In a study that examined the effect of insulin on liver cells taken from mice, researchers have uncovered how insulin amounts shape the flow of information through the signalling network. The study also provides insights into the degree to which major and minor components are important in keeping this signalling process intact. This knowledge can direct further studies to identify targets for therapy.
Larger role of insulin
Insulin is a hormone secreted by the b cells of the pancreas. It is commonly associated with an ability to regulate glucose metabolism. However, later studies (from around 1949 until recently) have shown it plays a larger role and helps in growth and maintenance of tissues. Despite years of study, fundamental details as to how differential amounts of insulin impact cells are unknown.
An important mechanism in the cell is insulin signalling, which is a series of biochemical reactions that convey information about availability of insulin and the necessity to regulate the glucose in the blood. There are two main pathways for insulin signalling, named AKT and ERK, which together balance metabolism and growth. These specifically control storage of glucose in the liver and also stimulate glucose transport in skeletal muscle and fat. Abnormalities in insulin signalling thus impact health and survival itself of organisms and the study addresses an important piece of the puzzle.
Study design
The study was done on liver cells isolated from mice. The experimental design mimicked both normal levels of insulin, as in a healthy individual, and abnormal levels of insulin that is associated with pathophysiology. “This was achieved by treating cells with (a) low fasted concentrations of insulin (b) high fed concentrations of insulin (c) very high hyperinsulinemic levels (d) pulsatile fasted insulin followed by fed insulin and (e) continuous or repeat exposure to fed insulin levels,” says Namrata Shukla from Tata Institute of Fundamental Research (TIFR), Mumbai, the first author of a paper on this work published in Proceedings of the National Academy of Sciences. The study was a collaboration between TIFR Mumbai, TIFR Hyderabad and Indian Institute of Technology Bombay.
Ullas Kolthur-Seetharaman from TIFR (Mumbai and Hyderabad), who led the work, explains that previous studies employed different, often very high amounts of insulin to investigate changes in signalling.
While these have revealed the components, the network properties and robustness of signaling has not been assessed by varying insulin inputs.
“Our study employs multiple regimes of insulin, both normal and abnormal, which together have illustrated how changes in levels of insulin is able to shape the flow of information within cells,” he says.
The study found that the inputs from the fasted insulin levels created a memory that improved the fed insulin inputs. “ It also elucidates the detrimental impact of constant high insulin as in the case of uncontrolled feeding habits, without a fasting phase, and its effects on signaling molecules that govern tissue maintenance and growth,” says Prof Kolthur-Seetharaman.
Future interventions
“Finally, it identifies potential novel regulatory components and parameters whose modulation could lead to better therapeutic interventions in the future to reduce tissue damage, beyond the usual impact on blood glucose,” he adds.
Ranjith Padinhateeri and Shantanu Kadam from IIT Bombay collaborated with the TIFR group on the mathematical modelling or simulation part of the study.