ß-cell dysfunction, resulting in insulin resistance and glucose metabolic dyshomeostasis in the offspring. Prenatal exposure to cadmium is also associated with increasing epigenetic effects on the offspring's multi-organ functions. However, whether and how maternal exposure to low-dose cadmium impacts the risks of developing type 2 diabetes (T2D) in the young and/or adult offspring remains unclear. This review collected available data to address the current evidence for the potential role of cadmium exposure, leading to insulin resistance and the development of T2D in offspring. However, this review reveals that underlying mechanisms linking prenatal cadmium exposure during pregnancy with T2D in offspring remain to be adequately investigated.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Metabolic Syndrome , Prenatal Exposure Delayed Effects , Adult , Pregnancy , Female , Humans , Metabolic Syndrome/chemically induced , Metabolic Syndrome/complications , Maternal Exposure , Cadmium/toxicity , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/complications , Placenta/metabolism , Prenatal Exposure Delayed Effects/metabolism
4.
Article in English | MEDLINE | ID: mdl-36674378

ABSTRACT

Studies would indicate a reduction in hemoglobin A1c levels following moderate and/or vigorous physical activity (PA) for people managing diabetes. However, prior investigations rarely looked at glucose variability in an adolescent population. PURPOSE: The purpose of this investigation was to test the relationship between physical activity intensity levels and glucose variability in a sample of adolescents with type 1 diabetes mellitus, and if the amount of time accumulated for each intensity level is predictive of changes in glucose variability. METHODS: Glucose variability was determined using continuous glucose monitor data and physical activity intensity time was retrieved through Fitabase®. Both glucose and physical activity data were collected over a two-week timeframe. Data analysis was completed using Pearson's correlation and a simple linear regression with a p-value of 0.05 to determine significance. RESULTS: A significant inverse relationship was observed (p = 0.04) between glucose variability and average minutes of daily moderate-intensity activity (r = -0.59), as well as moderate and vigorous physical activity (MVPA) combined (r = -0.86; p = 0.03). A simple linear regression indicated that only MVPA was a significant predictor of glucose variability (ß = -0.12; 95% CI: -0.23--0.01, p = 0.03). CONCLUSION: These data demonstrated that the total amount of daily physical activity is important when properly managing type 1 diabetes mellitus, but time spent in MVPA over two weeks may have an inverse relationship with glucose variability in children and adolescents over a span of two weeks.


Subject(s)
Diabetes Mellitus, Type 1 , Humans , Adolescent , Child , Glucose , Exercise , Blood Glucose/analysis , Glycated Hemoglobin
5.
J Diabetes Sci Technol ; 17(4): 976-987, 2023 Jul.
Article in English | MEDLINE | ID: mdl-35343269

ABSTRACT

OBJECTIVES: Achieving optimal glycemic outcomes in young children with type 1 diabetes (T1D) is challenging. This study examined the durability of continuous glucose monitoring (CGM) coupled with a family behavioral intervention (FBI) to improve glycemia. STUDY DESIGN: This one-year study included an initial 26-week randomized controlled trial of CGM with FBI (CGM+FBI) and CGM alone (Standard-CGM) compared with blood glucose monitoring (BGM), followed by a 26-week extension phase wherein the BGM Group received the CGM+FBI (BGM-Crossover) and both original CGM groups continued this technology. RESULTS: Time in range (70-180 mg/dL) did not improve with CGM use (CGM+FBI: baseline 37%, 52 weeks 41%; Standard-CGM: baseline 41%, 52 weeks 44%; BGM-Crossover: 26 weeks 38%, 52 weeks 40%). All three groups sustained decreases in hypoglycemia (<70 mg/dL) with CGM use (CGM+FBI: baseline 3.4%, 52 weeks 2.0%; Standard-CGM: baseline 4.1%, 52 weeks 2.1%; BGM-Crossover: 26 weeks 4.5%, 52 weeks 1.7%, P-values <.001). Hemoglobin A1c was unchanged with CGM use (CGM+FBI: baseline 8.3%, 52 weeks 8.2%; Standard-CGM: baseline 8.2%, 52 weeks 8.0%; BGM-Crossover: 26 weeks 8.1%, 52 weeks 8.3%). Sensor use remained high (52-week study visit: CGM+FBI 91%, Standard-CGM 92%, BGM-Crossover 88%). CONCLUSION: Over 12 months young children with T1D using newer CGM technology sustained reductions in hypoglycemia and, in contrast to prior studies, persistently wore CGM. However, pervasive hyperglycemia remained unmitigated. This indicates an urgent need for further advances in diabetes technology, behavioral support, and diabetes management educational approaches to optimize glycemia in young children.


