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  • 1.
    López-Pérez, Ana R.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Norlin, Stefan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Steneberg, Pär
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Remeseiro, Silvia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 24410Article in journal (Refereed)
    Abstract [en]

    AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

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  • 2.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nuclear factor-{kappa}B activity in {beta}-cells is required for glucose-stimulated insulin secretion.2005In: Diabetes, ISSN 0012-1797, Vol. 54, no 1, p. 125-32Article in journal (Refereed)
  • 3.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 877Article in journal (Refereed)
    Abstract [en]

    Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.

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  • 4.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Parekh, Vishal
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 1, article id dev154468Article in journal (Refereed)
    Abstract [en]

    Asna1, also known as TRC40, is implicated in the delivery of tail-anchored (TA) proteins into the endoplasmic reticulum (ER), in vesicle-mediated transport, and in chaperoning unfolded proteins during oxidative stress/ATP depletion. Here, we show that Asna1 inactivation in pancreatic progenitor cells leads to redistribution of the Golgi TA SNARE proteins syntaxin 5 and syntaxin 6, Golgi fragmentation, and accumulation of cytosolic p62(+) puncta. Asna(1-/-) multipotent progenitor cells (MPCs) selectively activate integrated stress response signaling and undergo apoptosis, thereby disrupting endocrine and acinar cell differentiation, resulting in pancreatic agenesis. Rescue experiments implicate the Asna1 ATPase activity and a CXXC di-cysteine motif in ensuring Golgi integrity, syntaxin 5 localization and MPC survival. Ex vivo inhibition of retrograde transport reproduces the perturbed Golgi morphology, and syntaxin 5 and syntaxin 6 expression, whereas modulation of p53 activity, using PFT-alpha and Nutlin-3, prevents or reproduces apoptosis in Asna1-deficient and wild-type MPCs, respectively. These findings support a role for the Asna1 ATPase activity in ensuring the survival of pancreatic MPCs, possibly by counteracting p53-mediated apoptosis.

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  • 5.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Parekh, Vishal S.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Naredi, Peter
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 1, p. 110-119Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) is characterized by insulin resistance and beta-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory beta-cell function is maintained. The increased demand for insulin stresses the beta-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with beta-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and beta-cell function, we inactivated Asnal in beta-cells of mice. We show that Asna1 beta(-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asnal function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in beta-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(beta-/-) beta-cells and resulted in reduced insulin content and ER stress. These data support a model where Asnal ensures retrograde transport and, hence, ER and insulin homeostasis in beta-cells.

  • 6.
    Svensson, Per
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bergqvist, Ingela
    Norlin, Stefan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    MFng is dispensable for mouse pancreas development and function2009In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 29, no 8, p. 2129-2138Article in journal (Refereed)
    Abstract [en]

    Notch signaling regulates pancreatic cell differentiation, and mutations of various Notch signaling components result in perturbed pancreas development. Members of the Fringe family of beta1,3-N-acetylglucosaminyltransferases, Manic Fringe (MFng), Lunatic Fringe (LFng), and Radical Fringe (RFng), modulate Notch signaling, and MFng has been suggested to regulate pancreatic endocrine cell differentiation. We have characterized the expression of the three mouse Fringe genes in the developing mouse pancreas between embryonic days 9 and 14 and show that the expression of MFng colocalized with the proendocrine transcription factor Ngn3. In contrast, the expression of LFng colocalized with the exocrine marker Ptf1a, whereas RFng was not expressed. Moreover, we show that expression of MFng is lost in Ngn3 mutant mice, providing evidence that MFng is genetically downstream of Ngn3. Gain- and loss-of-function analyses of MFng by the generation of mice that overexpress MFng in early pancreatic progenitor cells and mice with a targeted deletion of MFng provide, however, evidence that MFng is dispensable for pancreas development and function, since no pancreatic defects in these mice were observed.

1 - 6 of 6
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