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Cardiovascular Research Feb 2024Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a serious life-threatening complication, the mechanisms of which have not been fully established, and...
AIMS
Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a serious life-threatening complication, the mechanisms of which have not been fully established, and therefore no effective treatment is currently available. The purpose of the study was to identify new molecular signatures of the cardiomyopathy development in DMD.
METHODS AND RESULTS
For modelling of DMD-associated cardiomyopathy, we prepared three pairs of isogenic control and dystrophin-deficient human induced pluripotent stem cell (hiPSC) lines. Two isogenic hiPSC lines were obtained by CRISPR/Cas9-mediated deletion of DMD exon 50 in unaffected cells generated from healthy donor and then differentiated into cardiomyocytes (hiPSC-CM). The latter were subjected to global transcriptomic and proteomic analyses followed by more in-depth investigation of selected pathway and pharmacological modulation of observed defects. Proteomic analysis indicated a decrease in the level of mitoNEET protein in dystrophin-deficient hiPSC-CM, suggesting alteration in iron metabolism. Further experiments demonstrated increased labile iron pool both in the cytoplasm and mitochondria, a decrease in ferroportin level and an increase in both ferritin and transferrin receptor in DMD hiPSC-CM. Importantly, CRISPR/Cas9-mediated correction of the mutation in the patient-derived hiPSC reversed the observed changes in iron metabolism and restored normal iron levels in cardiomyocytes. Moreover, treatment of DMD hiPSC-CM with deferoxamine (DFO, iron chelator) or pioglitazone (mitoNEET stabilizing compound) decreased the level of reactive oxygen species in DMD hiPSC-CM.
CONCLUSION
To our knowledge, this study demonstrated for the first time impaired iron metabolism in human DMD cardiomyocytes, and potential reversal of this effect by correction of DMD mutation or pharmacological treatment. This implies that iron overload-regulating compounds may serve as novel therapeutic agents in DMD-associated cardiomyopathy.
Topics: Humans; Cardiomyopathies; CRISPR-Cas Systems; Dystrophin; Gene Editing; Homeostasis; Induced Pluripotent Stem Cells; Iron; Muscular Dystrophy, Duchenne; Myocytes, Cardiac; Proteomics
PubMed: 38078368
DOI: 10.1093/cvr/cvad182 -
Pharmacological Research Jan 2024Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further... (Review)
Review
Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further investigation is warranted to explore the advantageous impacts of Sirtuin 1 (SIRT1), a constituent of the sirtuin group, on lipid metabolism, in addition to its well-researched involvement in extending lifespan. The regulation of gene expression has been extensively linked to SIRT1. Sterol regulatory element-binding protein (SREBP) is a substrate of SIRT1 that has attracted significant interest due to its role in multiple cellular processes including cell cycle regulation, DNA damage repair, and metabolic functions. Hence, the objective of this analysis was to investigate and elucidate the correlation between SIRT1 and SREBPs, as well as assess the contribution of SIRT1/SREBPs in mitigating lipid metabolism dysfunction. The objective of this research was to investigate whether SIRT1 and SREBPs could be utilized as viable targets for therapeutic intervention in managing complications associated with diabetes.
Topics: Sirtuin 1; Lipid Metabolism; Sirtuins; NAD
PubMed: 38070792
DOI: 10.1016/j.phrs.2023.107037 -
BMJ Open Diabetes Research & Care Nov 2023Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists...
INTRODUCTION
Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RA) are medications used in T2D that can resolve MASH and should be considered in all patients with T2D and MASH. We assessed prescription rates of evidence-based T2D pharmacotherapy (EBP) in MASH, and ascertained racial/ethnic disparities in prescribing.
RESEARCH DESIGN AND METHODS
We conducted a cross-sectional study on patients in Duke University Health System with diagnosis codes for T2D and MASH between January 2019 and January 2021. Only patients with ≥1 primary care or endocrinology encounter were included. The primary outcome was EBP, defined as ≥1 prescription for pioglitazone and/or a GLP-1RA during the study period. A multivariable logistic regression model was used to examine the primary outcome.
RESULTS
A total of 847 patients with T2D and MASH were identified; mean age was 59.7 (SD 12) years, 61.9% (n=524) were female, and 11.9% (n=101) and 4.6% (n=39) were of Black race and Latino/a/x ethnicity, respectively. EBP was prescribed in 34.8% (n=295). No significant differences were noted in the rates of EBP use across racial/ethnic groups (Latino/a/x vs White patients: adjusted OR (aOR) 1.82, 95% CI 0.78 to 4.28; Black vs White patients: aOR 0.76, 95% CI 0.44 to 1.33, p=0.20).
CONCLUSIONS
EBP prescriptions, especially pioglitazone, are low in patients with T2D and MASH, regardless of race/ethnicity. These data underscore the need for interventions to close the gap between current and evidence-based care.
Topics: Female; Humans; Male; Middle Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Ethnicity; Hispanic or Latino; Pioglitazone; Black or African American; White; Aged; Glucagon-Like Peptide-1 Receptor; Fatty Liver
PubMed: 38030391
DOI: 10.1136/bmjdrc-2023-003763 -
ACS Omega Nov 2023Diabetes mellitus (DM) represents one of the most important reasons for chronic kidney diseases due to the high level of blood glucose that destructs blood vessels....
