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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.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.Several epidemiological studies have revealed significant deleterious effects of antimony on the cardiovascular system in 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.More direct evidence from pre-clinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs.

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 upregulation of IDH2 expression and improving mitochondrial function of diabetic EPCs.

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.

Objectives: Individuals living with type 1 diabetes (T1D) are encouraged to participate in physical activity (PA) . It is vital that technology used to manage diabetes, such as a continuous glucose monitor (CGM) , provides reliable results during and after exercise. Currently, the Dexcom G6 CGM is approved to be inserted on the abdomen or upper buttock. The following study compared various location sites to assess reliability of those differing locations during times of moderate intensity PA. Methods: Thirty adolescents and young adults (age 13-20 years, µ=14.3 years) with T1D performed moderate intensity PA on a treadmill. Intensity was determined by Karvonen heart rate reserve formula. The PA consisted of walking/jogging for 40 minutes, with a 10-minute break occurring at the halfway point. Dexcom G6 CGM and glucometer measurements were collected and analyzed every minutes during and after exercise. Dexcom locations included arm, abdomen, thigh, and upper buttock. Analysis of accuracy metrics included mean absolute relative difference (MARD) and clinical reliability was assessed by Clarke Error Grid Analysis. Results: Analysis of CGM location sites revealed that CGMs placed on the arm and buttocks, statistically, had a worse MARD in comparison to abdomen. The CGM being placed on the buttocks increased the MARD by a ratio of 2.15 when compared to the abdomen. Additionally, we found that individuals who wore the CGM on their buttocks had an increased risk of having glucoses in Zone D of the Clarke Error Grid in comparison to those wearing it on the abdomen. Conclusions: The results suggest that CGM location does matter during and after exercise, with the abdomen providing the most reliable results. Furthermore, we found that CGM placement on the buttocks may lead to failure to detect dysglycemia during exercise. We hypothesize this may be due to interstitial fluid changes in actively exercising muscles which alter the accuracy during exercise. However, additional research in this area is needed to support this theory. Disclosure B.J.Thrasher: None. R.J.Dyess: None. T.E.Mckay: None. K.A.Wintergerst: None.

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 (

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.

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.

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 (FGF1(ΔHBS)) 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 FGF1(ΔHBS) against the progression of renal dysfunction in a late-stage T2D mouse model with established DN. Nine-month-old db/db mice were administered FGF1(ΔHBS) every other day for 3 months. db/db mice at 12-month-old without FGF1(ΔHBS) treatment exhibited high blood glucose level and elevated urine albumin-to-creatinine ratio. FGF1(ΔHBS) treatment effectively reversed hyperglycemia, delayed the development of renal dysfunction, and reduced kidney size and weight. Furthermore, FGF1(ΔHBS) treatment significantly prevented the progression of renal morphologic impairment. FGF1(ΔHBS) 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, FGF1(ΔHBS) 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, FGF1(ΔHBS) treatment directly protected mouse proximal tubule cells against palmitate-induced apoptosis, which was abolished by PPARα inhibition. In conclusion, this study demonstrated that FGF1(ΔHBS) 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.

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 (β = −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.

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.

In this study, we present the case of a 5-year-old female who presented for evaluation of dehydration with labs that revealed significant hypernatremia concerning for diabetes insipidus (DI). Further evaluation revealed that she had underlying chronic malnutrition. Her diagnostic work up for DI produced some evidence consistent with DI while other data indicated otherwise, bringing up the possibility of partial DI. She was ultimately diagnosed with sporadic vasopressin release secondary to her chronic malnutrition. This case illustrates another effect chronic malnutrition can have on pediatric patients along with the importance of a broad differential for patients with severe hypernatremia.

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 &gt, 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 &lt, 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.

