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A stem cell model of diabetes due to glucokinase deficiency

ABSTRACT: Diabetes is a disorder characterized by loss of beta cell mass and/or beta cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell derived-beta cells faithfully reflect the phenotypes of a diabetic subject, we generated induced pluripotent stem cells from diabetic subjects (MODY2) with heterozygous loss-of-function of the gene encoding glucokinase (GCK). These stem cells differentiated into beta cells with an efficiency comparable to controls, and expressed markers of mature beta cells, urocotin-3 and zinc transporter 8 upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to cells from healthy controls, GCK mutant beta cells required higher glucose levels to stimulate insulin secretion. Importantly this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that stem cell-derived beta cells reflect beta cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on beta cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45777 | GEO | 2013/04/05

SECONDARY ACCESSION(S): PRJNA196306

REPOSITORIES: GEO

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A stem cell model of diabetes due to glucokinase deficiency

Project description:Diabetes is a disorder characterized by loss of beta cell mass and/or beta cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell derived-beta cells faithfully reflect the phenotypes of a diabetic subject, we generated induced pluripotent stem cells from diabetic subjects (MODY2) with heterozygous loss-of-function of the gene encoding glucokinase (GCK). These stem cells differentiated into beta cells with an efficiency comparable to controls, and expressed markers of mature beta cells, urocotin-3 and zinc transporter 8 upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to cells from healthy controls, GCK mutant beta cells required higher glucose levels to stimulate insulin secretion. Importantly this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that stem cell-derived beta cells reflect beta cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on beta cell function. Induced pluripotent stem cells with munations in the glucokinase gene were differentiationed into pancreas cells using published protocol (D'Amour et al, 2006) with certain modifications. 1 million cells(fibroblast or stem cells or differentiated pancreatic cells) was used for RNA extraction and labeling using the Illumina total prep RNA amplification kit.

2013-04-05 | E-GEOD-45777 | biostudies-arrayexpress

Expression data from pancreatic beta-cells obtained from type 2 diabetic subjects and non-diabetic controls

Project description:Changes in gene expression in pancreatic Î² cells from type 2 diabetes should provide insights into their abnormal insulin secretion and turnover. Gene expression profile of Î² cells obtained from type 2 diabetic subjects and non-diabetic controls was evaluated by microarray analysis. Frozen sections were obtained from cadaver pancreases of 10 control and 10 type 2 diabetic human subjects. Î²-cell enriched samples were obtained by laser capture microdissection. RNA was extracted, amplified and subjected to microarray analysis.

2010-03-20 | E-GEOD-20966 | biostudies-arrayexpress

Checkpoint Kinase 2 Controls Insulin Secretion and Glucose Homeostasis

Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.

2023-10-25 | GSE239335 | GEO

Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure

Project description:Type 2 diabetes (T2D) is associated with defective insulin secretion, reduced β-cell mass, and β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) serves as a marker of β-cell dedifferentiation and correlates with T2D progression. ALDH1A3-positive β-cells (A+) demonstrate impaired insulin secretion, and their numbers decrease when diabetic mice are rendered euglycemic by pair-feeding. It is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of A+ cells under pair-feeding is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Molecular interrogation of β-cells following ALDH1A3 inhibition show a reactivation of differentiation as well as regeneration pathways through the REG gene family. We conclude that ALDH1A3 inhibition offers a therapeutic strategy for β-cell dysfunction in diabetes.

2023-01-09 | GSE218047 | GEO

Transcription profiling of skeletal muscle from diabetic or non-diabetic Mexican Americans with or without a family history of diabetes

Project description:Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta-cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, and glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. While NRF-1 expression is decreased only in diabetic subjects, expression of both PPARg coactivator 1-alpha and -beta (PGC1-a/PPARGC1, and PGC1-b/PERC), coactivators of NRF-1 and PPARg-dependent transcription, is decreased in both diabetic subjects and family history positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRFdependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

2007-06-28 | E-CBIL-28 | biostudies-arrayexpress

SC-beta Cell in vivo Maturation

Project description:Stem cell-derived β (SC-β) cells are an emerging regenerative therapy to compensate for loss of functional β cell mass in diabetes. Glucose-stimulated insulin secretion in SC-β cells is variable in vitro but stabilizes after transplantation and maturation under the kidney capsule of mice. We identified mechanisms correlated with functional maturation using RNA-sequencing and co-expression network analysis. In vivo maturation enhanced glucose-stimulated but not basal insulin secretion, up-regulated β cell hormones IAPP and ADCYAP1, increased expression of maturation markers MAFA, UCN3, and SIX2, and resolved endocrine identity of incompletely specified polyhormonal cells produced during differentiation. Transplantation promoted calcium signalling, induced exocytotic machinery supporting hormone secretion and improved stimulus-secretion coupling that fine-tunes insulin secretion. Growth hormone signalling emerged as candidate driver of in vivo maturation and was confirmed in vitro. Also, a large co-expression module correlated with HbA1c and was enriched in genes up-regulated during in vivo maturation but down-regulated in hyperglycaemic and palmitate stress conditions, suggesting that transcriptional maturation of SC-β cells in vivo mirrors processes lost in diabetic β cells.

2019-08-19 | GSE135944 | GEO

Human skeletal muscle - type 2 diabetes and family history positive individuals - Mexican American

2010-04-27 | E-GEOD-21340 | biostudies-arrayexpress

Klf6 protects β-cells against insulin resistance-induced dedifferentiation

Project description:In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain poorly defined. Here, through a systems biology approach, we identify the transcription factor Klf6 as a regulator of β-cell adaptation to metabolic stress. We show that inactivation of Klf6 in mouse β-cells blunts their proliferation induced by the insulin resistance of pregnancy, high-fat high-sucrose feeding, and insulin receptor antagonism. Transcriptomic analysis showed that Klf6 controls the expression of β-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature β-cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of β-cells into alpha cells. Our study identifies a new transcription factor that protects β-cells against dedifferentiation and which may be targeted to prevent diabetes development.

2020-03-01 | GSE137187 | GEO

Increased insulin secretion in ZNT8 mutant stem-cell derived beta cells

Project description:Increased insulin secretion in ZNT8 mutant stem-cell derived beta cells

| PRJNA701465 | ENA

MicroRNA-21 Promotes Pancreatic β cell Function through Modulating Glucose Uptake

Project description:Pancreatic β cell dysfunction greatly contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we studied the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We found that miR-21βKO mice developed glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies revealed that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets resulted in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrated that delivery of miR-21 into the pancreas of type 2 diabetic db/db mice is able to promote Glut2 expression and significantly reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the adaptation of pancreatic β cell function in type 2 diabetes.

2022-05-16 | GSE191194 | GEO

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