| 1. |
- Dahlman, I, et al.
(författare)
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Numerous Genes in Loci Associated With Body Fat Distribution Are Linked to Adipose Function
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:2, s. 433-437
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Tidskriftsartikel (refereegranskat)abstract
- Central fat accumulation is a strong risk factor for type 2 diabetes. Genome-wide association studies have identified numerous loci associated with body fat distribution. The objectives of the current study are to examine whether genes in genetic loci linked to fat distribution can be linked to fat cell size and number (morphology) and/or adipose tissue function. We show, in a cohort of 114 women, that almost half of the 96 genes in these loci are indeed associated with abdominal subcutaneous adipose tissue parameters. Thus, adipose mRNA expression of the genes is strongly related to adipose morphology, catecholamine-induced lipid mobilization (lipolysis), or insulin-stimulated lipid synthesis in adipocytes (lipogenesis). In conclusion, the genetic influence on body fat distribution could be mediated via several specific alterations in adipose tissue morphology and function, which in turn may influence the development of type 2 diabetes.
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| 2. |
- Strawbridge, RJ, et al.
(författare)
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Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:10, s. 2888-2899
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe−/− cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.
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| 3. |
- Strodthoff, D, et al.
(författare)
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Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:10, s. 3425-3438
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptors (TLRs) have been implicated in the pathogenesis of type 2 diabetes. We examined the function of TLR3 in glucose metabolism and type 2 diabetes–related phenotypes in animals and humans. TLR3 is highly expressed in the pancreas, suggesting that it can influence metabolism. Using a diet-induced obesity model, we show that TLR3-deficient mice had enhanced glycemic control, facilitated by elevated insulin secretion. Despite having high insulin levels, Tlr3−/− mice did not experience disturbances in whole-body insulin sensitivity, suggesting that they have a robust metabolic system that manages increased insulin secretion. Increase in insulin secretion was associated with upregulation of islet glucose phosphorylation as well as exocytotic protein VAMP-2 in Tlr3−/− islets. TLR3 deficiency also modified the plasma lipid profile, decreasing VLDL levels due to decreased triglyceride biosynthesis. Moreover, a meta-analysis of two healthy human populations showed that a missense single nucleotide polymorphism in TLR3 (encoding L412F) was linked to elevated insulin levels, consistent with our experimental findings. In conclusion, our results increase the understanding of the function of innate receptors in metabolic disorders and implicate TLR3 as a key control system in metabolic regulation.
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