“In healthy body, healthy spirit.”

We all know this ancient quote, emphasizing how close physical health is related to our mental well-being and vice-versa. But besides a mental comfort, being in shape first of all means preventing and resisting development of different diseases, particularly the ones currently known as civilization diseases. These kind of diseases, which include cancer, metabolic syndrome and diabetes, although related to some genetic predispositions, very often result from lifestyle behaviors such as lack of physical activity and poor eating habits.

Thus, the best way to prevent the occurrence of these “civilization diseases” is by engaging in regular exercise and maintaining a balanced diet. In this context, we could paraphrase a famous quote of French gastronomer-Jean Anthelme Brillat-Savarin: “Tell me what you eat and I will tell you who you become.” In other words, you are what you eat.

We cannot survive without food, the main source of energy required for proper functioning of our cells. Energy is mainly stored in our bodies in the form of sugars (i.e. glucose, fructose), but also proteins and fatty acids. Glucose, a basic type of sugar, is indispensable to producing ATP, the energy currency that is used as a fuel in most biological processes, including in the division of our cells. We need glucose to function. On the other hand, blood levels of glucose must be tightly controlled. Glucose blood levels that are too high, or too low, can cause a range of health issues, including blood vessel destruction which when it occurs within the eye can lead to blindness. And of course, prolonged hyperglycemia is defined as diabetes, a disease also known as a “silent killer”.

How is blood glucose level controlled?

It starts in your pancreas, an organ located next to the stomach. Our pancreas is built of islets of Langerhans that contain different types of cells, each responsible for secretion of a specific hormone (Gabriela da Silva X, J Clin Med, 2018). In response to glucose, special pancreatic cells called beta cells secrete a type of hormone – insulin. This helps to diminish the glucose levels in your blood. With the help of insulin, glucose is transported directly into your cells where it serves as a fuel for different cellular processes.

Diabetes occurs when your body is incapable of keeping blood glucose within a tight range of concentrations in the blood. This happens when the body isn’t able to properly produce and use insulin to transport this glucose to the inside of our cells. Diabetes is a group of physiological dysfunctions involving pancreatic beta cells impairments. These dysfunctions lead to excessive blood glucose levels (so called hyperglycemia). Diabetes can result from a drop in beta cell number, insulin unresponsiveness in various tissues throughout your body (called insulin resistance), inadequate insulin secretion by beta cells, or excessive glucagon secretion by alpha cells in the pancreas (glucagon works opposite to insulin by increasing blood glucose).

There are three different types of diabetes: Type 1, Type 2 and gestational diabetes. Type 1 diabetes (T1D) is an autoimmune disorder. This means that the immune cells of a given person attack other types of cells, such as the person’s own pancreatic beta cells in the case of diabetes, leading to their destruction and loss of function. This leads to insulin deficiency and hyperglycemia (elevated blood glucose) because the beta cells can no longer effectively secrete insulin when glucose is around. T1D is also known as a juvenile diabetes, as it manifests mostly in children or teenagers.

Type 2 diabetes (T2D) is much more common – it accounts for 90% of all cases of diabetes. T2D affects particularly adults. One in every 11 adults worldwide has diabetes (Salunkhe VA et al., Diabetologia, 2018). It results primarily from progressively impaired glucose regulation, due to a combination of dysfunctional pancreatic beta cells and insulin resistance resulting in ineffective glucose transport into cells.

It is commonly thought that a global rise in T2D is tightly associated with an increase in obesity. T2D is often accompanied and also preceded by obesity. Both obesity and diabetes are important independent risk factors for the development of cardiovascular disease. On the other hand, obesity is the leading risk factor for type 2 diabetes.

T1D and often T2D-suffering patients require insulin injections to help them regulate their blood glucose levels. The exact cause and possible therapies of T1D are still not fully recognized. But there is no doubt that T2D is largely dependent on our lifestyle and habits, therefore it can be much more easily prevented through proper diet and exercise regimens (contrary to T1D). Both types of diabetes are known for producing complications in the cardiovascular system, kidneys and bones, often resulting in diabetes nephropathy (in the worse scenario causing a kidney failure) and osteoporosis (Kibel A et al., J Int Med Res., 2017; Thomas MC et al., Nat Rev Dis Primers, 2015; Ruano B & Isidro ML, Curr Diabetes Rev., 2010).