Glucose level recommendations have yet to be established for adolescents diagnosed with type 1 diabetes (T1D) who participate in VO2 max exercise testing for clinical or strength and conditioning purposes. Although a decrease in glucose may be expected throughout, and immediately after exercise testing, a minimal pre-test glucose setpoint has not been established to reduce the risk of hypoglycemia. Retrospective medical and sports medicine chart reviews were conducted of clinical pediatric sports medicine and physical activity program patients with a diagnosis of T1D (N = 24; mean age = 15.5 ± 1.7 years; male = 14, 58.3%) who participated in a modified Bruce protocol for maximal oxygen uptake (VO2 max). The majority of the participants identified as non-Hispanic (n = 22, 91.7%) and white (n = 19, 79.2%). Their average body mass index (BMI) based on age and sex was in the 66th percentile ± 19.5 and their average hemoglobin A1c (HbA1c) was 8.8% ± 1.8. Almost 2/3 of the participants (n = 15, 62.5%) wore a continuous glucose monitor. Their average VO2 max peak was 43.7 ml/kg/min ± 7.1. A paired-samples t-test was employed to detect a statistically significant reduction in glucose levels between pretest (< 30 minutes, mean = 191.1 mg/dl ± 61.2) and post-test VO2 max (< 5 minutes, mean = 166.7 mg/dl ± 57.9); t(21) = 2.3, p Disclosure K. King: None. B. J. Thrasher: None. T. E. Mckay: None. K. A. Wintergerst: None.

OBJECTIVE This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to RESEARCH DESIGN AND METHODS This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to RESULTS Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level CONCLUSIONS CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.

Fibroblast growth factor 1 (FGF1) demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic (T2D) and obese mice by uncertain mechanism. This study investigated the therapeutic activity and mechanism of a non-mitagenic FGF1 variant (FGF1ΔHBS) against NAFLD. FGF1ΔHBS administration was effective in 9-month old db/db mice with established NAFLD; liver weight, lipid deposition and inflammation declined and liver function improved. FGF1ΔHBS reduced oxidative stress by nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1ΔHBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of AMP-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 FGF1ΔHBS. In palmitate treated hepatic cells, siRNA knockdown of Nrf2 abolished only FGF1ΔHBS anti-oxidative actions but not lipid metabolism improvement. In contrast, AMPK inhibition by pharmacological agents or siRNA abolished both FGF1ΔHBS benefits on oxidative stress and lipid metabolism that was FGF receptor 4 (FGFR4) dependent. Further support of these in vitro findings is that liver specific AMPK knockout abolished therapeutic effects of FGF1ΔHBS against high-fat-high-sugar diet-induced hepatic steatosis. These findings indicate that FGF1ΔHBS is effective in late stage NAFLD and acts by activation of AMPK via hepatocyte FGFR4. Disclosure Q. Lin: None. G. Cai: None. Z. Liu: None. J. Li: None. J. Li: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Li: None. Y. Tan: None. Funding American Diabetes Association (1-13-JF-53 to Y.T.), (1-18-IBS-082 to L.C.)

Use of continuous glucose monitors (CGM) is associated with lower HbA1c, with the best effect seen for those using the sensor at least 6 of 7 days. Prior studies have shown youth with type 1 diabetes to have poor adherence to CGM use. We aim to evaluate CGM adherence during typical use in our patients with type 1 diabetes. In this retrospective chart review, the medical records for all patients treated with type 1 diabetes mellitus at the University of Louisville Physicians Pediatric Endocrinology outpatient clinic who initiated CGM use between 2017-2019 were reviewed to determine CGM utilization. CGM use data for patients, ages 2-18 years, was extracted from downloads performed at each clinic visit. Data available for review was 14 or 30 days, determined by receiver type. During the 2-year study period, CGM was initiated for 253 youth mean age 12 years (SD 3.78). Patients were followed for a mean of 13.4 months (SD 6.7), encompassing 784 follow-up visits (3.1 visits per patient, SD 1.94). Within this time, 64 patients (25%) discontinued use, with a mean of 4.7 months of use (SD 5.4), including 24 patients (9.5%) who received the device and never used it. Of the 190 who initiated CGM use, only 142 (56%) reported current CGM use at each follow-up visit during the study period. Continuous use was associated with younger age at initiation of CGM (p=0.001), shorter duration of diabetes (p=0.005), lower HbA1c (p For youth initiating CGM use during a 2-year period, we found a low rate of adherence to CGM use. However, the majority of those with consistent use wore the sensor at least 6 of 7 days, as recommended for effective use. Factors associated with continuous use included earlier implementation and prior professional CGM trial. Disclosure E.L. Montgomery: None. K.S. Jawad: None. S. Eubanks: None. K.A. Wintergerst: None. H.M. Rush: None. S. Watson: None.

