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Edlund, Helena
Publications (10 of 33) Show all publications
Norlin, S., Axelsson, J., Ericsson, M. & Edlund, H. (2023). O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function. Communications Biology, 6(1), Article ID 877.
Open this publication in new window or tab >>O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
2023 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 877Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214065 (URN)10.1038/s42003-023-05255-6 (DOI)37626210 (PubMedID)2-s2.0-85168748980 (Scopus ID)
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-09-05Bibliographically approved
Ericsson, M., Steneberg, P., Nyrén, R. & Edlund, H. (2021). AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice. Communications Biology, 4(1), Article ID 1306.
Open this publication in new window or tab >>AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice
2021 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1306Article in journal (Refereed) Published
Abstract [en]

Age is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Cell and Molecular Biology Physiology
Identifiers
urn:nbn:se:umu:diva-189961 (URN)10.1038/s42003-021-02837-0 (DOI)000720447400003 ()34795407 (PubMedID)2-s2.0-85119445550 (Scopus ID)
Funder
Swedish Research Council, 2018-02999Knut and Alice Wallenberg Foundation, KAW 2015.0278
Available from: 2021-12-07 Created: 2021-12-07 Last updated: 2023-03-23Bibliographically approved
López-Pérez, A. R., Norlin, S., Steneberg, P., Remeseiro, S., Edlund, H. & Hörnblad, A. (2021). Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice. Scientific Reports, 11(1), Article ID 24410.
Open this publication in new window or tab >>Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 24410Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-190971 (URN)10.1038/s41598-021-03567-3 (DOI)000734163400004 ()34949756 (PubMedID)2-s2.0-85121738771 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2015.0278Swedish Research Council, 2018-05973The Kempe Foundations, SMK-1863
Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2022-09-15Bibliographically approved
Mucibabic, M., Steneberg, P., Lidh, E., Straseviciene, J., Ziolkowska, A., Dahl, U., . . . Edlund, H. (2020). alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice. Scientific Reports, 10(1), Article ID 20438.
Open this publication in new window or tab >>alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 20438Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes (T2D), alike Parkinson's disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in beta -cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (alpha Syn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in beta -cells. Here we show that alpha Syn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, alpha Syn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of alpha Syn in hIAPPtg mice enhanced beta -cell amyloid formation in vivo whereas beta -cell amyloid formation was reduced in hIAPPtg mice on a Snca (-/-) background. Taken together, our findings provide evidence that alpha Syn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for alpha Syn in beta -cell amyloid formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-178308 (URN)10.1038/s41598-020-77409-z (DOI)000596280500007 ()33235246 (PubMedID)2-s2.0-85096611352 (Scopus ID)
Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2023-03-23Bibliographically approved
Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., . . . Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI INSIGHT, 3(12), Article ID e99114.
Open this publication in new window or tab >>PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
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2018 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 3, no 12, article id e99114Article in journal (Refereed) Published
Abstract [en]

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

Place, publisher, year, edition, pages
American Society for Clinical Investigation, 2018
National Category
Endocrinology and Diabetes Physiology
Identifiers
urn:nbn:se:umu:diva-150778 (URN)10.1172/jci.insight.99114 (DOI)000436144100013 ()29925691 (PubMedID)2-s2.0-85061843820 (Scopus ID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2023-03-23Bibliographically approved
Nagatake, T., Shiogama, Y., Inoue, A., Kikuta, J., Honda, T., Tiwari, P., . . . Kunisawa, J. (2018). The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. Journal of Allergy and Clinical Immunology, 142(2), 470-482.e12
Open this publication in new window or tab >>The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques
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2018 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 142, no 2, p. 470-482.e12Article in journal (Refereed) Published
Abstract [en]

Background: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. Objective: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. Methods: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-alpha shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. Results: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. Conclusion: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER, 2018
Keywords
17 18-Epoxyeicosatetraenoic acid, G protein-coupled receptor 40, omega 3 fatty acid, contact persensitivity, dermatitis, neutrophil
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-151058 (URN)10.1016/j.jaci.2017.09.053 (DOI)000440664400016 ()29288079 (PubMedID)2-s2.0-85041690451 (Scopus ID)
Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2023-03-23Bibliographically approved
Norlin, S., Parekh, V. & Edlund, H. (2018). The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival. Development, 145(1), Article ID dev154468.
Open this publication in new window or tab >>The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 1, article id dev154468Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD, 2018
Keywords
Asna1/TRC40, Pancreatic hypoplasia, Pancreatic progenitor cell, Apoptosis, Impaired differentiation, tegrated stress response, Mouse
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-144961 (URN)10.1242/dev.154468 (DOI)000423820200013 ()29180572 (PubMedID)2-s2.0-85040795169 (Scopus ID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2023-03-24Bibliographically approved
Norlin, S., Parekh, V. S., Naredi, P. & Edlund, H. (2016). Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport. Diabetes, 65(1), 110-119
Open this publication in new window or tab >>Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport
2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 1, p. 110-119Article in journal (Refereed) Published
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.