Diabetes mellitus (DM) represents one of the most important reasons for chronic kidney diseases due to the high level of blood glucose that destructs blood vessels. The present study focused on investigating the protective impact of sitagliptin on kidney complication in type 2 diabetes mellitus (T2DM) patients in comparison to pioglitazone to examine which has the superior effect against the nephritic complication of DM. Eighty adult subjects were classified into four groups: control group, pioglitazone-treated T2DM patients (P group), sitagliptin-treated T2DM patients for less than one year (SL group), and sitagliptin-treated T2DM patients for more than one year (SM group). Blood samples were withdrawn from all subjects for analysis of neutrophil gelatinase-associated lipocalin (NGAL), vanin-1, kidney injury molecule-1 (KIM-1), glyoxalase-1 (Glo-1), methylglyoxal (MG), cystatin-C, and interleukin-18 (IL-18) using competitive ELISA kits. Also, long noncoding myocardial infarction associated transcript (lncMIAT) was measured in whole blood using qRT-PCR. The present study revealed that the lncMIAT expression level was significantly higher in the P group as compared to the SL group, SM group, or healthy control group. Additionally, serum NGAL, vanin-1, KIM-1, Glo-1, MG, and cystatin-C were significantly higher in the P group and SL group as compared to the SM group and healthy control group. Sitagliptin protected the kidney through downregulation of lncMIAT besides amelioration of kidney injury marker levels, which was more preferable than in pioglitazone therapy.
PubMed: 38024775
DOI: 10.1021/acsomega.3c07008 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35%... (Review)
Review
Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopulmonary dysplasia (BPD), and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal period. In newborn animal models, pioglitazone has been shown to be protective against BPD, necrotising enterocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelopment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema, seen rarely in adults, may be avoided with a short treatment course. The other effects of pioglitazone, including improved glycaemic control and lipid metabolism, may provide added benefit in the context of prematurity. Currently, there is no formulation of pioglitazone suitable for administration to preterm babies. A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.
PubMed: 38004396
DOI: 10.3390/ph16111530 -
Biomedicines Nov 2023Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and... (Review)
Review
Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes.
Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson's and Huntington's diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.
PubMed: 38001993
DOI: 10.3390/biomedicines11112993 -
NPJ Digital Medicine Nov 2023Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML)...
Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate's probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: -14.8% ± 3.1%, p = 0.001; SPRINT: -17.6% ± 3.6%, p < 0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all simulations with Cox regression-derived p value of < 0.01 for the effect of the intervention on the respective primary outcome). This adaptive framework has the potential to maximize RCT enrollment efficiency.
PubMed: 38001154
DOI: 10.1038/s41746-023-00963-z -
BMC Medicine Nov 2023Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM.
METHODS
This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373.
RESULTS
Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence.
CONCLUSIONS
The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.
Topics: Humans; Diabetes Mellitus, Type 2; Exenatide; Hypoglycemic Agents; Liraglutide; Non-alcoholic Fatty Liver Disease; Network Meta-Analysis; Pioglitazone; Insulin Resistance; Bayes Theorem
PubMed: 37974258
DOI: 10.1186/s12916-023-03129-6 -
Current Opinion in Psychiatry Jan 2024The circular interactions between type 2 diabetes (TMD2) and major depressive disorder (MDD) are well documented but the understanding of their mechanisms has only... (Review)
Review
PURPOSE OF REVIEW
The circular interactions between type 2 diabetes (TMD2) and major depressive disorder (MDD) are well documented but the understanding of their mechanisms has only recently gained more clarity. Latest research indicates, that the association between TMD2 and MDD is largely mediated by insulin resistance (IR).
RECENT FINDINGS
A metabolic subtype of MDD can be distinguished from other MDD subpopulations, that is characterized by predominantly atypical clinical presentation, IR and different responsiveness to antidepressant interventions. IR is a predictor of nonresponse to some antidepressants. The IR seems to be a state-marker of clinical or subclinical depression and the relationship between IR and MDD varies between sexes and ethnicities. Insulin has a direct impact on the monoaminergic systems known to underlie MDD symptoms: serotoninergic and dopaminergic, which are dysregulated in IR subjects. Several trials assessed the efficacy of insulin-sensitizing drugs in MDD with mixed results for metformin and more consistent evidence for pioglitazone and lifestyle intervention/physical activity.
SUMMARY
Recently published data suggest a significant role of IR in the clinical presentation, pathophysiology and treatment response in MDD. Further research of IR in MDD and integration of existing data into clinical practice are needed.
Topics: Humans; Depressive Disorder, Major; Insulin Resistance; Diabetes Mellitus, Type 2; Depression; Antidepressive Agents; Insulins
PubMed: 37972981
DOI: 10.1097/YCO.0000000000000905 -
MedRxiv : the Preprint Server For... Nov 2023Randomized controlled trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML)...
Randomized controlled trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate's probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: -14.8% ± 3.1%, =0.001; SPRINT: -17.6% ± 3.6%, <0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all with <0.01). This adaptive framework has the potential to maximize RCT enrollment efficiency.
PubMed: 37961715
DOI: 10.1101/2023.06.18.23291542