Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Diabetic cardiomyopathy - Zinc preventive and therapeutic potentials by its anti-oxidative stress and sensitizing insulin signaling pathways.

Oxidative stress and insulin resistance are two key mechanisms for the development of diabetic cardiomyopathy (DCM, cardiac remodeling and dysfunction). In this review, we discussed how zinc and metallothionein (MT) protect the heart from type 1 or type 2 diabetes (T1D or T2D) through its anti-oxidative function and insulin-mediated PI3K/Akt signaling activation. Both T1D and T2D-induced DCM, shown by cardiac structural remodeling and dysfunction, in wild-type mice, but not in cardiomyocyte-specific overexpressing MT mice. In contrast, mice with global MT gene deletion were more susceptible to the development of DCM. When we used zinc to treat mice with either T1D or T2D, cardiac remodeling and dysfunction were significantly prevented along with increased cardiac MT expression. To support the role of zinc homeostasis in insulin signaling pathways, treatment of diabetic mice with zinc showed the preservation of phosphorylation levels of insulin-mediated glucose metabolism-related Akt2 and GSK-3ß and even rescued cardiac pathogenesis induced by global deletion of Akt2 gene in a MT-dependent manner. These results suggest the protection by zinc from DCM is through both the induction of MT and sensitization of insulin signaling. Combined our own and other works, this review comprehensively summarized the roles of zinc homeostasis in the development and progression of DCM and its therapeutic implications. At the end, we provided pre-clinical and clinical evidence for the preventive and therapeutic potential of zinc supplementation through its anti-oxidative stress and sensitizing insulin signaling actions. Understanding the intricate connections between zinc and DCM provides insights for the future interventional approaches.

Congenital Hypothyroidism: Screening and Management.

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.

Congenital Hypothyroidism: Screening and Management.

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.

Does maternal low-dose cadmium exposure increase the risk of offspring to develop metabolic syndrome and/or type 2 diabetes?

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.

Association between Intensity Levels of Physical Activity and Glucose Variability among Children and Adolescents with Type 1 Diabetes.

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.

Cardiovascular Effects of Environmental Metal Antimony: Redox Dyshomeostasis as the Key Pathogenic Driver.

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.

Long-term Continuous Glucose Monitor Use in Very Young Children With Type 1 Diabetes: One-Year Results From the SENCE Study.

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.

Factory-Calibrated Continuous Glucose Monitoring System Accuracy During Exercise in Adolescents With Type 1 Diabetes Mellitus.

BACKGROUND: Continuous glucose monitors (CGMs) are widely used for individuals with diabetes mellitus, particularly those with type 1 diabetes (T1D). Advancements in CGM technology allow for glycemic assessment without capillary glucose measurements as many come factory calibrated. However, exercise, an essential component of diabetes care, has been reported to alter accuracy of earlier generation CGM. Considering the importance of physical activity for individuals with T1D and the progression of CGM technology, we aimed to investigate the accuracy of the Dexcom G6 during physical activity. METHODS: Adolescents (ages 13-20 years) exercised on a treadmill for 40 minutes, with a 10-minute break at minute 20. We obtained paired CGM and glucometer measurements before and every 10 minutes during and after exercise. Accuracy analysis was determined by mean absolute relative difference (MARD), mean absolute difference (MAD), and Clarke Error Grid Analyses. RESULTS: Mean absolute relative difference and MAD increased during exercise (14%-33% and 24.3-34 mg/dL) but improved after exercise. We noted certain CGM locations produced greater changes in accuracy as MARD and MAD increased markedly when the CGM was on the buttocks (18%-46% and 30-41 mg/dL). We also noted decreased odds of Zone A in the Clarke error grid when the CGM was on the buttocks compared to the abdomen (odds ratio [OR]: 0.146; P = 0.0003; 95% CI = 0.052-0.415). CONCLUSIONS: This CGM system showed alterations in accuracy during exercise. Our findings additionally suggest interstitial fluid changes in muscles during exercise alter accuracy of CGM; however, additional research is required.

