Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion
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ABSTRACT:
PROVIDER: PRJNA546494 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9158190.fastq.gz | Fastqsanger.gz | |||
| SRR9158191.fastq.gz | Fastqsanger.gz | |||
| SRR9158189.fastq.gz | Fastqsanger.gz | |||
| SRR9202502_1.fastq.gz | Fastqsanger.gz | |||
| SRR9202502_2.fastq.gz | Fastqsanger.gz |
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Project description:The activity of pancreatic islets’ insulin-producing β-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-β-cells” (namely α-, δ- and γ-cells). Still, it is unclear whether the presence of the non-β-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of β-cells, and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. This is particularly relevant in diabetes, where non-β-cells become dysfunctional and worsen the disease’s pathophysiology. These results support efforts aimed at developing diabetes treatments by generating β-like cell clusters devoid of non-β-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-β-cells into insulin producers.
2024-07-19 | GSE226479 | GEO
Project description:Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion [RNA-Seq]
| PRJNA546496 | ENA
Project description:Identification of C2CD4A as a human diabetes susceptibility gene with a role in β-cell insulin secretion [ChIP-Seq]
| PRJNA545416 | ENA
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4. Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.
2014-08-20 | E-GEOD-60505 | biostudies-arrayexpress
Project description:Chronic islet inflammation is a hallmark of type 2 diabetes (T2D) and involves in the dysfunction of β cells. However, how β cells participate in this process remains unclear. Here, we report that the immune checkpoint molecule B7-H4(B7S1, B7x, VTCN1) expressed in β cells is critical to maintain β cell mass and insulin secretion. Lesion of B7-H4 in β cells results in glucose intolerance due to less β cell mass and deficient insulin secretion with upregulated cytokines and activated signal transducer and activator of transcription 5 (Stat5) signaling, while overexpression of B7-H4 in β cells ameliorates glucose intolerance in high-fat diet (HFD)-treated mice. Mechanistically, B7-H4 deficiency actives the Stat5 signaling, which inhibits the expression of Apolipoprotein F (ApoF), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing the insulin processing and secretion. Inhibiting Stat5 activity or overexpression of ApoF in β cells can rescue the glucose intolerance and insulin secretion deficiency in β-cell-specific B7-H4 knockout (B7-H4 cKO) mice. Our study demonstrates that β cell expressed immune checkpoint molecule B7-H4 is essential for islet immune homeostasis and β cell function maintenance, and for the first time unravels the mechanism by which B7-H4 regulates insulin secretion through regulating cholesterol metabolism via Stat5 signaling, which may shed new light on the development of novel strategies for T2D treatment.
2024-12-19 | GSE268688 | GEO
Project description:Pancreatic beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state beta-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to beta-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo, and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild-type by only ~2% of the > 4,000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects beta-cell function by limiting mitochondrial lipid utilization, and raise the possibility that inhibition of fatty acid oxidation in β-cells is beneficial to diabetes treatment.
2016-05-10 | GSE77652 | GEO
Project description:Pancreatic beta-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair beta-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on beta-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during beta-cell glucose toxicity that impairs expression of proteins with critical roles in beta-cell function.
2023-12-01 | GSE248349 | GEO
Project description:Lifestyle intervention including exercise restores glucose homeostasis and pancreatic β-cell function in type 2 diabetes (T2D). However, exercise compliance is a challenge. Novel alternative or adjuvant approaches are necessary. During exercise, the contracting skeletal muscle acts as endocrine organ via the secretion and endocrine signaling of functional proteins. We postulated that contracting skeletal muscle secretes proteins that target pancreatic β-cells and regulate insulin secretion and glucose metabolism. To test this hypothesis, we used an in vitro cell-based skeletal muscle contraction system to uncover proteins released in the muscle secretome. Using an RNAseq screen, we identified growth differentiation factor 15 (GDF15) as a lead candidate. β-cells, human pancreatic islets, and C57BL/6J mice exposed to acute GDF15 treatment exhibited increased glucose-stimulated insulin secretion, and the mechanism involved activation of the insulin release pathway. Chronic GDF15 treatment in db/db mice reduced insulin resistance and preserved pancreatic PDX-1 expression. Consistently, plasma GDF15 increased concurrently with C-peptide prior to the onset of chronic hyperglycemia in humans with pre-diabetes. In addition, in humans with T2D, exercise-induced GDF15 was associated with enhanced β-cell function. These findings support GDF15 as a potential therapeutic target for type 2 diabetes and associated co-morbidities.
2022-10-31 | GSE139872 | GEO
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
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