Hormone Sensitive Lipase, a therapeutic target for type 2 diabetes mellitus?

By Cristina Riquelme Vano

In 2000, 171 million people were suffering with diabetes. Due to an increase in people being diagnosed with obesity and sedentarism, this number is expected to double by 2030 (Wild et al., 2004). Type 2 diabetes, the most common type, is a chronic condition that affects the way the human body metabolizes glucose, an important fuel source for your body. It is caused either by resistance to insulin, a hormone that regulates the movement of glucose into the cells or by inefficient production of insulin by the pancreas to maintain normal glucose levels. 

Insulin production increases with blood glucose levels. Glucokinase acts as a gluco-sensor and triggers the release of insulin by pancreatic β-cells when high blood glucose levels are detected (for example, after food intake). Glucose enters β-cells via the GLU2 transporter and undergoes glycolysis to form pyruvate. Pyruvate enters the TCA cycle and undergoes oxidative phosphorylation to produce ATP. ATP blocks ATP-sensitive K+ channels and accumulation of K+ within the beta cell causes depolarization of its membrane leading to the opening of voltage-gated Ca2+ channels. High intracellular calcium ions trigger exocytosis of membrane bound vesicles containing insulin (Koster, Permutt and Nichols, 2005). Secreted insulin circulates in the bloodstream enabling glucose, the main source of energy, to enter to the cells. Insulin increases glycogenesis and glycolysis as well as lipogenesis and protein synthesis. The main function of insulin is regulation of glucose homeostasis by lowering the amount of glucose in the bloodstream and as blood sugar levels drop, so does secretion of insulin by the pancreatic beta cells in a negative feedback.

However, this process does not work well in type 2 diabetes. Insulin, as mentioned before, is a hormone that helps glucose get into the cells to give them energy. In type 2 diabetes, glucose builds up in the bloodstream instead of diffusing into the cells. As blood glucose levels increase, pancreatic beta cells secrete more insulin to break down glucose but eventually beta cells become impaired and cannot make enough insulin to match the metabolic requirements. Over time, high blood glucose can lead to serious problems with your heart, eyes, kidneys, nerves, and gums and teeth. There is no current cure for type 2 diabetes but there are a range of treatments to lower blood sugar levels. Among the most well-know are metformin and thiazolidinediones that increase sensitivity to endogenous insulin and sulfonylureas that block the ATP-sensitive potassium channels. 

Researchers from Inserm at the Institute of Cardiovascular and Metabolic Diseases are developing a therapeutic strategy to treat type 2 diabetes using the properties of the enzyme hormone-sensitive lipase (HSL) which, when stimulating fatty-acid synthesis in the fat cells, has a beneficial effect on insulin action. HSL is an enzyme that breaks down fats into fatty acids and releases them into the bloodstream. Endogenous lipid stores (fatty acids) are thought to be involved in the mechanism whereby the β-cell adapts its secretory capacity in obesity and type 2 diabetes (Type 2 Diabetes: A Therapeutic Avenue is Emerging, 2020). Previous research from Inserm show that a decrease in HSL expression in the adipocytes led to a better response to insulin. However, this beneficial effect on insulin action coming from the reduction in HSL was not due to the reduced release of fatty acids but to the increased synthesis of oleic acid (the main fatty acid of olive oil). Interestingly, they found an interaction between HSL and ChREBP, a transcription factor responsible for the synthesis of fatty acids. When HSL binds ChREBP it blocks its activity. Thus, a decrease in HSL leads to the translocation of ChREBP into the nucleus which can carry out its function; synthesise oleic acid and increase sensitivity to insulin (Morigny et al., 2018). 

However, decreasing HSL expression to block its interaction with ChREBP is a challenging new therapeutic avenue, one which researchers are working on. Some preliminary results have reported a known inhibitor to prevent its binding to ChREBP but this is just the beginning for the development of molecules that target this interaction (Morigny et al., 2018). Hopefully, in the future we can see new drugs to treat type 2 diabetes which use the proposed therapeutic strategy: a decreased HSL expression which enhances oleic acid synthesis, leading to a better response to insulin for type 2 diabetes patients.

References:

Wild, S., Roglic, G., Green, A., Sicree, R. and King, H., 2004. Global Prevalence Of Diabetes. [online] Who.int. Available at: <https://www.who.int/diabetes/facts/en/diabcare0504.pdf&gt; [Accessed 29 August 2020].

Koster, J., Permutt, M. and Nichols, C., 2005. Diabetes and Insulin Secretion: The ATP-Sensitive K+ Channel (KATP) Connection. Diabetes, 54(11), pp.3065-3072.

Newsroom | Inserm. 2020. Type 2 Diabetes: A Therapeutic Avenue Is Emerging. [online] Available at: <https://presse.inserm.fr/en/type-2-diabetes-a-therapeutic-avenue-is-emerging/33156/&gt; [Accessed 29 August 2020].

Morigny, P., Houssier, M., Mairal, A., Ghilain, C., Mouisel, E., Benhamed, F., Masri, B., Recazens, E., Denechaud, P., Tavernier, G., Caspar-Bauguil, S., Virtue, S., Sramkova, V., Monbrun, L., Mazars, A., Zanoun, M., Guilmeau, S., Barquissau, V., Beuzelin, D., Bonnel, S., Marques, M., Monge-Roffarello, B., Lefort, C., Fielding, B., Sulpice, T., Astrup, A., Payrastre, B., Bertrand-Michel, J., Meugnier, E., Ligat, L., Lopez, F., Guillou, H., Ling, C., Holm, C., Rabasa-Lhoret, R., Saris, W., Stich, V., Arner, P., Rydén, M., Moro, C., Viguerie, N., Harms, M., Hallén, S., Vidal-Puig, A., Vidal, H., Postic, C. and Langin, D., 2018. Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity. Nature Metabolism, 1(1), pp.133-146.

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