In diabetes, cells eventually fail to respond to insulin, a hormone involved in regulating glucose levels in the blood. Researchers from Inserm have shown, in vitro, that a defect in communication between two intracellular organelles is involved in the onset of this insulin resistance. A finding which paves the way for a potential therapeutic strategy.
The regulation of blood glucose is dependent on insulin, a hormone secreted by the pancreas. Insulin is a blood glucose-lowering hormone: it promotes the storage of circulating blood glucose in muscle, fat and liver cells and inhibits its synthesis and release from the stored reserves. In people with diabetes, these cells do not respond so well to insulin: a phenomenon known as insulin resistance.
Researchers are interested in insulin resistance because it appears very early on in the development of diabetes: it precedes episodes of prolonged hyperglycemia and pancreatic impairment. Therefore, it is hoped to be able to prevent the onset of full-blown diabetes by improving the sensitivity of the peripheral tissues to insulin.
Intracellular processes involved
"A large amount of research has been performed on the subject of factors likely to affect insulin sensitivity, states Jennifer Rieusset*. However, in recent years the focus has been on two intracellular organelles, which present alterations in the event of insulin resistance: the mitochondria and endoplasmic reticulum. It is our hypothesis that a defect in communication between these two organelles could be involved in the onset of this resistance."
In 2014, Jennifer Rieusset and her colleagues were the first to demonstrate, using liver cells, that the interactions between the two organelles were indeed essential for glycemic balance and that they were impaired in the event of insulin resistance. In an article very recently published in Diabetes, the researchers point to a convergent body of data, confirming the importance of these interactions in the skeletal muscle. What is more, their results suggest a causal link between the impaired communication between the two organelles and muscle cell resistance to insulin.
Is a lack of communication to blame?
During this research, the team explored these interactions in detail using skeletal muscle cells. In response to insulin, 80% of the circulating blood glucose is taken up by the muscles alone. This makes them a privileged target for a treatment to improve sensitivity to this hormone.
One major original aspect of the study was to have used human myotubes in primary culture (muscle cells obtained by biopsy which are then cultured). By comparing the data obtained from myotubes from obese patients both with and without diabetes, the researchers showed that the number of interactions between the organelles is correlated with the degree of insulin sensitivity: the more the organelles communicate, the more the cells are sensitive to insulin. Conversely, the less they communicate, the more the cell is resistant.
Towards a new therapeutic strategy
The causal nature of this relationship is suggested by additional experiments performed on the myotubes of healthy subjects. The team was able to show that altering the exchanges between the two organelles using molecular approaches caused the cell to become insulin-resistant. Conversely, if insulin resistance was created by treating the cells with palmitate (one of the most commonly-occurring fatty acids in animals), an interaction defect was observed between the mitochondria and the endoplasmic reticulum. In addition, if this interaction was restored artificially, insulin sensitivity was improved. These findings are supported by data obtained by the team in parallel from various animal models.
“The next step is to test whether it’s possible to restore insulin sensitivity in vivo, by acting on the communication between the mitochondria and endoplasmic reticulum, concludes Jennifer Rieusset. To do this we need to elucidate the physiological regulation processes of these interactions, in order to develop pharmacological tools able to stimulate or inhibit this communication."
Inserm/Inra/Université de Lyon 1/INSA Lyon unit 1060, team Organelle Communication and Diabetes, CarMeN laboratory, Oullins.
E. Tubbs et al., Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) integrity contributes to muscle insulin resistance in mice and humans. Diabetes, online edition of January 11, 2018.