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Centre of Inflammation and Metabolism (CIM)


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100Bimodal effect on pancreatic beta-cells of secretory products from normal or insulin-resistant human skeletal muscle.
Bouzakri K; Plomgaard P; Berney T; Donath MY; Pedersen BK; Halban PA
Diabetes 2011; 60(4): 1111-21
PubMed ID: 21378173

OBJECTIVE: Type 2 diabetes is characterized by insulin resistance with a relative deficiency in insulin secretion. This study explored the potential communication between insulin-resistant human skeletal muscle and primary (human and rat) beta-cells. RESEARCH DESIGN AND METHODS: Human skeletal muscle cells were cultured for up to 24 h with tumor necrosis factor (TNF)-alpha to induce insulin resistance, and mRNA expression for cytokines was analyzed and compared with controls (without TNF-alpha). Conditioned media were collected and candidate cytokines were measured by antibody array. Human and rat primary beta-cells were used to explore the impact of exposure to conditioned media for 24 h on apoptosis, proliferation, short-term insulin secretion, and key signaling protein phosphorylation and expression. RESULTS: Human myotubes express and release a different panel of myokines depending on their insulin sensitivity, with each panel exerting differential effects on beta-cells. Conditioned medium from control myotubes increased proliferation and glucose-stimulated insulin secretion (GSIS) from primary beta-cells, whereas conditioned medium from TNF-alpha-treated insulin-resistant myotubes (TMs) exerted detrimental effects that were either independent (increased apoptosis and decreased proliferation) or dependent on the presence of TNF-alpha in TM (blunted GSIS). Knockdown of beta-cell mitogen-activated protein 4 kinase 4 prevented these effects. Glucagon-like peptide 1 protected beta-cells against decreased proliferation and apoptosis evoked by TMs, while interleukin-1 receptor antagonist only prevented the latter. CONCLUSIONS: Taken together, these data suggest a possible new route of communication between skeletal muscle and beta-cells that is modulated by insulin resistance and could contribute to normal beta-cell functional mass in healthy subjects, as well as the decrease seen in type 2 diabetes. Bouzakri, Karim

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