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BIOLOGY INSULIN RESISTANCE IN TYPE 2 DIABETES? Question?

Hello, I am working through a little case study exercise related to insulin resistance, which is the primary cause of type-2 diabetes. According to my reading, "a continuous over stimulation of insulin signaling alters how the insulin receptor and its down-stream signaling pathways will respond to insulin."
Here is a list of possible research topics to investigate and determine their relative role in insulin resistance: 
Some of the documented changes in insulin signaling as a result of diabetes are: 
1. Decreased insulin receptor kinase activity upon binding of insulin to the receptor. 
2. Decreased binding of signaling effectors to the insulin receptor due to: a) less phosphorylation sites on the insulin receptor, and b)feedback inhibition on the signaling molecule, preventing its binding to the insulin receptor. 
3. Decreased signaling effector binding leads to defective downstream activation of the kinase cascade and second messenger signaling pathways. 
4. Decreased glut4 (glucose transporter) fusion to the cell membrane and less glucose transported into the cell. 
 
Considering these topics, which project would you pick to study and why? What  kind of experiments would you do? 
 
I am really lost on this, and it looks like any potential topic could be a good one, but I was just wondering on your reasoning between picking one project over the other and how you would experiment it. 
 
Thank you for any help! I am really lost!

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Naina B. | Naina, a versatile tutorNaina, a versatile tutor
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Angelica, 
 
For successful or rather fruitful research outcome one has to pick up the project that is feasible in the lab setting where one is likely to work.
The next point is to find out if research material is easily available.
 
It is a safe bet to start with cell lines that other people have tried to work with, they already have the information about how to maintain those cell lines. In general, cell lines have less complications than human subjects. To work with patients, one has to go through protocol approval and myriads of other regulations concerning privacy of patients etc. Then there is much variability in such experiments. 
 
Best bet is to find an animal model ( mouse or rat), study its relevant literature and consider the project based on that. For instance, you may find out through literature which kinase molecules are defective in mouse model. 
 
Based on published literature, you have to decide what is the best possible experimental strategy in terms of being feasible and providing clear results. 
 
Best, 
 
 

Comments

Hi Naina, 
I appreciate your post. It does seem like it would be important to test on animals. Is there a particular experiment in mind you would focus on? It appears that all of them are well-correlated with insulin resistance in type-2 diabetes. Certainly there is insulin being produced, but the cells are not responding to it as heavily. Do you believe it would be best to research the first topic: Decreased insulin receptor kinase activity upon binding of insulin to the receptor., the fourth topic :decreased glut 4 fusion to the cell membrane, or one of the topics in between? This is merely hypothetical (not actually carrying out any experiments). If I didn't want to research the decreased insulin receptor kinase activity but rather wanted to study glut4's reduced ability to fuse to the membrane, would it sound justified by stating that it is important to study this because the glut4 transporter needs to fuse in order for the excess glucose to be taken up into the cells. Maybe I could hypothetically test this by having test subjects such as mice develop insulin resistance and somehow examine the cells to determine how frequent the glut4 transporter is present and how much the levels of glucose in the blood vary when it is present or not. I am guessing there is no wrong answer to this question, but I feel most comfortable with the last experiment because it is the most understandable to me. 
Hi Angelica,
 
If you need to write a probable experimental proposal then glut4 will be good one since you feel comfortable with it and it is outside the box experimental thought. You would need qualitative and quantitative test for glut4, for instance is it altered in sequence to carry out the function? Is it expressed at reduced level?  Is it sensitive to diet or to media if using cell lines. And so on. Just make sure to cite adequate references from the literature to support your arguments.
 
Best