Diabetes-induced oxidative stress contributes to endothelial progenitor cells (EPCs) dysfunction and impairs endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial-specific MT transgenic (JTMT) mice with high fat diet and streptozocin (HFD/STZ)-induced diabetes. Compared with littermate wild type (WT) diabetic mice, JTMT 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 function: mobilization and infiltration in JTMT mice; and, enhanced capillary EPC incorporation in db/db mice. Further, cultured JTMT-EPCs had enhanced cell survival, migration, and capillary tube formation in hypoxia/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 MT’s anti-oxidant action. These results indicate that endothelial-specific MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC functions though upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress. Disclosure K. Wang: None. X. Dai: None. J. Chen: None. F. Shen: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Tan: None. Funding American Diabetes Association (1-11-BS-017, 1-15-BS-018 to L.C.)

Studies have consistently shown improvements in daily glucose and hemoglobin A1c (HbA1c) for both type 1 and type 2 diabetes with increased moderate and/or vigorous physical activity (PA). A limitation with prior investigations is that they only tested this relationship in adult populations and seldom looked at glucose variability (GV). Whether or not similar results would be observed in a pediatric population with type 1 diabetes (T1D) is unknown. Purpose: The purpose of this investigation was to test the relationship between GV and intensity of PA, and if duration of activity is predictive of changes in GV in a sample of teenagers with T1D. Methods: Data for this investigation were used from an ongoing study at a local pediatric Diabetes Center. Participants who wore a continuous glucose monitor (CGM) and Fitbit consecutively for a period of two weeks or more were included in the data analysis. GV was determined using 2-weeks of CGM data and PA intensity time was retrieved through Fitabase. Pearson’s correlation and a simple linear regression were used for final analysis with a p-value of 0.05 to determine significance. Results: Minutes of daily moderate intensity activity had a significant inverse relationship (r= -0.59; p = 0.04) with GV, whereas moderate and vigorous PA (MVPA) combined showed a stronger inverse relationship (r= -0.86; p = 0.03). When placed in a simple linear regression only MVPA significantly predicted changes in glucose variability (β= -0.12, p=0.03). Conclusion: These data show that not only is duration of PA an important factor when it comes to managing diabetes, but that more attention should be paid to the time spent at various intensity levels. Although more research is needed to determine feasibility it could be of great benefit for individuals managing diabetes to incorporate an activity monitor into their daily routine to share with their diabetes care team to better understand how PA levels impact their blood glucose. Disclosure J.R. Jaggers: None. K. King: None. T.E. McKay: None. R.J. Dyess: None. K.A. Wintergerst: None.

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 diabetic patients exhibited decreased MT expression, increased cell apoptosis and impaired tube formation; while cultured JTMT-EPCs had enhanced cell survival, migration, and tube formation in hypoxia/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 MT’s anti-oxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC functions most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

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.

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 (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.

Aims Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice. Methods and results Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei. In vitro up-regulation of Nrf2 by SFN was abolished and nuclear Fyn accumulation was increased when cardiac cells were exposed to a PI3K inhibitor or GSK-3β-specific activator. Conclusion These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3β/Fyn-mediated Nrf2 activation., Graphical abstract fx1, Highlights • Sulforaphane (SFN) can prevent angiotensin II (AngII) -induced cardiomyopathy. • SFN prevents AngII-induced cardiomyopathy via up-regulating and activating Nrf2. • Cardiac overexpression of Nrf2 prevents Ang II-induced cardiomyopathy. • Up-regulation and activation of Nrf2 by SFN is achieved through the Akt/GSK-3β/Fyn pathway.