Subject(s)
Diabetes Mellitus, Type 1 , Hyperglycemia , Hypoglycemia , Humans , Child , Child, Preschool , Blood Glucose , Diabetes Mellitus, Type 1/drug therapy , Blood Glucose Self-Monitoring
6.
Antioxid Redox Signal ; 38(10-12): 803-823, 2023 04.
Article in English | MEDLINE | ID: mdl-36424825

ABSTRACT

Significance: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals, and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed. Recent Advances: Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized. Critical Issues: Several epidemiological studies have revealed the significant deleterious effects of antimony on the cardiovascular system in the absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis. Future Directions: More direct evidence from preclinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs. Antioxid. Redox Signal. 38, 803-823.


Subject(s)
Cardiovascular Diseases , Cardiovascular System , Humans , Aged , Antimony , Epigenesis, Genetic , Metals , Oxidation-Reduction
7.
Redox Biol ; 56: 102449, 2022 10.
Article in English | MEDLINE | ID: mdl-36063728

ABSTRACT

Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mitochondrial fragmentation and EPC dysfunction. In a therapeutic approach, supplementation of an Nrf2 activator sulforaphane enhanced angiogenesis and blood perfusion recovery in db/db mice with hind limb ischemia. Collectively, these findings indicate that Nrf2 is a potential therapeutic target for improving diabetic EPC function. Thus, elevating Nrf2 expression enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia likely via transcriptional upregulating IDH2 expression and improving mitochondrial function of diabetic EPCs.


Subject(s)
Diabetes Mellitus , Endothelial Progenitor Cells , Animals , Humans , Mice , Diabetes Mellitus/metabolism , Endothelial Progenitor Cells/metabolism , Hindlimb/metabolism , Ischemia/metabolism , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Mitochondrial Dynamics/genetics , Neovascularization, Physiologic/genetics , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , RNA , Up-Regulation
8.
Article in English | MEDLINE | ID: mdl-35564936

ABSTRACT

Assessing maximal oxygen uptake (VO2 max) is generally considered safe when performed properly for most adolescents; however, for adolescents with type 1 diabetes mellitus (T1DM), monitoring glucose levels before and after exercise is critical to maintaining euglycemic ranges. Limited guidance exists for glucose level recommendations for the pediatric population; therefore, the purpose of this retrospective clinical chart review study was to determine the effects of VO2 max testing on blood glucose levels for adolescents with T1DM. A total of 22 adolescents (mean age = 15.6 ± 1.8 years; male = 13, 59.1%) with a diagnosis of T1DM participated in a Bruce protocol for VO2 max from January 2019 through February 2020. A statistically significant reduction in glucose levels between pretest (<30 min, mean = 191.1 mg/dL ± 61.2) and post-test VO2 max (<5 min, mean = 166.7 mg/dL ± 57.9); t(21) = 2.3, p < 0.05) was detected. The results from this current study can help guide health and fitness professionals in formulating glycemic management strategies in preparatory activities prior to exercise testing and during exercise testing.


Subject(s)
Diabetes Mellitus, Type 1 , Adolescent , Blood Glucose , Child , Exercise Test/methods , Humans , Male , Oxygen , Oxygen Consumption , Retrospective Studies
9.
Biochim Biophys Acta Mol Basis Dis ; 1868(8): 166414, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35447340

