Let's Fly: What Drosophila Can Teach Us About Diabetes

Contributors: Jocelyn Drasdauskis, Chris Fetterly

Our unique perspective at Future Fields gives us hope for a future where the impact of diabetes on patients and our health care systems is significantly diminished. Through our work, we have developed a deep understanding and appreciation for the humble fruit fly (Drosophila melanogaster) as a genetic powerhouse, and see it as a beacon of hope in the fight against Diabetes.

As we grow and find our place in society, it unfortunately does not take one long to learn that diabetes is ubiquitous in our communities, in our families, and among our friends. The disease is so common that global cases are predicted to top half a billion by 2030. To improve global health outcomes it is imperative to avoid complacency and continue to research new ways to mitigate the disease, make life with diabetes easier to manage, and find a cure. In this short primer, we describe how important Drosophila melanogaster (D. mel) is to diabetes research, and new areas to push the boundaries of diabetes research.

First Things First: Defining Diabetes

In humans, blood sugar is regulated by the hormone insulin, a protein that signals for glucose in the blood to be taken up by tissues as a source of energy or stored as fat in times of abundance (e.g. after a meal). Diabetes mellitus is a group of chronic conditions characterised by dysregulated insulin signalling. For the purpose of this exploration, we will focus on Type 1 and Type 2 diabetes.

Type 1 Diabetes

In the case of Type 1 diabetes, the insulin producing cells (islet beta-cells) are destroyed by the immune system, and the body loses its ability to remove glucose from the blood where it could be used by tissues for energy or stored as fat. Symptoms of Type 1 include muscle wasting, failure to grow, and excessive thirst.

Type 2 Diabetes

In Type 2 diabetes, the body becomes resistant to the effect of insulin and eventually this resistance can lead islet cells to stop producing insulin altogether. [1] Symptoms of Type 2 diabetes include weight loss, excessive thirst and urination, and fatigue. Both Type 1 and Type 2 diabetes are characterised by high levels of glucose in circulation, which also causes a number of health problems unrelated to the immediate disease such as: retinopathy, heart disease, dementia, and kidney disease. [2][3]

As cases of both types of diabetes are increasing globally, it is critical that researchers find a way to mitigate the disease. One of the best ways to do this research is by using model organisms to mimic the pathways and understand how diseases happen.

D. Mel Modelling for Diabetes

Insulin-peptide signalling in the fruit fly mimics insulin signalling in humans, and fruit flies have been used as models to understand several concepts: the mechanisms by which diabetes occurs, the comorbidities with diabetic conditions, and possible treatment options. To create a Type 1 diabetes model, researchers will disable the insulin-peptide producing cells by modifying genetic pathways; and to make a Type 2 diabetes model, researchers can overfeed flies with protein or sugar until they start showing symptoms of insulin resistance.

What happens to a fly with diabetes? In the Type 1 model, the fruit flies exhibit the same symptoms humans do: failure to grow, issues with fertility, and defects in their heart, eyes, and brain. [4][5] The Type 2 flies have some similar symptoms as above but also have increased circulating triglycerides, obesity, and a reduced tendency to climb around. [1][3]

One striking symptom similarity is that the flies also get thirsty and drink more water than their wild type counterparts when used as a model of diabetes. [6] Interestingly, as is the case with humans, the gut bacteria of the fly are important for regulating disease progression. Lactobacillus can rescue growth in poorly fed larvae, and flies infected with Wolbachia have increased insulin signalling. Lack of Wolbachia worsens T1D models, most strongly in the decrease of both reproduction and adult weight. [2][7]

Like Fly, Like Human: Potential in Cross Investigating Fly Peptides and Human Prolactin

While we can utilise our understanding of D. mel and its genetics to unravel mechanisms of disease initiation and progression, we can also use them to ethically investigate potential therapeutics without resorting to mammalian models. One proposed treatment for Type 2 progression is to decrease the amount of circulating insulin. Researchers believe this may be possible to do with decretins, or fasting hormones that were investigated using the Drosophila equivalent molecule, limostatin. [8] In Type 1 treatments, new research is focusing on stem cell therapy or islet cell replacement therapies—but how do you reproducibly grow these cells?

