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Backlund, Fredrik
Publications (3 of 3) Show all publications
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
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
Steneberg, P., Bernardo, L., Edfalk, S., Lundberg, L., Backlund, F., Ostenson, C.-G. & Edlund, H. (2013). The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells. Diabetes, 62(6), 2004-2014
Open this publication in new window or tab >>The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells
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2013 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 6, p. 2004-2014Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired beta-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed beta-cell function in Ide knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content are reduced in beta-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that a-synuclein and IDE levels are inversely correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of a-synuclein in beta-cells in vivo impair not only GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for a-synuclein in beta-cell function.

National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-76787 (URN)10.2337/db12-1045 (DOI)000319845000030 ()2-s2.0-84878253079 (Scopus ID)
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2023-03-24Bibliographically approved
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