Diabetes Remission Using Glucose-Responsive Insulin-Producing Human α-Cells
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PROVIDER: PRJNA482144 | ENA |
REPOSITORIES: ENA
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Project description:Diabetes Remission Using Glucose-Responsive Insulin-Producing Human alpha-Cells
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Project description:Natural and stable cell identity switches, where terminally-differentiated cells convert into different cell-types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells become insulin expressers upon ablation of insulin-secreting β-cells, promoting diabetes recovery. Whether human islets also display this plasticity for reconstituting β-like cells, especially in diabetic conditions, remains unknown. Here we show that two different islet non-β-cell types, α- and γ–cells, obtained from deceased non-diabetic or diabetic human donors can be lineage-traced and induced to produce insulin and secrete it in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and remain producing insulin even after 6 months. Insulin-producing α-cells maintain α-cell markers, as seen by deep transcriptomic and proteomic characterization, and display hypo-immunogenic features when exposed to T-cells derived from diabetic patients. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity in islet cells, as well as in other organs, as a therapy for degenerative diseases by fostering the highly-regulated intrinsic cell regeneration.
2018-12-15 | GSE123844 | GEO
Project description:Natural and stable cell identity switches, where terminally-differentiated cells convert into different cell-types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells become insulin expressers upon ablation of insulin-secreting β-cells, promoting diabetes recovery. Whether human islets also display this plasticity for reconstituting β-like cells, especially in diabetic conditions, remains unknown. Here we show that two different islet non-β-cell types, α- and γ–cells, obtained from deceased non-diabetic or diabetic human donors can be lineage-traced and induced to produce insulin and secrete it in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and remain producing insulin even after 6 months. Insulin-producing α-cells maintain α-cell markers, as seen by deep transcriptomic and proteomic characterization, and display hypo-immunogenic features when exposed to T-cells derived from diabetic patients. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity in islet cells, as well as in other organs, as a therapy for degenerative diseases by fostering the highly-regulated intrinsic cell regeneration.
2018-12-13 | GSE117454 | GEO
Project description:Gastric bypass surgery (GBP) emerging as a powerful tool for treatment of obesity has been applied for remission of diabetes. However, the GBP global molecular effects on diabetes remission independent of weight loss remain largely unknown. We profiled plasma metabolites and proteins of 10 normoglycemic obese (NO) and 9 diabetic obese (DO) patients at 1-week, 3-months and 1-year stages after Roux-en-Y gastric bypass (RYGB) as well pre-RYGB stage, by which 146 proteins and 128 metabolites were detected from both NO and DO groups at all four stages. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the representing physiological states (called the edge-states, in contrast to the traditional node-states) and the related molecular networks of NO and DO patients, respectively. The PCA results and hubnetworks of NO subjects were significantly different from those of DO patients; particularly, the hub-network rearrangement of both groups differentially went through after RYGB. In conclusion, by developing network-based systems signatures rather than relying on individual molecules, we for the first time reveal that RYGB generates a unique recovering-path for diabetes remission independent of weight loss.
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Project description:Global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. Compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians. Keywords: other
2002-12-17 | GSE121 | GEO
Project description:Type 1 diabetes is a progressive autoimmune disease with unknown etiology. Although the destruction of β-cells is recognized as an irreversible process, many type 1 diabetes patients experience the partial remission stage characterized by spontaneous and transient recovery of β-cell function. However, a comprehensive understanding of immune disturbances in the progression of type 1 diabetes as well as the immunological mechanisms responsible for the partial remission stage remains to be elucidated.
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| S-EPMC3048179 | biostudies-literature
Project description:Partial remission (PR) occurs in only half of patients with new-onset type 1 diabetes (T1D) and correspond to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of newly-onset T1D patients with significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified nearly 1500 unique proteins with 98 significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters that yielded to the selection of 26 protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally validated several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasmatic biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and β-cell function is key to stratify patients with new-onset T1D for β-cell preservation therapies
2024-04-05 | PXD049795 | Pride
Project description:Targeted pharmacological therapy restores β-cell function for diabetes remission
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Project description:The targeted muscle insulin receptor knockout (MIRKO) model was used, in which there is a complete absence of the insulin-receptor signaling in skeletal muscle but normal insulin and glucose levels. By comparing skeletal muscle gene-expression profiles from MIRKO mice and their controls (lox/lox) under three different metabolic conditions (namely, in the basal state, after streptozotocin (STZ)-induced diabetes, and after STZ-induced diabetes rendered euglycemic with insulin treatment), we can address the following three important questions. (i) What is the direct effect of the loss of insulin signaling on gene expression in skeletal muscle? (ii) What is the contribution of the metabolic and other changes that accompany diabetes to induce indirect changes in gene expression? (iii) How are these pathways regulated and implicated in the pathophysiology of diabetes?
2006-11-24 | E-CBIL-19 | biostudies-arrayexpress