This report describes a requirement for mechanical stress to Drosophila tissues in order to activate insulin signaling. How mechanical stress effected by physical activity may affect insulin signaling and insulin resistance in humans is a complex question (Marson et al. 2016, pubmed:27773709; Keshel and Coker 2015, pubmed:26523243), but aspects of it can be modeled in flies.
In Drosophila, insulin-like peptides (FBgg0000048) are released in response to nutrients in circulating hemolymph, which promote glucose uptake via the insulin signaling pathway (FBgg0000904). Conversely, starvation causes a gradual reduction in insulin signaling activity.
In all animals, movement causes mechanical stress to tissues, which can be sensed by cells. Insulin signaling / Tor pathway activity (as measured by phosphorylated S6k) is reduced in immmobilized, starved Drosophila larvae compared to free-moving starved controls, using several immobilization techniques. Even in the fat body of carcasses cultured ex vivo in medium with insulin, nutation of the sample increases insulin signaling, as measured by localization of insulin signaling components to the membrane and increased levels of phosphorylated Akt and S6k. Impairing integrins (FBgg0000058) will also block this increase in insulin signaling activity.
[updated July 2019 by FlyBase; FBrf0222196]
Physiological alterations associated with obesity, such as the increased availability of pro-inflammatory cytokines and free fatty acids, reduce the tissue sensitivity to insulin, increasing the need for insulin secretion for maintenance of glycemic homeostasis. At first, this compensatory mechanism is efficient, but increased levels of fasting insulin may already indicate insulin resistance, even with normal glycemic levels. Without effective therapeutic intervention, pancreatic secretion of insulin too will fail, increasing the fasting glucose, leading to pre-diabetes and type 2 diabetes. (Marson et al. 2016, pubmed:27773709.)
Both high caloric intake and sedentary behavior are linked to type 2 diabetes, but whether their effects are mediated solely through increased adiposity is unclear. (Kim et al. 2018, FBrf0238100.)
The overall etiology of insulin resistance is quite complex. It is known that a disproportionate accumulation of subcutaneous and abdominal fat contributes to the desensitization of insulin receptors that is characterized by an inhibited uptake of glucose within skeletal muscle and an impaired ability to suppress endogenous glucose production. From a simplistic standpoint, these physiological alterations may lead not only hyperglycemia, but also to exacerbations in fat deposition, promoting a chronic state of inflammation characterized by the release of pro-inflammatory cytokines. As insulin resistance worsens, β-cells continually stimulate insulin production in an attempt to reduce overwhelming hyperglycemia, but remain ineffective and may influence an additional state of hyperinsulinemia. (Keshel and Coker 2015 and references therein, pubmed:26523243.)