National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-114567 (URN)10.2337/db15-0699 (DOI)000367424900014 ()26438609 (PubMedID)2-s2.0-84962135687 (Scopus ID)
Available from: 2016-02-17 Created: 2016-01-25 Last updated: 2023-03-24Bibliographically approved
Ali, Y., Diez, J., Selander, L., Zheng, X., Edlund, H. & Berggren, P.-O. (2016). The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice. Diabetologia, 59(5), 1007-1011
Open this publication in new window or tab >>The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 5, p. 1007-1011Article in journal (Refereed) Published
Abstract [en]

In vivo imaging of the developing pancreas is challenging due to the inaccessibility of the tissue. To circumvent this, on embryonic day 10.5 (E10.5) we transplanted a mouse developing pancreatic bud into the anterior chamber of the eye (ACE) to determine whether the eye is a useful transplant site to support pancreas development. We transplanted an E10.5 dorsal pancreatic bud into the ACE of a syngeneic recipient mouse. Using a mouse insulin promoter-green fluorescent protein (MIP-GFP) mouse as the tissue donor, we non-invasively imaged the pancreatic bud as it develops at single beta cell resolution across time. The transplanted pancreatic bud rapidly engrafts and vascularises when transplanted into the ACE. The pancreatic progenitor cells differentiate into exocrine and endocrine cells, including cells expressing insulin, glucagon and somatostatin. The morphology of the transplanted pancreatic bud resembles that of the native developing pancreas. Beta cells within the transplanted pancreatic bud respond to glucose in a manner similar to that of native fetal beta cells and superior to that of in vitro developed beta cells. Unlike in vitro grown pancreatic explants, pancreatic tissue developing in the ACE is vascularised, providing the developing pancreatic tissue with a milieu resembling the native situation. Altogether, we show that the ACE is able to support growth, differentiation and function of a developing pancreatic bud across time in vivo.

Keywords
Beta cells, Eye transplantation, In vivo imaging, Pancreas development, Pancreatic islets
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-120087 (URN)10.1007/s00125-016-3883-x (DOI)000373993300017 ()26847769 (PubMedID)2-s2.0-84957578941 (Scopus ID)
Available from: 2016-06-13 Created: 2016-05-09 Last updated: 2023-03-23Bibliographically approved
Steneberg, P., Sykaras, A. G., Backlund, F., Straseviciene, J., Söderström, I. & Edlund, H. (2015). Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance. Journal of Biological Chemistry, 290(31), 19034-19043
Open this publication in new window or tab >>Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 31, p. 19034-19043Article in journal (Refereed) Published
Abstract [en]

Hepatosteatosis is associated with the development of both hepatic insulin resistance and Type 2 diabetes. Hepatic expression of Cd36, a fatty acid transporter, is enhanced in obese and diabetic murine models and human nonalcoholic fatty liver disease, and thus it correlates with hyperinsulinemia, steatosis, and insulin resistance. Here, we have explored the effect of hyperinsulinemia on hepatic Cd36 expression, development of hepatosteatosis, insulin resistance, and dysglycemia. A 3-week sucrose-enriched diet was sufficient to provoke hyperinsulinemia, hepatosteatosis, hepatic insulin resistance, and dysglycemia in CBA/J mice. The development of hepatic steatosis and insulin resistance in CBA/J mice on a sucrose-enriched diet was paralleled by increased hepatic expression of the transcription factor Ppar gamma and its target gene Cd36 whereas that of genes implicated in lipogenesis, fatty acid oxidation, and VLDL secretion was unaltered. Additionally, we demonstrate that insulin, in a Ppar gamma-dependent manner, is sufficient to directly increase Cd36 expression in perfused livers and isolated hepatocytes. Mouse strains that display low insulin levels, i.e. C57BL6/J, and/or lack hepatic Ppar gamma, i.e. C3H/HeN, do not develop hepatic steatosis, insulin resistance, or dysglycemia on a sucrose-enriched diet, suggesting that elevated insulin levels, via enhanced CD36 expression, provoke fatty liver development that in turn leads to hepatic insulin resistance and dysglycemia. Thus, our data provide evidence for a direct role for hyperinsulinemia in stimulating hepatic Cd36 expression and thus the development of hepatosteatosis, hepatic insulin resistance, and dysglycemia.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-107866 (URN)10.1074/jbc.M115.640292 (DOI)000358781100021 ()26085100 (PubMedID)2-s2.0-84940532511 (Scopus ID)
Available from: 2015-09-16 Created: 2015-08-28 Last updated: 2023-03-24Bibliographically approved
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