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  1. Article ; Online: Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes.

    Yung, Justin Hou Ming / Giacca, Adria

    Cells

    2020  Volume 9, Issue 3

    Abstract: Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated ...

    Abstract Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
    MeSH term(s) Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Fatty Acids, Nonesterified/metabolism ; Glucose/metabolism ; Humans ; Inflammation ; Insulin Resistance ; Insulin Secretion ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; JNK Mitogen-Activated Protein Kinases/genetics ; JNK Mitogen-Activated Protein Kinases/metabolism ; Obesity/drug therapy ; Obesity/metabolism ; Obesity/pathology ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Fatty Acids, Nonesterified ; Protein Kinase Inhibitors ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2020-03-13
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9030706
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: β-Cell Insulin Resistance Plays a Causal Role in Fat-Induced β-Cell Dysfunction In Vitro and In Vivo.

    Ivovic, Aleksandar / Yung, Justin Hou Ming / Oprescu, Andrei I / Vlavcheski, Filip / Mori, Yusaku / Rahman, S M Niazur / Ye, Wenyue / Eversley, Judith A / Wheeler, Michael B / Woo, Minna / Tsiani, Evangelia / Giacca, Adria

    Endocrinology

    2024  Volume 165, Issue 5

    Abstract: In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in β-cells where they play a role in β-cell ... ...

    Abstract In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in β-cells where they play a role in β-cell function. Therefore, inhibition of the insulin/insulin-like growth factor 1 pathway may be involved in fat-induced β-cell dysfunction. To address the role of β-cell insulin resistance in FFA-induced β-cell dysfunction we co-infused bisperoxovanadate (BPV) with oleate or olive oil for 48 hours in rats. BPV, a tyrosine phosphatase inhibitor, acts as an insulin mimetic and is devoid of any antioxidant effect that could prevent β-cell dysfunction, unlike most insulin sensitizers. Following fat infusion, rats either underwent hyperglycemic clamps for assessment of β-cell function in vivo or islets were isolated for ex vivo assessment of glucose-stimulated insulin secretion (GSIS). We also incubated islets with oleate or palmitate and BPV for in vitro assessment of GSIS and Akt (protein kinase B) phosphorylation. Next, mice with β-cell specific deletion of PTEN (phosphatase and tensin homolog; negative regulator of insulin signaling) and littermate controls were infused with oleate for 48 hours, followed by hyperglycemic clamps or ex vivo evaluation of GSIS. In rat experiments, BPV protected against fat-induced impairment of β-cell function in vivo, ex vivo, and in vitro. In mice, β-cell specific deletion of PTEN protected against oleate-induced β-cell dysfunction in vivo and ex vivo. These data support the hypothesis that β-cell insulin resistance plays a causal role in FFA-induced β-cell dysfunction.
    MeSH term(s) Animals ; Insulin Resistance/physiology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Rats ; Mice ; Male ; PTEN Phosphohydrolase/metabolism ; Oleic Acid/pharmacology ; Insulin/metabolism ; Mice, Inbred C57BL ; Insulin Secretion/drug effects ; Fatty Acids, Nonesterified/metabolism ; Rats, Sprague-Dawley
    Chemical Substances PTEN Phosphohydrolase (EC 3.1.3.67) ; Oleic Acid (2UMI9U37CP) ; Insulin ; Fatty Acids, Nonesterified
    Language English
    Publishing date 2024-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqae044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Prevention of Lipotoxicity in Pancreatic Islets with Gammahydroxybutyrate.

    Yung, Justin Hou Ming / Yeung, Lucy Shu Nga / Ivovic, Aleksandar / Tan, Yao Fang / Jentz, Emelien Mariella / Batchuluun, Battsetseg / Gohil, Himaben / Wheeler, Michael B / Joseph, Jamie W / Giacca, Adria / Mamelak, Mortimer

    Cells

    2022  Volume 11, Issue 3

    Abstract: Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma- ...

    Abstract Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.
    MeSH term(s) Animals ; Antioxidants/pharmacology ; Diabetes Mellitus, Type 2 ; Islets of Langerhans ; Mice ; NADP ; Palmitates/pharmacology ; Sodium Oxybate/pharmacology
    Chemical Substances Antioxidants ; Palmitates ; NADP (53-59-8) ; Sodium Oxybate (7G33012534)
    Language English
    Publishing date 2022-02-04
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11030545
    Database MEDical Literature Analysis and Retrieval System OnLINE

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