ABSTRACT

Elderly adults are at higher risk for developing diabetic complications including diabetic nephropathy (DN), contributing to excess morbidity and mortality in elderly individuals. A non-mitogenic variant of fibroblast growth factor 1 (FGF1ΔHBS) was demonstrated to prevent DN in an early-stage (2-month-old) type 2 diabetes (T2D) mouse model. The present study aimed to investigate the potential therapeutic effects of FGF1ΔHBS against the progression of renal dysfunction in a late-stage T2D mouse model with established DN. Nine-month-old db/db mice were administered FGF1ΔHBS every other day for 3 months. db/db mice at 12-month-old without FGF1ΔHBS treatment exhibited high blood glucose level and elevated urine albumin-to-creatinine ratio. FGF1ΔHBS treatment effectively reversed hyperglycemia, delayed the development of renal dysfunction, and reduced kidney size and weight. Furthermore, FGF1ΔHBS treatment significantly prevented the progression of renal morphologic impairment. FGF1ΔHBS treatment demonstrated anti-inflammatory and anti-fibrotic effects, with significantly decreased protein levels of key pro-inflammatory cytokines and pro-fibrotic factors in kidney. Moreover, FGF1ΔHBS treatment greatly decreased apoptosis of renal tubular cells, accompanied by significant downregulation of the proapoptotic protein and upregulation of the antiapoptotic protein and peroxisome proliferator-activated receptor α (PPARα) expression in kidney. Mechanistically, FGF1ΔHBS treatment directly protected mouse proximal tubule cells against palmitate-induced apoptosis, which was abolished by PPARα inhibition. In conclusion, this study demonstrated that FGF1ΔHBS delays the progression of renal dysfunction likely through activating PPARα to prevent renal tubule cell death in late-stage T2D, exhibiting a promising translational potential in treating DN in elderly T2D individuals by ameliorating renal inflammation, fibrosis and apoptosis.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Fibroblast Growth Factor 1 , Animals , Apoptosis , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Disease Models, Animal , Fibroblast Growth Factor 1/genetics , Fibroblast Growth Factor 1/therapeutic use , Fibrosis , Humans , Inflammation/drug therapy , Inflammation/metabolism , Mice , PPAR alpha/metabolism
10.
Article in English | MEDLINE | ID: mdl-34682355

ABSTRACT

Current technology commonly utilized in diabetes care includes continuous glucose monitors (CGMs) and insulin pumps. One often overlooked critical component to the human glucose response is daily physical activity habits. Consumer-based activity monitors may be a valid way for clinics to collect physical activity data, but whether or not children with type 1 diabetes (T1D) would wear them or use the associated mobile application is unknown. Therefore, the purpose of this study was to test the feasibility of implementing a consumer-based accelerometer directly into ongoing care for adolescents managing T1D. METHODS: Adolescents with T1D were invited to participate in this study and instructed to wear a mobile physical activity monitor while also completing a diet log for a minimum of 3 days. Clinical compliance was defined as the number of participants who were compliant with all measures while also having adequate glucose recordings using either a CGM, insulin pump, or on the diet log. Feasibility was defined as >50% of the total sample reaching clinical compliance. RESULTS: A total of 57 children and teenagers between the ages of 7 and 19 agreed to participate in this study and were included in the final analysis. Chi-square results indicated significant compliance for activity tracking (p < 0.001), diet logs (p = 0.04), and overall clinical compliance (p = 0.04). CONCLUSION: More than half the children in this study were compliant for both activity monitoring and diet logs. This indicates that it is feasible for children with T1D to wear a consumer-based activity monitor while also recording their diet for a minimum of three days.


Subject(s)
Diabetes Mellitus, Type 1 , Adolescent , Adult , Blood Glucose , Blood Glucose Self-Monitoring , Child , Diabetes Mellitus, Type 1/drug therapy , Feasibility Studies , Humans , Insulin Infusion Systems , Young Adult
11.
Article in English | MEDLINE | ID: mdl-34299946

ABSTRACT

PURPOSE: To determine associations between physical activity (PA) and sport participation on HbA1c levels in children with type 1 diabetes (T1D). METHOD: Pediatric patients with T1D were invited to complete a PA and sport participation survey. Data were linked to their medical records for demographic characteristics, diabetes treatment and monitoring plans, and HbA1c levels. RESULTS: Participants consisted of 71 females and 81 males, were 13 ± 3 years old with an average HbA1c level of 8.75 ± 1.81. Children accumulating 60 min of activity 3 days or more a week had significantly lower HbA1c compared to those who accumulated less than 3 days (p < 0.01) of 60 min of activity. However, there was no significant difference in HbA1c values based on sport participation groups. A multiple linear regression model indicated that PA, race, age, duration of diagnosis, and CGM use all significantly predicted HbA1c (p < 0.05). CONCLUSION: This study demonstrated the significant relationship between daily PA and HbA1c. Those in this sample presented with lower HbA1c values even if accumulating less than the recommended number of days of activity. Further, it was shown that sport participation alone may not be adequate enough to impact HbA1c in a similar manner.


