An introduction by Dr Alex Ryan




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Welcome to my first post, and let me introduce myself. I’m a research scientist studying Type 2 diabetes and obesity at the University of California San Diego. Last year I completed my Diabetes UK-funded PhD at the University of Manchester. My colleagues and I are currently going through the trials and tribulations of publishing a scientific paper, so I won’t go into detail about my research, but I’ll give you a brief overview. The title of my PhD thesis was “The Role of Phosphatidylinositol (4,5)-bisphosphate and its regulatory proteins in the development of insulin resistance in cell culture models.”

I know that this sounds awful, but I’ll attempt to explain it in bits and pieces.

Let’s start with an easy one: insulin resistance(1). This is the precursor to Type 2 diabetes, when cells around the body fail to respond appropriately to insulin. In the case of fat and skeletal muscle cells(2), insulin resistance means that glucose is not taken up, leading to the high blood glucose levels typical of Type 2 diabetes. Luckily, if caught early enough, those suffering from insulin resistance can take action to avoid Type 2 diabetes(3).

Instead of studying animals or human tissue, the lab I carried out my PhD in carries out experiments on cultured cells. This allows us to model muscle or fat cells individually and can be very beneficial, because it allows single treatments to be investigated, and allows us to carry out experiments which we would not be able to perform in whole organisms. In Type 2 diabetes, levels of lots of chemical compounds are altered4–9. Therefore models are incredibly useful, as they enable us to look at individual factors and how they affect different cells under different conditions.

So, finally, that awful long word: phosphatidylinositol (4,5)-bisphosphate. This can immediately be shortened to PIP2, so we’ll stick with that. PIP2 is a lipid (or fat) molecule found in the surface membrane of all cells, and is needed for lots of biological processes. Recently studies have shown that PIP2 is needed for glucose uptake10,11, and suggested that levels of PIP2 are lower in cells that are resistant to insulin12–14.

During my PhD I was able to show that decreased PIP2 levels are found in many cases of insulin resistance, in both fat and muscle cells. Furthermore, my work suggested that, not only were they linked, but that low PIP2 was actually causing insulin resistance. Simply adding PIP2 back to the cells helped to reverse insulin resistance. However, it is difficult to deliver a lipid as a medication to someone with diabetes, so I then began to investigate the mechanism behind the decrease.
And this is where I’ll have to leave you for now, as we’re currently writing that work up for publication in a science journal.

In the meantime I’m continuing my diabetes research at UCSD. I have changed areas slightly, to look at the pancreas as well as fat and muscle cells. In Type 2 diabetes, muscle and fat become inflamed, and they release higher than normal levels of pro-inflammatory molecules15. I am currently investigating the effect of these molecules on the pancreas and on insulin release stimulated by glucose. We are also using fat and muscle biopsies from people with diabetes to investigate possible treatments, including a novel mechanism for modelling exercise using electric stimulation on isolated muscle cells.

I really enjoy my work, and relish the idea that my work could improve the lives of people with diabetes. Developing a model for exercise is particularly interesting, as it could directly benefit people without all of the clinical trials required for therapeutics. If I’m able, I would love to spend the rest of my career researching and explaining Type 2 diabetes.

I’ve included a list of references for further reading, but they are all scientific papers, so may be a bit difficult to read. But if anyone has any questions, then feel free to leave a comment and I’ll attempt to and answer them for you.
(1) Shanik, M. H., Xu, Y., Skrha, J., Dankner, R., Zick, Y., and Roth, J. (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31 Suppl 2, S262–8.
(2) DeFronzo, R. A., Jacot, E., Jequier, E., Maeder, E., Wahren, J., and Felber, J. P. (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30, 1000–7.
(3) Knowler, W. C., Fowler, S. E., Hamman, R. F., Christophi, C. A., Hoffman, H. J., Brenneman, A. T., Brown-Friday, J. O., Goldberg, R., Venditti, E., and Nathan, D. M. (2009) 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374, 1677–86.
(4) Reaven, G. M., and Laws, A. (1994) Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease. Diabetologia 37, 948–52.
(5) Timmers, S., Schrauwen, P., and de Vogel, J. (2008) Muscular diacylglycerol metabolism and insulin resistance. Physiol. Behav. 94, 242–51.
(6) Hotamisligil, G. S. (1999) The role of TNFalpha and TNF receptors in obesity and insulin resistance. J. Intern. Med. 245, 621–5.
(7) O’Leary, V. B., Jorett, A. E., Marchetti, C. M., Gonzalez, F., Phillips, S. A., Ciaraldi, T. P., and Kirwan, J. P. (2007) Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults. Am. J. Physiol. Endocrinol. Metab. 293, E421–7.
(8) Patiag, D., Qu, X., Gray, S., Idris, I., Wilkes, M., Seale, J. P., and Donnelly, R. (2000) Possible interactions between angiotensin II and insulin: effects on glucose and lipid metabolism in vivo and in vitro. J. Endocrinol. 167, 525–31.
(9) Ak, G., Buyukberber, S., Sevinc, A., Turk, H. M., Ates, M., Sari, R., Savli, H., and Cigli, A. The relation between plasma endothelin-1 levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy in patients with Type 2 diabetes mellitus. J. Diabetes Complications 15, 150–7.
(10) Funaki, M., DiFransico, L., and Janmey, P. A. (2006) PI 4,5-P2 stimulates glucose transport activity of GLUT4 in the plasma membrane of 3T3-L1 adipocytes. Biochim. Biophys. Acta 1763, 889–99.
(11) Funaki, M., Randhawa, P., and Janmey, P. A. (2004) Separation of insulin signaling into distinct GLUT4 translocation and activation steps. Mol. Cell. Biol. 24, 7567–77.
(12) Strawbridge, A. B., and Elmendorf, J. S. (2005) Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism. Diabetes 54, 1698–705.
(13) Bhonagiri, P., Pattar, G. R., Habegger, K. M., McCarthy, A. M., Tackett, L., and Elmendorf, J. S. (2011) Evidence coupling increased hexosamine biosynthesis pathway activity to membrane cholesterol toxicity and cortical filamentous actin derangement contributing to cellular insulin resistance. Endocrinology 152, 3373–84.
(14) Chen, G., Raman, P., Bhonagiri, P., Strawbridge, A. B., Pattar, G. R., and Elmendorf, J. S. (2004) Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J. Biol. Chem. 279, 39705–9.
(15) Ciaraldi, T. P., Aroda, V., Mudaliar, S. R., and Henry, R. R. (2013) Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: Effects of pioglitazone and metformin treatment. Metabolism. 62, 1587–96.

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