Dataset Information

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

ABSTRACT: The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze ?,?-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.

SUBMITTER: Bloom K

PROVIDER: S-EPMC5524623 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

Bloom Kaitlyn K Mohsen Al-Walid AW Karunanidhi Anuradha A El Demellawy Dina D Reyes-Múgica Miguel M Wang Yudong Y Ghaloul-Gonzalez Lina L Otsubo Chikara C Tobita Kimi K Muzumdar Radhika R Gong Zhenwei Z Tas Emir E Basu Shrabani S Chen Jie J Bennett Michael M Hoppel Charles C Vockley Jerry J

Journal of inherited metabolic disease 20170124 1

The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that ...[more]

PMID: 28120165

Similar Datasets

Project description:(1) Background: Magnesium deficiency is usually associated with type 2 diabetes mellitus (T2DM). Individuals living with T2DM with hypomagnesemia show a more rapid disease progression and have an increased risk for diabetes complications. (2) Methods: This is a cross-sectional and descriptive study in the National Institute of Nutrition and Food Technology of Tunis in Tunisia, including all adult outpatients (≥18 years old) with a diagnosis of T2DM from 1 September 2018 to 31 August 2019. The aim of this study was to evaluate the prevalence of plasmatic magnesium deficiency in a Tunisian population of T2DM and to study the relationship between magnesium status and intake, glycemic control and long-term diabetes-related complications. (3) Results: Among the 101 T2DM outpatients, 13 (12.9%) presented with a plasmatic magnesium deficiency. The mean age was 56 ± 7.9 years with a female predominance (62%, n = 63). The mean of the plasmatic magnesium level was 0.79 ± 0.11 mmol/L (0.5-1.1), and the mean of 24 h urinary magnesium excretion was 87.8 ± 53.8 mg/24 h [4.8-486.2]. HbA1c was significantly higher in the plasmatic magnesium deficiency group than the normal magnesium status group (10% ± 1.3 vs. 8.3% ± 1.9; p = 0.04), with a significant difference in participants with a poor glycemic control (HbA1c > 7%) (100%, n = 13/13 vs. 53%, n = 47/88; p = 0.001). A weak negative relationship was also found between plasmatic magnesium and HbA1c (r = -0.2, p = 0.03). Peripheral artery disease was more commonly described in individuals with low plasmatic magnesium levels than in individuals with normal levels (39%, n = 5 vs. 0%, n = 0; p < 0.001). The mean plasmatic magnesium level in participants without diabetic nephropathy and also peripheral artery disease was significantly higher compared to individuals with each long-term diabetes-related complication (0.8 mmol/L ± 0.1 vs. 0.71 mmol/L ± 0.07; p = 0.006) and (0.8 mmol/L ± 0.1 vs. 0.6 mmol/L ± 0.08; p < 0.001), respectively. (4) Conclusions: Hypomagnesemia was identified in individuals with T2DM, causing poor glycemic control and contributing to the development and progression of diabetes-related microvascular and macrovascular complications.

Project description:BackgroundNeutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD.Material and methods102 patients with > 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis >50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes.ResultsCirculating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p<0.001), while dsDNA, H3Cit, PAD4 and gene expression of PAD4 did not differ with respect to the presence of T1DM. There were no significant associations between NETs markers and HbA1c in the T1DM group. None of the NETs markers differed according to the presence of CAD in patients with T1DM. While all circulating NETs markers correlated significantly with circulating neutrophils in the control group (r=0.292-393, p<0.014), only H3Cit and PAD4 correlated with neutrophils in the T1DM group (r= 0.330-0.449, p ≤ 0.001).ConclusionsIn this cross-sectional study of patients with long-term T1DM and age-matched controls, circulating NETs levels were not consistently associated with the presence of T1DM or glycemic status, and did not differ according to the presence of CAD in patients with T1DM. Our results entail the possibility of altered neutrophil function and reduced NETosis in T1DM. This warrants further investigation.

Project description:Hyperglycemia is an independent risk factor for the rapid progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis with an incompletely defined mechanism. Ferroptosis is a novel form of programmed cell death that has been identified as a pathogenic mechanism in various diseases. However, the role of ferroptosis in the development of liver fibrosis in NASH with type 2 diabetes mellitus (T2DM) is unclear. Here, we observed the histopathological features of the progression of NASH to liver fibrosis as well as hepatocyte epithelial-mesenchymal transition (EMT) in a mouse model of NASH with T2DM and high-glucose-cultured steatotic human normal liver (LO2) cells. The distinctive features of ferroptosis, including iron overload, decreased antioxidant capacity, the accumulation of reactive oxygen species, and elevated lipid peroxidation products, were confirmed in vivo and in vitro. Liver fibrosis and hepatocyte EMT were markedly alleviated after treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, a decrease in the gene and protein levels of AGE receptor 1 (AGER1) was detected in the transition from NASH to liver fibrosis. Overexpression of AGER1 dramatically reversed hepatocyte EMT in high-glucose-cultured steatotic LO2 cells, whereas the knockdown of AGER1 had the opposite effect. The mechanisms underlying the phenotype appear to be associated with the inhibitory effects of AGER1 on ferroptosis, which is dependent on the regulation of sirtuin 4. Finally, in vivo adeno-associated virus-mediated AGER1 overexpression effectively relieved liver fibrosis in a murine model. Collectively, these findings suggest that ferroptosis participates in the pathogenesis of liver fibrosis in NASH with T2DM by promoting hepatocyte EMT. AGER1 could reverse hepatocyte EMT to ameliorate liver fibrosis by inhibiting ferroptosis. The results also suggest that AGER1 may be a potential therapeutic target for the treatment of liver fibrosis in patients with NASH with T2DM. Chronic hyperglycemia is associated with increased advanced glycation end products, resulting in the downregulation of AGER1. AGER1 deficiency downregulates Sirt4, which disturbs key regulators of ferroptosis (TFR-1, FTH, GPX4, and SLC7A11). These lead to increased iron uptake, decreasing the antioxidative capacity and enhanced lipid ROS production, ultimately leading to ferroptosis, which further promotes hepatocyte epithelial-mesenchymal transition and fibrosis progression in NASH with T2DM.

Dataset Information

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

Publications

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets