| 1. |
- Ling, Charlotte, et al.
(författare)
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Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 51, s. 615-622
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion. METHODS: The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA). RESULTS: PPARGC1A mRNA expression was reduced by 90% (p < 0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p
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| 2. |
- Granhall, Charlotte, et al.
(författare)
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High-resolution QTL Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals less than 800-kb in the Species Conserved Niddm1i of the GK Rat.
- 2006
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 174:Sep 1, s. 1565-1572
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Tidskriftsartikel (refereegranskat)abstract
- Niddmli, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM11 strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine mapping located one hyperglycemia locus within 700 kb (Niddmli4, P = 5 X 10(-6)). Two adjacent loci were also detected, and the GK allele at Niddn1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while TJ712 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2(GK) and Niddm1i3(GK)) act in opposite directions.
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| 3. |
- Granhall, Charlotte, et al.
(författare)
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Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:12, s. 3494-3500
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Tidskriftsartikel (refereegranskat)abstract
- The effects of genetic variation on molecular functions predisposing to type 2 diabetes are still largely unknown. Here, in a specifically designed diabetes model, we couple separate gene loci to mechanisms of P-cell pathology. Niddm1i is a major glucose-controlling 16-Mb region in the diabetic GK rat that causes defective insulin secretion and corresponds to loci in humans and mice associated with type 2 diabetes. Generation of a series of congenic rat strains harboring different parts of GK-derived Niddm1i enabled fine mapping of this locus. Congenic strains carrying the GK genotype distally in Niddm1i displayed reduced insulin secretion in response to both glucose and high potassium, as well as decreased single-cell exocytosis. By contrast, a strain carrying the GK genotype proximally in Niddm1i exhibited both intact insulin release in response to high potassium and intact single-cell exocytosis, but insulin secretion was suppressed when stimulated by glucose. Islets from this strain also failed to respond to glucose by increasing the cellular ATP-to-ADP ratio. Changes in P-cell mass did not contribute to the secretory defects. We conclude that the failure of insulin secretion in type 2 diabetes includes distinct functional defects in glucose metabolism and insulin exocytosis of the P-cell and that their genetic fundaments are encoded by different loci within Niddm1i.
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| 4. |
- Granhall, Charlotte
(författare)
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Type 2 Diabetes Genes Contributing to Insulin Secretion Defects
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes is caused by a combination of environmental and inherited factors influencing the progression of insulin resistance and impaired insulin secretion leading to chronically elevated blood glucose levels. The aim of this thesis was to functionally and genetically characterise the species-conserved diabetes locus Niddm1i of the GK rat encoding hyperglycaemia and defect insulin secretion. High-resolution QTL mapping revealed that Niddm1i is a composite of at least four subloci influencing diabetes-associated phenotypes (Niddm1i1-Niddm1i4). Sorcs3 and Sorcs1 were positionally mapped as diabetes candidate genes within Niddm1i2 and Niddm1i3. Investigation of pancreatic islets and beta-cells identified two separately inherited insulin secretion defects. A 3-Mb region in the proximal part of Niddm1i encoded impaired beta-cell glucose metabolism and ATP production, and a 4.5-Mb region in the distal half of Niddm1i encoded impaired insulin exocytosis. These findings were in line with the observed decreased transcript levels of genes involved in cellular respiration and vesicle transport in young NIDDM1I rat pancreas. Niddm1i also caused increased transcriptional levels of genes involved in pancreatic immune response and inflammation. By use of congenic strains dissecting the 4.5-Mb region in the distal half of Niddm1i, impaired insulin secretion in islets was mapped to the same chromosomal region as Niddm1i4 encoding hyperglycaemia. Increased gene expression level of Adra2a was observed for the GK genotype in islets. In conclusion, several loci and genes influencing glucose homeostasis and insulin secretion within Niddm1i were identified. Further studies of the identified candidate genes in human populations could establish their potential role in human type 2 diabetes.
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| 5. |
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| 6. |
- Rosengren, Anders, et al.
(författare)
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Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 327:5962, s. 217-20
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Tidskriftsartikel (refereegranskat)abstract
- Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.
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