The challenge

Time-series data can be difficult to analyse and interpret

Insulin is a key ingredient in cell metabolism and plays an essential role in long-term health, in obesity, and in diseases such as diabetes.

When we eat glucose it comes into the bloodstream and triggers insulin secretion. Insulin then travels via the blood and binds to receptor molecules, principally on muscle, fat or liver tissue. The insulin binds to that tissue, which initiates a convoluted series of thousands of molecular events.

Recent research to measure the complex processes that take place inside a cell stimulated by insulin created a new kind of dataset. However, there were no adequate methods or tools to analyse, visualise and interpret the multidimensional datasets that resulted from these studies.

Our response

Visualising data to understand complexity

Working in an interdisciplinary team with colleagues from the University of Sydney on the BioCode project, we set about explaining the complexities of the insulin signaling pathway to make it easier for researchers to understand and interpret the data they had collected. We did this by applying data visualisation, integration, user experience design and graphic design to the research problem.

The results

Showing how insulin works with Minardo

A technical diagram with a large u-shape with purple centre representing a cell's nucleus; around the outside are numerous lines and arrows indicating the process of insulin signaling inside the cell.

Minardo is a tool for visualising complex time-course data from high-throughput mass spectrometry experiments. Here, Minardo has been used to show the insulin/IGF1 signaling pathway inside a cell; this work has been published in the prestigious journal Cell (Ma et al. 2015).

Our data visualisation team created Minardo, a web-based tool inspired by Charles Minard, a nineteenth Century French civil engineer who was a pioneer in the field of information graphics.

Minardo condenses multiple dimensions of information, including time and a range of specific biochemical processes, into one image. An interactive online version allows users to see moving parts and find additional information by hovering over the displayed events.

As a result of this simplification, we helped improve understanding of a vitally important but poorly understood process. The set of methods and tools we developed can also be used by other life scientists to understand similar complex datasets.

[Image appears of a hand drawing a human figure outline on a whiteboard]

Narrator: What is the role of insulin and how does it help your body regulate blood glucose?

[Image shows the human figure outline eating an apple and the hand drawing in the small intestine]

When eating a meal such as this apple your body will begin breaking it down so that it can absorb its’ nutrients in the small intestine.

[Image shows the hand now drawing the path of the apple through the stomach into the small intestine and adding the pancreas]

Here the bite of the apple travels through the stomach and into the small intestine. Right next to the small intestine and stomach we can find the pancreas.

[Image adds a red box around the small intestine area and then the hand draws the small intestine area in greater detail]

Let us zoom into this area here. One of the final products of food digestion is glucose, commonly known as sugar. Glucose is absorbed from the small intestine into your blood.

[Image now shows the blood stream and the pancreas being drawn and it shows the path of the insulin into the blood stream]

As a result we have high blood glucose levels. This will stimulate the pancreas to release the hormone insulin into the bloodstream. Insulin targets many cells to promote the clearance of glucose from the blood. Defects in this process can be catastrophic as we often see in individuals with Type 1 Diabetes who lack the ability to make insulin.

[Image now shows the hand drawing in skeletal muscle cells, liver cells and fat cells]

Insulin targets cells such as skeletal muscle cells, liver cells and fat cells.

[Image shows the hand drawing in a fat cell with insulin receptors on the surface, the path of the insulin into the fat cell and the glucose storage area]

Let us look at the fat cell in more detail and the effects insulin has on it. The fat cells have insulin receptors on its’ cell surface. Insulin binds to these receptors in a very precise way which triggers a sequence of events to occur inside the cell, a cascade of events which will lead to a number of outcomes. These outcomes include the uptake of glucose and promoting glucose storage in the form of glycogen.

[Image shows the hand now adding the glucose storage lipids to the fat cell and the path of the insulin out of the cell]

In fat cells insulin promotes a glucose storage in the form of lipids, inhibits the breakdown of lipids, stimulates protein synthesis and modifies gene expression.

[Image shows the hand writing text: Insulin promotes energy storage and normal blood glucose]

Overall insulin promotes energy storage within fat cells, promoting the clearance of glucose from the blood, returning blood glucose back to normal.