Computer model of the insulin hormone. Type 1 diabetes is an autoimmune disease that attacks insulin-producing cells. In humans, these cells are islet beta-cells.

As humans develop in utero, there is an increase in the hormone prolactin during the time of islet cell formation. This molecule has been shown in mammalian models to increase the growth of islets in labs as well. [9] Mammalian prolactin is an important growth factor in secretory cells like mammary epithelial cells, sweat glands, and insulin-secreting islet beta-cells; prolactin is also linked to increased proliferation in glial cells in the brain.

In fruit flies, there are several insulin-producing cells (IPCs) and insulin-like peptides with complicated genetic pathways and overlapping regulative processes. Interestingly, the insulin-like peptides (DILP2 and DILP6) are found in similar cells as prolactin in humans: secretory cells, glial cells, and adipose cells. [10] It has also been shown that nutritional deprivation in flies causes the release of DILP2 and DILP6 from glial cells and insulin-producing cells. This effect will cause neural cells to exit quiescence (inactivity) and proliferate again. [11] It may be that studying the specifics of DILP2 and DILP6 in flies will give us insight into how to regenerate our own islet cells, and if prolactin will be an important molecule to move Type 1 therapeutics forward.

Let’s Fly

The fruit fly has been studied as a model organism for decades, with findings providing humanity with insights in human genetics, developmental biology, how we smell, and even how we sleep. It is exciting to dream of the potential breakthroughs we can achieve with the tiny but mighty drosophila. While scientists use the genetic swiss army knife, D. mel, to help untangle the mechanisms and potential treatments of disease like diabetes, we’re using it to produce the world's most sustainable recombinant proteins. That’s pretty fly!

Sources:

1. Deshpande, Anjali D., Marcie Harris-Hayes, and Mario Schootman. "Epidemiology of diabetes and diabetes-related complications." Physical therapy 88, no. 11 (2008): 1254-1264.
2. Labriola, Leticia, Wagner R. Montor, Karin Krogh, Fernando H. Lojudice, Tércio Genzini, Anna C. Goldberg, Freddy G. Eliaschewitz, and Mari C. Sogayar. "Beneficial effects of prolactin and laminin on human pancreatic islet-cell cultures." Molecular and cellular endocrinology 263, no. 1-2 (2007): 120-133.
3. Heller, T., M. Blum, M. Spraul, G. Wolf, and U. A. Müller. "Diabetic co-morbidities: prevalences in Germany." Deutsche Medizinische Wochenschrift (1946) 139, no. 15 (2014): 786-791.
4. Álvarez-Rendón, Jéssica P., Rocio Salceda, and Juan R. Riesgo-Escovar. "Drosophila melanogaster as a model for diabetes type 2 progression." BioMed Research International 2018 (2018).
5. Baenas, Nieves, and Anika E. Wagner. "Drosophila melanogaster as a Model Organism for Obesity and Type-2 Diabetes Mellitus by Applying High-Sugar and High-Fat Diets." Biomolecules 12, no. 2 (2022): 307.
6. Chen, Danping, Jie Yang, Zhengyun Xiao, Sicong Zhou, and Liming Wang. "A diet-induced type 2 diabetes model in Drosophila." Science China Life Sciences 64, no. 2 (2021): 326-329.
7. Alfa, Ronald W., and Seung K. Kim. "Using Drosophila to discover mechanisms underlying type 2 diabetes." Disease models & mechanisms 9, no. 4 (2016): 365-376.
8. Alfa, R.W., Park, S., Skelly, K.R., Poffenberger, G., Jain, N., Gu, X., Kockel, L., Wang, J., Liu, Y., Powers, A.C. and Kim, S.K., 2015. Suppression of insulin production and secretion by a decretin hormone. Cell metabolism, 21(2), pp.323-334.
9. Bernichtein, Sophie, Philippe Touraine, and Vincent Goffin. "New concepts in prolactin biology." Journal of Endocrinology 206, no. 1 (2010): 1-11.
10. Nässel, Dick R., Olga I. Kubrak, Yiting Liu, Jiangnan Luo, and Oleh V. Lushchak. "Factors that regulate insulin producing cells and their output in Drosophila." Frontiers in physiology 4 (2013): 252.
11. Sousa-Nunes R., Yee L. L., Gould A. P. . Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 471 (2011): 508–512

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