Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA258439 | ENA |
REPOSITORIES: ENA
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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: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.
2014-08-20 | GSE60505 | GEO
Project description:A strong association of the gain-of-function mutation in the TALK-1 K+ channel (p.L114P) with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS). KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell–restricted K+ channel transcript and KCNK16 locus is strongly associated to type-2 diabetes. To investigate the impact of TALK-1-L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the TALK-1-L114P mutation was generated. Heterozygous and homozygous TALK-1-L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous TALK-1-L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increases whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and a complete loss of glucose-induced Ca2+ oscillations. Thus, adult TALK-1-L114P mice have reduced GSIS and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment for diabetes
2023-09-26 | GSE239566 | GEO
Project description:Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.
2019-09-05 | GSE136948 | GEO
Project description:Mutations in several transcription factors lead to a subtype of type 2 diabetes called maturity-onset diabetes of the young (MODY), which are characterized by autosomal dominant inheritance, an early age of disease onset, and development of marked hyperglycemia with a progressive impairment in insulin secretion (Shih and Stoffel, 2002). The most frequent form of MODY is caused by mutations in the gene encoding hepatocyte nuclear factor-1a (HNF-1a, TCF1). Mutant mice with loss of Tcf1 function as well as transgenic mice expressing a naturally occurring dominant-negative form of human TCF1(P291fsinsC) in pancreatic beta cells develop progressive hyperglycemia due to impaired glucose-stimulated insulin secretion (Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002). Importantly, these mice exhibit a progressive reduction in beta cell number, proliferation rate, and pancreatic insulin content. These data indicate that Tcf-1 target genes are also required for maintenance of normal beta cell mass. In this study we sought to identify target genes of Tcf-1 that may be responsible of mediating beta cell growth by comparing gene expression profiles of Tcf-1 knock-out and wild-type littermates in isolated pancreatic islets.
2007-02-27 | E-CBIL-21 | biostudies-arrayexpress
Project description:Activating mutations in the KATP channel cause a rare genetic form of diabetes called neonatal diabetes. These mutations render the channel permanently open results in membrane hyperpolarisation of the pancreatic beta-cell. This prevents calcium influx and impairs insulin secretion. Mice expressing the human neonatal diabetes mutation Kir6.2-V59M specifically in pancreatic beta-cells are diabetic but do not display dyslipidaemia or insulin resistance. In this experiment, gene expression changes were analysed to explore the effect of high blood glucose per se on isolated pancreatic islets
2017-07-05 | E-MTAB-5086 | biostudies-arrayexpress
Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4. Liver tissue samples were collected from hepatocyte- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice after fasting (22 h) or refeeding (4 h). Gene expression was analyzed by microarray. Mice were on a mixed background of C57BL/6J and 129.
2014-08-20 | E-GEOD-60527 | biostudies-arrayexpress
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).
2015-06-18 | E-GEOD-68317 | biostudies-arrayexpress
Project description:Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (MIRKO) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (QKO). Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in MIGIRKO muscle, and these were reversed with FoxO knockout. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.
2021-07-21 | GSE178356 | GEO
Project description:Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein. The Wfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of the present study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1-deficient mice. WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after stimulation with 2 and 10 mM glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mM glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After stimulation with 2 mM glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1-deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. These findings suggest an interactive role of WFS1 and TRPM5 in insulin secretion. 12 samples: three genotypes, 4 individuals in each genotype
2015-02-14 | E-GEOD-65929 | biostudies-arrayexpress