Skeletal muscle is the main tissue responsible for insulin-stimulated glucose uptake, so it plays a major role in regulating glycemia after meals. In insulin resistance, the muscle is less able to use glucose in response to insulin, thus participating in the hyperglycemia of diabetic patients, responsible for serious complications. Any strategy to improve insulin sensitivity of skeletal muscle would therefore reduce hyperglycemia in diabetic patients and improve associated complications. This is the challenge of any studies trying to identify new molecular mechanisms involved in muscle insulin resistance. The work of the team 3 managed by Jennifer Rieusset, in collaboration with the teams 2 and 5, have just highlighted the critical role of endoplasmic reticulum (ER)-mitochondria miscommunication in the development of the muscle insulin resistance, suggesting future avenues for improving blood glucose levels in diabetic patients.
In the study published at January 11, 2018 in the journal “Diabetes”, we demonstrate that the communication between ER and mitochondria plays a key role in the control of insulin action in skeletal muscle and that organelle miscommunication is associated with muscle insulin resistance in mice and humans. More specifically, the main advances of this work are:
– ER-mitochondrial contacts are altered in the skeletal muscle of different mouse models of insulin resistance and type 2 diabetes, and this lack of intracellular communication precedes the onset of mitochondrial dysfunction and muscle insulin resistance.
– The induction of insulin resistance in human myotubes is associated with a reduction of ER-mitochondria interactions and calcium exchange, and the increase in these structural contacts prevents palmitate-induced insulin resistance.
– Decreasing ER-mitochondria interactions is sufficient to alter muscle insulin action both in vitro and in vivo
– The myotubes of obese patients with or without diabetes, which conserve their insulin resistance in primary culture, show a significant reduction of ER-mitochondrial interactions, compared to myotubes of control subjects.
Therefore, a loss of communication between ER and mitochondria could be a common alteration to several insulin-sensitive tissues, and thus could play a major role in the hyperglycemia of diabetic patients. Finding strategies to improve organelle communication may be a new treatment pathway to improve insulin sensitivity and glucose homeostasis in type 2 diabetes. For that, future studies to better understand how ER-mitochondria interactions are regulated and how they participate in the control of insulin action are necessary, in order to identify new therapeutic strategies to modulate organelle communication and hopefully improve metabolic diseases.
A lack of communication between ER and mitochondria contributes to muscle insulin resistance. In physiological situations, ER and mitochondria interact and exchange calcium and this contributes to the control of insulin-stimulated glucose uptake into skeletal muscle, and thus to the maintenance of normoglycemia. In insulin resistance, both organelles interact less, disrupting calcium transfer, and probably mitochondrial function, and thus altering the action of insulin. The resultant decrease in insulin-stimulated glucose transport then contributes to hyperglycemia observed during obesity and type 2 diabetes, and which is a source of serious complications.
Tubbs E, Chanon S, Robert M, Bendridi N, Bidaux G, Chauvin MA, Ji-Cao J, Durand C, Gauvrit-Ramette D, Vidal H, Lefai E, Rieusset J. Disruption of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans. Diabetes. 2018 Jan 11. pii: db170316. doi: 10.2337/db17-0316. [Epub ahead of print] PMID: 29326365
Team 3 – Laboratoire CarMeN