Nrf2 transcriptional upregulation of IDH2 to tune mitochondrial dynamics and rescue angiogenic function of diabetic EPCs.

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.

Maximal Oxygen Uptake, VO2 Max, Testing Effect on Blood Glucose Level in Adolescents with Type 1 Diabetes Mellitus.

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.

FGF1ΔHBS delays the progression of diabetic nephropathy in late-stage type 2 diabetes mouse model by alleviating renal inflammation, fibrosis, and apoptosis.

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.

Exposure to low-dose cadmium induces testicular ferroptosis.

As an environmental pollutant, cadmium (Cd) has been widely reported to induce male infertility due to its gonadotoxicity. However, the specific mechanism of Cd-induced testicular damage remains unclear. We investigated whether Cd causes testicular injury through ferroptosis. Male C57BL/6 J mice were exposed to 0, 0.5, or 5 ppm Cd via drinking water, starting in utero, and continuing through 24 weeks post-weaning. The results showed that Cd accumulated in the testes in a dose-dependent manner. Cd exposure at a concentration of 5 ppm, but not 0.5 ppm, caused a mass loss and detachment of germ cells, as well as a decreased meiotic index and testis weight. Exposure to 5 ppm Cd caused iron accumulation, increased levels of malondialdehyde (MDA) and nitro tyrosine (3-NT), and decreased expression of Nrf2, HO-1 and SOD2. We also found that exposure to 5 ppm Cd significantly decreased the expression of SLC7A11, a marker of ferroptosis in mice, along with the expression of SLC40A1 mRNA and ferritin heavy chain (FTH) protein, whereas there was no obvious change in the mRNA expression of Tfrc, ZIP8, ZIP14, and NCOA4. These findings indicate that 5 ppm Cd exposure increased testicular ferroptosis, which may be attributed to the reduction of stored iron export.

Effects of whole-life exposure to low-dose cadmium with post-weaning high-fat diet on offspring testes in a male mouse model.

Although several studies have reported testicular impairments caused by cadmium (Cd) or obesity alone, the combined effect of Cd and obesity on the testes and its underlying mechanism remains unclear. We examined the combined effect of whole-life exposure to low-dose Cd started at preconception and post-weaning high-fat diet (HFD) on the testes of offspring mice. At weaning, male offspring parented with and without exposure to low-dose Cd were continued on the same drinking water regimen as their parents and fed with either a normal diet (ND) or HFD for 10 or 24 weeks. Whole-life exposure to Cd resulted in its accumulation in testes, and HFD induced obesity and lipid metabolism disorder. Exposure to Cd or HFD alone significantly decreased Johnsen scores, disrupted testicular structure, and increased germ cell apoptosis at both 10 and 24 weeks. However, co-exposure to Cd and HFD did not induce the toxic effects that were induced by either alone, as revealed by preserved testicular structure and spermatogenesis, lack of significant apoptosis, and increased cell proliferation. Mechanistically, the combined effects of low-dose Cd and HFD consumption were associated with the activation of the JAK/STAT pathway. These findings suggest that co-exposure to low-dose Cd and HFD did not cause Cd- or HFD-induced testicular injury, probably because of the activation of the JAK/STAT pathway to prevent germ cell apoptosis.

Severe Hypernatremia in a Significantly Underweight Female Child.

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.

Integration of Consumer-Based Activity Monitors into Clinical Practice for Children with Type 1 Diabetes: A Feasibility Study.

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.

Association between Physical Activity and Sport Participation on Hemoglobin A1c Among Children and Adolescents with Type 1 Diabetes.

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.

Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.

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.

Endothelial Overexpression of Metallothionein Prevents Diabetes-Induced Impairment in Ischemia Angiogenesis Through Preservation of HIF-1α/SDF-1/VEGF Signaling in Endothelial Progenitor Cells.

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.

Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence.

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.