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 &lt, 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 &lt, 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.

Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy (DCM), but the mechanism remains largely unclear. We found that diabetic hearts exhibited decreased phosphorylation of total Akt and isoform Akt2 but not Akt1 in wild-type (WT) male FVB mice, which was accompanied by attenuation of Akt downstream glucose metabolic signal. All of these signal changes were not observed in metallothionein cardiac-specific transgenic (MT-TG) hearts. Furthermore, insulin-induced glucose metabolic signals were attenuated only in WT diabetic hearts. In addition, diabetic hearts exhibited increased Akt-negative regulator tribbles pseudokinase 3 (TRB3) expression only in WT mice, suggesting that MT may preserve Akt2 function via inhibiting TRB3. Moreover, MT prevented tert-butyl hydroperoxide (tBHP)–reduced insulin-stimulated Akt2 phosphorylation in MT-TG cardiomyocytes, which was abolished by specific silencing of Akt2. Specific silencing of TRB3 blocked tBHP inhibition of insulin-stimulated Akt2 phosphorylation in WT cardiomyocytes, whereas overexpression of TRB3 in MT-TG cardiomyocytes and hearts abolished MT preservation of insulin-stimulated Akt2 signals and MT prevention of DCM. Most importantly, supplementation of Zn to induce MT preserved cardiac Akt2 signals and prevented DCM. These results suggest that diabetes-inhibited cardiac Akt2 function via TRB3 upregulation leads to aberrant cardiac glucose metabolism. MT preservation of cardiac Akt2 function by inhibition of TRB3 prevents DCM.

Recently, the dipeptidyl peptidase‐4 (DPP‐4) inhibitor sitagliptin, a major anti‐hyperglycaemic agent, has received substantial attention as a therapeutic target for cardiovascular diseases via enhancing the number of circulating endothelial progenitor cells (EPCs). However, the direct effects of sitagliptin on EPC function remain elusive. In this study, we evaluated the proangiogenic effects of sitagliptin on a diabetic hind limb ischaemia (HLI) model in vivo and on EPC culture in vitro. Treatment of db/db mice with sitagliptin (Januvia) after HLI surgery efficiently enhanced ischaemic angiogenesis and blood perfusion, which was accompanied by significant increases in circulating EPC numbers. EPCs derived from the bone marrow of normal mice were treated with high glucose to mimic diabetic hyperglycaemia. We found that high glucose treatment induced EPC apoptosis and tube formation impairment, which were significantly prevented by sitagliptin pretreatment. A mechanistic study found that high glucose treatment of EPCs induced dramatic increases in oxidative stress and apoptosis; pretreatment of EPCs with sitagliptin significantly attenuated high glucose‐induced apoptosis, tube formation impairment and oxidative stress. Furthermore, we found that sitagliptin restored the basal autophagy of EPCs that was impaired by high glucose via activating the AMP‐activated protein kinase/unc‐51‐like autophagy activating kinase 1 signalling pathway, although an autophagy inhibitor abolished the protective effects of sitagliptin on EPCs. Altogether, the results indicate that sitagliptin‐induced preservation of EPC angiogenic function results in an improvement of diabetic ischaemia angiogenesis and blood perfusion, which are most likely mediated by sitagliptin‐induced prevention of EPC apoptosis via augmenting autophagy.

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.