Subject(s)
Diabetes Mellitus, Type 1 , Sports , Adolescent , Child , Diabetes Mellitus, Type 1/epidemiology , Exercise , Female , Glycated Hemoglobin , Humans , Male , Surveys and Questionnaires
12.
Hepatology ; 73(6): 2206-2222, 2021 06.
Article in English | MEDLINE | ID: mdl-32965675

ABSTRACT

BACKGROUND AND AIMS: Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1△HBS ) against NAFLD. APPROACH AND RESULTS: FGF1△HBS administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased. FGF1△HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1△HBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1△HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1△HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1△HBS benefits on both oxidative stress and lipid metabolism that were FGF receptor (FGFR) 4 dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1△HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1△HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. CONCLUSIONS: These findings indicate that FGF1△HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Fibroblast Growth Factor 1/pharmacology , NF-E2-Related Factor 2/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Receptor, Fibroblast Growth Factor, Type 4/metabolism , AMP-Activated Protein Kinases/genetics , Animals , Diabetes Mellitus, Experimental , Diet, High-Fat , Hep G2 Cells , Humans , Lipid Metabolism/drug effects , Liver , Male , Mice , Mice, Knockout , Mice, Obese , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Oxidative Stress , Palmitates/pharmacology , Receptor, Fibroblast Growth Factor, Type 4/genetics
13.
Diabetes ; 69(8): 1779-1792, 2020 08.
Article in English | MEDLINE | ID: mdl-32404351

ABSTRACT

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet- and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in db/db mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from patients with diabetes exhibited decreased MT expression, increased cell apoptosis, and impaired tube formation, while cultured JTMT EPCs had enhanced cell survival, migration, and tube formation in hypoxic/hyperglycemic conditions compared with WT EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT's pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.


Subject(s)
Chemokine CXCL12/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/prevention & control , Endothelial Progenitor Cells/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Metallothionein/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/prevention & control , Animals , Blotting, Western , Cell Survival/genetics , Cell Survival/physiology , Chemokine CXCL12/genetics , Enzyme-Linked Immunosorbent Assay , Female , Hindlimb/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Ischemia/genetics , Ischemia/metabolism , Leukocytes, Mononuclear/metabolism , Male , Metallothionein/genetics , Mice , Oxidative Stress/genetics , Oxidative Stress/physiology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
14.
Nat Rev Cardiol ; 17(9): 585-607, 2020 09.
Article in English | MEDLINE | ID: mdl-32080423

ABSTRACT

The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.


Subject(s)
Diabetic Cardiomyopathies , Animals , Cardiotonic Agents/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Heart Failure , Humans
15.
Clin Pediatr (Phila) ; 59(4-5): 445-449, 2020 05.
Article in English | MEDLINE | ID: mdl-32066264

ABSTRACT

Adolescents with diabetes are at increased risk for depression and anxiety, which when untreated negatively affects diabetes control. During a 6-month period, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) screening tool was utilized. Those with a positive screen then completed the Patient Health Questionnaire for Adolescents (PHQ-A) and the Generalized Anxiety Disorder 7-item (GAD-7) scale. In this article, we report on the correlations in outcomes between the PHQ-4 and the PHQ-A and GAD-7 and its clinical utility for determining the need for standard versus acute behavioral health care. Over 6 months, 77 patients aged 10 to 18 years screened positive on the PHQ-4. Thirty-two patients had positive screening with the PHQ-A and/or the GAD-7. Thoughts of self-harm were reported by 13 (40%), with 1 experiencing current/active symptoms. The PHQ-4 as a screening tool was able to identify adolescents with symptoms of depression and/or anxiety who would benefit from further evaluation by a behavioral health provider.


