TY - JOUR
T1 - Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle
AU - Bouzakri, Karim
AU - Plomgaard, Peter
AU - Berney, Thierry
AU - Donath, Marc Y
AU - Pedersen, Bente Klarlund
AU - Halban, Philippe A
PY - 2011/4
Y1 - 2011/4
N2 - 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) β-cells. RESEARCH DESIGN AND METHODS - Human skeletal muscle cells were cultured for up to 24 h with tumor necrosis factor (TNF)-α to induce insulin resistance, and mRNA expression for cytokines was analyzed and compared with controls (without TNF-α). Conditioned media were collected and candidate cytokines were measured by antibody array. Human and rat primary β-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 β-cells. Conditioned medium from control myotubes increased proliferation and glucose-stimulated insulin secretion (GSIS) from primary β-cells, whereas conditioned medium from TNF-α-treated insulin-resistant myotubes (TMs) exerted detrimental effects that were either independent (increased apoptosis and decreased proliferation) or dependent on the presence of TNF-α in TM (blunted GSIS). Knockdown of β-cell mitogen-activated protein 4 kinase 4 prevented these effects. Glucagon-like peptide 1 protected β-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 β-cells that is modulated by insulin resistance and could contribute to normal β-cell functional mass in healthy subjects, as well as the decrease seen in type 2 diabetes.
AB - 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) β-cells. RESEARCH DESIGN AND METHODS - Human skeletal muscle cells were cultured for up to 24 h with tumor necrosis factor (TNF)-α to induce insulin resistance, and mRNA expression for cytokines was analyzed and compared with controls (without TNF-α). Conditioned media were collected and candidate cytokines were measured by antibody array. Human and rat primary β-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 β-cells. Conditioned medium from control myotubes increased proliferation and glucose-stimulated insulin secretion (GSIS) from primary β-cells, whereas conditioned medium from TNF-α-treated insulin-resistant myotubes (TMs) exerted detrimental effects that were either independent (increased apoptosis and decreased proliferation) or dependent on the presence of TNF-α in TM (blunted GSIS). Knockdown of β-cell mitogen-activated protein 4 kinase 4 prevented these effects. Glucagon-like peptide 1 protected β-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 β-cells that is modulated by insulin resistance and could contribute to normal β-cell functional mass in healthy subjects, as well as the decrease seen in type 2 diabetes.
U2 - http://dx.doi.org/10.2337/db10-1178
DO - http://dx.doi.org/10.2337/db10-1178
M3 - Journal article
SN - 0012-1797
VL - 60
SP - 1111
EP - 1121
JO - Diabetes
JF - Diabetes
IS - 4
ER -