Diabetes mellitus associated dysfunction of endothelial progenitor cells (EPCs) may contribute to dysregulation of endothelial regeneration. Whether oxidative protection of EPCs by an antioxidant, such as the protein metallothionein (MT) can have positive angiogenic effects and by what mechanisms remain unclear. Endothelial-specific MT overexpression (JTMT) mice were made diabetic by high fat diet followed by streptozocin administration (HFD/STZ). Diabetic hind limb ischemia (HLI) was established by femoral artery ligation. Bone marrow mononuclear cells (MNCs) collected from JTMT mice were transplanted into db/db mice with HLI. Blood reperfusion was monitored. High glucose and hypoxia conditions in culture were adopted to mimic diabetic ischemia. Compared with wild-type (WT) littermates, JTMT mice were resistant to diabetes-induced impairment in ischemia angiogenesis and blood reperfusion in HFD/STZ diabetes. Similarly, transplantation of MT overexpressing MNCs showed better therapeutic effect on db/db mice with HLI than transplantation of WT MNCs. These changes were accompanied by increased mobilization and infiltration of EPCs in JTMT mice, and enhanced incorporation of EPCs into capillaries in JTMT MNCs transplanted db/db mice. Furthermore, EPCs from JTMT mice exhibited augmented cell survival, tube formation, and migration capacities under diabetic ischemia-like conditions. Mechanistically, the expression of hypoxia-inducible factor 1α (HIF-1α) and the secretion of stromal cell-derived factor (SDF-1) in blood and expression in ischemic tissues were upregulated in JTMT and JTMT-MNC transplanted db/db mice, and in cultured JTMT EPCs, which were accompanied by marked amelioration of oxidative stress. However, MT-mediated elevation of SDF-1 and improvements of function in EPCs were all abrogated by siRNA knockdown of HIF-1α expression without effect on the anti-oxidative capacity of MT. Endothelial-specific MT elevation is sufficient to protect against diabetes mellitus-induced impairment of ischemia angiogenesis by promoting EPC function. The benefits of MT are predominantly mediated by upregulation of the HIF-1α/SDF-1 pathway.

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 readings70 mg/dL, at 5-min intervals, with an episode ending with at least two CGM readings70 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

Background: The burden of T1D includes multiple visits to an endocrinologist each year, often requiring significant travel. Youth with T1D are especially impacted as pediatric endocrinologists are primarily concentrated at academic centers in urban areas. Objectives: To assess the impact of distance to the diabetes treatment center on diabetes outcome measures. And to determine if the prevalence of technology use for the management of diabetes differs among youth with T1D living in urban versus rural communities. Methods: Retrospective data was collected for youth ≤ 18 years of age, with a diagnosis of T1D for ≥ 6 months, seen at the Wendy Novak Diabetes Care Center. GIS mapping was used to analyze outcome measures by distance to the treatment center. Rural-Urban Commuting Area (RUCA) Codes were assigned to identify those living in metropolitan (RUCA 1-3), micropolitan (RUCA 4-6), and rural communities (RUCA 7-10). Results: Inclusion criteria were met by 823 youth. Of these, 710 (86.3%) were white. Current CGM use was identified for 288 (35%), and pump use by 385 (46.8%). The mean distance traveled to the center was 18 miles (S.D. 8.8-52.2). Those traveling farther distances attended fewer clinic visits (p=0.0033). Those using a CGM or an insulin pump had more visits per year (p < 0.0001 and p=0.01, respectively). Among white youth, those traveling Conclusions: Those with a greater burden of travel to receive specialty care attended fewer visits and were less likely to use CGM technology that has important benefits in improving blood glucose management and safety for those living with T1DM. This will be important to consider when developing strategies to improve access and support for this technology. Disclosure S. Watson: None. K.S. Jawad: None. M.A. Rodriguez Luna: None. K.A. Wintergerst: None. Funding Jaeb Center for Health Research