Subject(s)
Anxiety Disorders/diagnosis , Depressive Disorder/diagnosis , Diabetes Mellitus, Type 1 , Mass Screening , Adolescent , Child , Female , Humans , Psychiatric Status Rating Scales
16.
Trends Mol Med ; 26(2): 185-200, 2020 02.
Article in English | MEDLINE | ID: mdl-31679988

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.


Subject(s)
NF-E2-Related Factor 2/metabolism , Stem Cells/metabolism , Stem Cells/physiology , Animals , Cell Differentiation/physiology , Cell Proliferation/physiology , Homeostasis/physiology , Humans , Oxidation-Reduction
18.
Diabetes Technol Ther ; 21(7): 406-408, 2019 07.
Article in English | MEDLINE | ID: mdl-31265348

ABSTRACT

For someone managing type 1 diabetes, understanding their body's glucose response to physical activity could aid in effectively addressing nocturnal hypoglycemia. The purpose of this investigation was to examine the acute temporal associations between blood glucose and measures of moderate-vigorous physical activity (MVPA) through an accelerometer. Ten adolescent athletes with type 1 diabetes wore an accelerometer and continuous glucose monitor (CGM) consecutively for a minimum of 2 weeks. Physical activity was analyzed according to intensity indicating time spent in light, moderate, and vigorous intensities. Hypoglycemic episodes were defined as two successive CGM readings <70 mg/dL, at 5-min intervals, with an episode ending with at least two CGM readings >70 mg/dL. Incidence of nocturnal hypoglycemia occurred during 29% of the nights measured with an average duration of 52.33 ± 41.04 min. When combining total minutes of moderate and vigorous intensities a significant difference was observed between combined MVPA and number of nocturnal hypoglycemic episodes (62.92 min vs. 49 episodes, P = 0.02). Moderate intensity activity alone was not significant in predicting hypoglycemic events or duration. Vigorous intensity physical activity was a significant predictor of nocturnal hypoglycemia after controlling for sedentary and light intensity minutes, age, and gender (ß = 0.21, P = 0.01) with an average time of 26 min of vigorous intensity. Engaging in vigorous intensity physical activity increased the risk of prolonged nocturnal hypoglycemia in adolescent athletes with type 1 diabetes. Incorporating accelerometers into patient care could prove beneficial when making further recommendations for athletes.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Exercise/physiology , Hypoglycemia/etiology , Adolescent , Athletes , Blood Glucose Self-Monitoring , Circadian Rhythm , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/physiopathology , Female , Humans , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Insulin Infusion Systems , Linear Models , Male , Physical Exertion/physiology , Risk Assessment , Risk Factors , Time Factors
19.
Horm Res Paediatr ; 91(4): 241-251, 2019.
Article in English | MEDLINE | ID: mdl-31185471

ABSTRACT

BACKGROUND/OBJECTIVES: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. METHODS: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. RESULTS: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients. CONCLUSIONS: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.


Subject(s)
Body Height/drug effects , Dwarfism, Pituitary/drug therapy , Growth Disorders/drug therapy , Human Growth Hormone/administration & dosage , Adolescent , Child , Dwarfism, Pituitary/physiopathology , Female , Growth Disorders/physiopathology , Humans , Male , Prospective Studies
20.
Int J Neonatal Screen ; 4(2): 16, 2018.
Article in English | MEDLINE | ID: mdl-29862374

ABSTRACT

Newborn screening (NBS) identifies infants with rare conditions to prevent death or the onset of irreversible morbidities. Conditions on the Health and Human Services Secretary's Recommended Uniform Screening Panel have been adopted by most state NBS programs, providing a consistent approach for identification of affected newborns across the United States. Screen-positive newborns are identified and referred for confirmatory diagnosis and follow-up. The designation of a clinically significant phenotype precursor to a clinical diagnosis may vary between clinical specialists, resulting in diagnostic variation. Determination of disease burden and birth prevalence of the screened conditions by public health tracking is made challenging by these variations. This report describes the development of a core group of new case definitions, along with implications, plans for their use, and links to the definitions that were developed by panels of clinical experts. These definitions have been developed through an iterative process and are piloted in NBS programs. Consensus public health surveillance case definitions for newborn screened disorders will allow for consistent categorization and tracking of short- and long-term follow-up of identified newborns at the local, regional, and national levels.

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