[Image shows the hand drawing an enlarged insulin receptor and depicting how the insulin receptor works]

Importantly when insulin binds to the receptor the multiple processes that occur within the fat cell are not all turned on at once. Insulin regulates the multiple processes using protein phosphorylation. Protein phosphorylation is a normal chemical reaction that changes the behaviour of proteins inside the cell.

[Image shows the hand writing text: Turns processes on or off]

Thus by using protein phosphorylation the cell can select which processes to turn on or off and when.

[Image shows the hand drawing a researcher and writing text: Mass Spectometry]

Researchers can study protein phosphorylation in cells using a technique called mass spectrometry. Recent studies in the fat cell reveal that following insulin stimulation many thousands of changes in protein phosphorylation occur but importantly they do not occur simultaneously. Some happen rapidly, others more slow. Some go up and others go down.

[Image changes to show a Minardo plot tool]

To unravel this complexity they have recently developed a tool known as the Minardo plot as a way to visualise this complexity. Let us learn more about what this tool can reveal.

[Image changes to show the hand drawing a fat cell with a nucleus at the centre]

Here is a fat cell. This is a cell’s plasma membrane. Inside the cell there is a nucleus which contains the D.N.A., our genetic material.

[Image shows the hand writing in the text: Cytoplasm]

Surrounding the nucleus is a cytoplasm.

[Image shows the hand adding in lipids to the fat cell and then showing an arrow to show the path of the fatty acids]

At rest our body requires energy to function. The fat cell serves as an energy reserve, breaking down its’ lipids, releasing fatty acids into circulation and these can be used for energy in other organs such as the heart.

[Image shows the hand adding insulin and insulin receptors into the drawing]

After a meal, insulin is released and binds to insulin receptors on fat cells.

[Image shows the hand writing text inside the cell: Cascade of phosphorylation events]

This triggers a cascade of phosphorylation events inside the cell that leads to a number of outcomes occurring at different times.

[Image shows the hand drawing in an arrow around the fat cell beginning with 0 seconds and adding 15 sec, 30 sec, 1 min, 2 min, 5 min, 10 min and 20 min at intervals]

Here we will look at a time frame from zero seconds to 20 minutes following the binding of insulin to the insulin receptor. The insulin phosphorylation cascade leads to the inhibition of lipid breakdown beginning right away. By 30 seconds it stimulates

[Image shows the hand drawing in Glut4 glucose transporters at the 30 second mark in the cell]

Glut4 glucose transporters to make their way to the surface of the cell.

[Image shows the path of the Glut4 on the plasma membrane and the path of the glucose outside the cell moving into the cell at the 5 minute mark]

By five minutes Glut4 is highly active on a plasma membrane. Glut4 allows the high amounts of glucose outside the cell to move inside the cell.

[Image shows the hand adding glycogen to the cell at the 20 minute mark]

By 20 minutes the cascade of phosphorylation events stimulates glucose storage.

[Image shows the hand drawing in lipids at the 20 minute mark]

This is done by storing glucose as glycogen through glycogenesis and particularly in fat cells storing glucose as lipids through lypogenesis.

[Image shows the hand drawing in protein synthesis between the 1 minute and 2 minute marks on the cell]

Moving back another separate cascade of events stimulates protein synthesis and modification of gene expression. To modify gene expression certain proteins are activated in the cytoplasm of the cell. Some of these reactions occur within seconds and some within minutes.

[Image shows the hand drawing the path of the activated protein into the nucleus]

This activated protein is now able to move inside the nucleus. It can now interact with the D.N.A. to modify gene expression. By examining changes over time researchers are now able to piece together the precise order of events that the fat cell performs to take up glucose in response to insulin. One can imagine that if the cell did not respond to insulin properly it would not be able to process the glucose properly leading to the onset of Type 2 Diabetes.

[Image changes to show the Minardo plot tool and text appears:]

To understand diseases like diabetes it is crucial now to understand its’ underlying complexity and to utilise sophisticated ways like Minardo to visualise the data in a relatively simple way.

[Garvan Institute, University of Sydney and CSIRO logos and text appears: In collaboration with: David Ma, Christian Stolte, Dr. James Krycer, Dr. David James & Dr. Sean O’Donoghue,]

[Image changes and text appears:]

What is the role of insulin, and how does it help your body?

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