The potential of cell reprogramming

The most popular method still being extensively tested to treat diabetes is the replacement of dysfunctional islet cells, called islet transplantation. In this method, islets are transplanted from healthy donors to diabetes-suffering patients, to restore a proper number of insulin-producing beta cells. However, islet transplantation has many limitations and drawbacks. For example, patients need to constantly be on drugs suppressing their immune response in order to prevent transplanted islet destruction. Due to many side effects of these immunosuppressive drugs, this is dangerous in long term. Thus, diabetes researchers are trying to elaborate some alternative approaches. One of them is based on stimulating a diabetic patient’s own beta cells to divide. In this scheme, insulin-producing beta cells can be replenished with the use of various chemical agents, hormones and proteins, for example harmine (Wang P et al., Nature Med, 2015) or osteoprotegerin (Kondegowda NG et al., Cell Metab, 2015), two molecules demonstrated to stimulate beta cell divisions.

Besides looking for some new molecules to stimulate pancreas regeneration by boosting beta cell divisions, many research labs are now investigating another technique called islet cell reprogramming. The idea behind this method is to force different cell types of the pancreatic islets, other than beta cells, to become insulin-producing beta cells. If this approach is optimized and successful in clinical trials on diabetic human subjects, doctors will possibly be able to cure diabetes with this method, alternatively to islet transplantation (see the Fig.1 at the bottom of this post).

Interestingly, the process of islet cell reprogramming is not completely artificial. It can happen naturally in response to stress. For example, in mice that have had their insulin-secreting beta cells destroyed in the lab with chemical substances, some glucagon-producing pancreatic alpha cells and somatostatin-producing delta cells can become insulin-expressing beta-like cells. When alpha or delta cells start producing insulin, diabetes can be reversed (Thorel F et al., Nature, 2010). Although confirmed in mice, this phenomenon has not been observed so far in humans (human islet cells).

But very recently researchers from scientific institutions across Switzerland, Norway and the US resolved the mystery of whether islet cells could be programmed into insulin-producing beta cells in humans in a study published this year in the very prestigious journal Nature (Furuyama K et al., Nature, 2019). The researchers showed that terminally differentiated (meaning completely mature) human alpha cells, thought to be stuck in their cellular fate, can be converted into cells resembling functional insulin-producing beta cells. That conversion was possible with the use of genetic manipulation. Viruses carrying DNA of beta cell-specific factors were used to “infect” the alpha cells, inducing their transformation into beta-like cells.

Furuyama and colleagues were able to better understand the whole process by looking at the molecular features of the cells at different stages of their reprogramming. Step by step, they observed how alpha and gamma pancreatic cells acquired beta cell characteristics.

The scientists further proved functionality of these alpha-to-beta reprogrammed cells by testing them in animal models of diabetes (animal studies are required before performing clinical trials in humans). The reprogrammed cells were able to produce and secrete insulin in response to glucose. And when transplanted into diabetic mice, reprogrammed human alpha cells reversed diabetes and continued to produce insulin even after six months.

That is why the discovery made by Furuyama et al. is considered as a significant breakthrough in the field of diabetes research. What is so significant? Besides demonstrating the usefulness of islet cell reprogramming, the researchers showed that both islet alpha cells and pancreatic gamma cells that undergo reprogramming do not have to be taken necessarily from healthy subjects. Furuyama et al. demonstrated that cells isolated from T2D diabetic human donors can be effectively reprogrammed as well. This raises particular hope for diabetic patients who might recover a decreasing/malfunctioning population of insulin-producing beta cells with reprogramming of their own alpha or gamma cells!

The next step should likely be the optimization of this method to get as many reprogrammed cells as possible from a single human subject in vitro (outside his or her body). Once this is achieved, clinical trials in human subjects can be initiated. Getting to the point where this method is successfully applied could certainly revolutionize the therapy of diabetes.

Lifestyle Hope

Despite promising initial findings, forcing islet cells to become insulin-producing beta cells isn’t the best option for treating diabetes. The best option is effectively preventing it in the first place. To do this, we need to keep our beta cells in shape by not overloading our bodies with sugar.

Let your beta cells relax a bit in between your meals (for example, with intermittent fasting)! Instead of consuming high sugar-containing snacks or beverages, eat more fruits and vegetables and drink more water. A balanced diet will definitely keep your beta cells healthy and happy, so that they can stay themselves!

Fig.1. Potential, future application of pancreatic islet cell reprogramming in diabetes therapy. Based on the work by Furuyama and colleagues (Furuyama K et al., Nature, 2019).