Diabetes mellitus associated dysfunction of endothelial progenitor cells (EPCs) may contribute to dysregulation of endothelial regeneration. Metallothionein (MT) acts as an antioxidant in various pathophysiological processes. Whether MT in EPCs has positive angiogenic effects and the mechanisms involved remain unclear. Endothelial MT overexpression (JTMT) mice were made diabetic by high fat diet followed by STZ administration (HFD/STZ). Diabetic hind limb ischemia model was established by femoral artery ligation. Bone marrow derived mononuclear leucocytes (MNCs) collected from JTMT mice were transplanted into db/db mice with hind limb ischemia. Blood reperfusion was monitored and oxidative stress was measured. High glucose and hypoxia conditions in culture were adopted to mimic diabetic ischemia in vitro. MT improved blood perfusion of ischemic hind limb and promoted angiogenesis in HFD/STZ diabetes. Oxidative stress of ischemic muscles was aggravated under diabetic condition, which was reduced in JTMT mice. Compared with WT mice, the expression of HIF-1α, SDF-1, VEGF and p-Akt were all increased in JTMT mice, along with elevation of plasma SDF-1α and VEGF. Moreover, transplantation of MT overexpressed MNCs showed better therapeutic effect on db/db diabetic mice with hind limb ischemia than control or transplantation of normal MNCs. Transplantation was accompanied by elevated HIF-1α, SDF-1 and Akt signaling. Vitro studies demonstrated that MT overexpression reduced high glucose and hypoxia induced EPC dysfunction and preserved high glucose and hypoxia impaired HIF-1α, SDF-1, VEGF and Akt signaling, all of which were abolished by siRNA knockdown of HIF-1α. In conclusion, elevated MT enhances angiogenic function and therapeutic efficacy of EPCs in diabetic limb ischemia. The benefits of MT are predominantly mediated by a HIF-1α/SDF-1/Akt pathway under diabetic ischemia conditions. Disclosure K. Wang: None. X. Dai: None. J. He: None. C. Yang: None. J. Chen: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Tan: None. Funding American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.); 1-13-JF-53 (to Y.T.)

Context Treatment-induced neuropathy of diabetes (TIND) is a rarely reported but important consideration in patients presenting with an acute onset of neuropathic symptoms following rapid correction of hyperglycemia in diabetes. Although it has been reported in children, the preponderance of literature focuses on adults with TIND. Case Description We report an 18-year-old male with this condition and his clinical course. We then discuss the proposed pathophysiology of TIND and review the literature. We also provide a standard workup for the diagnosis of TIND. Conclusion In both pediatric and adult populations, TIND should be considered in diabetic patients who develop neuropathy acutely following rapid correction of hyperglycemia. Because the pathophysiology of TIND remains poorly understood, there is insufficient information regarding how to target susceptible individuals and prevent the development of TIND.

The transcription factor nuclear factor erythroid 2‐like 2 (NFE2L2) is essential for preventing type 2 diabetes mellitus (T2DM)‐induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2DM and its complications in Han Chinese volunteers. T2DM patients with (n = 214) or without (n = 236) complications, or healthy controls (n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms (SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre‐Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase‐1 (HMOX1) were determined through enzyme‐linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2DM patients for the GG genotype carriers compared with participants with CG+CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2DM risk, they were significantly associated with complications of T2DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2DM patients with CG+CC than those with GG genotype.

Background/Objective The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population. Methods A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012. Results The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p

Objective Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied. Methods Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for 3 or 6 months. This study examined associations between renal pathogenesis and dietary Zn levels, specifically assessing inflammatory pathways by utilizing P38 MAPK inhibitor SB203580. Results HFD feeding induced typical syndromes of obesity-related renal disorders, which worsened by Zn marginal deficiency. The progression of obesity-related renal disorders was delayed by Zn supplementation. HFD induced renal inflammation, reflected by increased P38 MAPK phosphorylation along with increases of inflammatory cytokines MCP-1, IL-1β, IL-6, and TNF-α. P38 MAPK inhibition prevented renal pathological changes in mice fed with HFD and HFD/Zn deficiency. Conclusions P38 MAPK mediated the renal inflammatory responses, which played a central role in the pathogenesis of HFD-induced renal disorders. Zn could delay the progression of obesity-related kidney disease by down-regulating P38 MAPK-mediated inflammation.