| 1. |
- Bader, Erik, et al.
(författare)
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Identification of proliferative and mature beta-cells in the islets of Langerhans
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 535:7612, s. 430-
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential(1-5); understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene(6), acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature beta-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs(7-9). We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger beta-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for beta-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional beta-cell heterogeneity and induce beta-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional beta-cell mass in diabetic patients.
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| 2. |
- Heni, Martin, et al.
(författare)
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Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:12, s. 2622-2631
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Methods: Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. Results: We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. Conclusions/interpretation: The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
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| 3. |
- 't Hart, Leen M., et al.
(författare)
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The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:9, s. 3275-3281
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Tidskriftsartikel (refereegranskat)abstract
- The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances -cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P 8.8 x 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 +/- 0.16% (5.6 +/- 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
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