Mitochondrial DNA atlas reveals physiopathology of type 2 diabetes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE136892 | GEO | 2022/08/30
REPOSITORIES: GEO
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Project description:Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. Whether this represents the underlying primary defect in T2D or effects of changes in hormones or circulating metabolites is unknown. To address this question, we have developed a “disease-in-a-dish” model by differentiating iPS cells from T2D patients and controls into myoblasts (iMyo) and studied their function in vitro. We find that T2D iMyos exhibit multiple defects mirroring human disease including altered insulin signaling through the IRS/AKT pathway, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. In addition, using global phosphoproteomics we find that T2D alters phosphorylation of a large network of targets of mTOR, S6K, PKC and other kinases including proteins involved in regulation of Rho-GTPases, mRNA splicing/processing, vesicular trafficking, gene transcription and chromatin remodeling. This cell-autonomous dysregulated phosphorylation network reveals a new dimension in the mechanism underlying insulin resistance in T2D.
2020-08-27 | PXD015430 | Pride
Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocyticanemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. We used microarrays to identify expression profiles and pathways that are differentially activated or suppressed in Ter119+ bone marrow cells isolated from phlebotomized wildtype or Polg mutant mice
2015-04-21 | E-GEOD-57761 | biostudies-arrayexpress
Project description:Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients wereare positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizeds insulin signaling and relieveds T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation.
2022-07-22 | PXD035076 | Pride
Project description:Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases. The objective of the present study was to detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.
2014-06-19 | E-GEOD-56676 | biostudies-arrayexpress
Project description:Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients. Results: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1β (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide; synthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. Conclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1β and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy. Experiment Overall Design: We obtained blood samples from 24 healthy volunteers, 43 newly diagnosed T1D patients and 12 newly diagnosed T2D patients. All study participants were between the ages of 2 and 18 years. We collected samples one and four months after diagnosis from the last 20 of the T1D patients. For each time point one sample did not pass quality control and was dropped from the analysis. Patients with T2D were distinguished from T1D on the basis of age, body habitus, Experiment Overall Design: presence (11/12 patients) of acanthosis nigricans, family history of type 2 diabetes (11/12 patients), and absence of autoantibodies to insulin, IA-2, and GAD65. We allowed low titers of insulin antibodies in T2D patients (< 4 U/mL), which have been previously reported. All but two Experiment Overall Design: of the T1D patients with positive anti-insulin antibodies were also positive for at least one additional autoantibody.
2008-06-16 | E-GEOD-9006 | biostudies-arrayexpress
Project description:The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mtDNA content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, induced impaired mitochondrial morphology and networking fragmentation, and impaired decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Indeed, pharmacologic mitofusin agonists rescued islet mtDNA depletion due to mitofusin deficiency independent of changes on mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
2022-02-16 | GSE194204 | GEO
Project description:Type 2 Diabetes (T2D) is a complex metabolic disorder due to a progressive insulin secretory defect on the background of insulin resistance. We found a muscle specific lncRNA we named TDNC1(T2D down-regulated non-coding RNA 1) whose expression is reduced in T2D patients as well as young individuals with family history of T2D. We used Microarray to assess for global gene expression pattern following ectopic expression of this lncRNA.
2018-06-06 | GSE70365 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE136887 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE98887 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE137766 | GEO