Perspectives of Regeneration Research in Diabetes

There are already a number of promising research approaches in regenerative diabetes research, all of which are aimed at preserving beta-cell mass and function or renewing destroyed beta cells. If it were possible to convert human progenitor cells and other pancreatic cells into insulin-producing beta cells, the secretion of insulin could be normalized and diabetes could be treated causally. Another long-term goal would be to even prevent the onset of type 1 diabetes – if it were possible to prevent the destruction of beta cells in people with genetic predisposition from the outset.

In brief:

The regeneration of beta cells is the focus of numerous activities in diabetes research. The aim is to stop the disease at an early stage and prevent dangerous secondary diseases.

As yet too little is known about the molecular mechanisms that regulate or control the preservation, renewal and differentiation of insulin-producing beta cells in the pancreas.

In Germany alone, however, there are several research centers that are working intensively on regenerative research approaches for diabetes. These research projects are funded, among others, by the German Center for Diabetes Research (DZD).

How do beta cells regenerate themselves?

It is not yet known in detail how the beta-cell mass regulates itself, whether by conversion from other cells, by new formation or by cell division from existing cells, and what significance the different processes have. However, scientists assume that, depending on the disease, different regeneration mechanisms, possibly also side by side, take place.

For example, it has already been shown that new beta cells are formed from the pancreatic duct cells or gland cells located outside the islets. Once the exact factors for this transformation have been understood, new treatment methods can be developed.  

Alpha becomes beta

If the beta cell function is lost and the dwindling insulin no longer inhibits the glucagon release of the alpha cells, the content of the hormone glucagon (= hyperglucagonemia) increases and the blood glucose level rises as the disease progresses. Interestingly, scientists were able to show in the model system that beta cells can also develop from the alpha cells of the pancreas. Various research groups are now working on identifying the suitable molecular and genetic mechanisms to actively control this transformation process. 

The different cell types regulate each other. Therefore, scientists are pursuing the approach of producing groups of alpha, beta and other cells from stem cells and transplanting this cell community. The mutual regulation of the antagonists limits the risk of hypoglycemia or hyperinsulinemia.

How can the destruction of beta cells be stopped?

Scientists are also currently investigating the hypothesis that beta cells can regress when they come under inflammatory stress, for example in the early stages of type 2 diabetes. These so-called dedifferentiated, progenitor-like cells could protect themselves against inflammatory stress and form the basis for redifferentiation into beta cells. However, glucose-dependent insulin secretion in these dedifferentiated beta cells is certainly disturbed.

One possible approach of beta cell regeneration is to differentiate such dedifferentiated beta cells into mature and functional beta cells. It has also been shown in animal models that this is possible by insulin therapy and lowering the blood glucose level.

Further evidence that beta cells can regenerate again is found in obesity surgery: In severely overweight patients requiring insulin, regeneration of the beta cells already occurred shortly after the surgical reduction of the size of the stomach (sleeve gastrectomy); the patients were able to dispense with the administration of insulin – even before they lost weight. Findings about the body's own mechanisms of beta cell regeneration after sleeve gastrectomy could provide future therapeutic approaches.

Overall, however, too little is known about the transformability of cells in the pancreas, and great hopes are pinned on the fact that this branch of research offers many possibilities for future therapeutic application.

Controlling the arrangement of islet cells

The polar orientation of the beta cells towards the blood vessels and the three-dimensional architecture of the islets of Langerhans play an important role in preserving their function. Scientists are investigating the question of which factors influence this alignment in detail. According to the current state of knowledge, molecules that control cell polarity and tissue polarity are of central importance.

Hormones as regulators for beta-cell mass

GLP-1 and other hormones control the release of insulin by beta cells, this has been known for some time. However, they also interfere with the mechanism of beta cell death. Clinical studies with hormone-like molecules suggest that a promising therapeutic approach to the preservation and new growth of beta-cell mass is opening up.

Cilia: small protuberances with great effect

Cilia are small protuberances on the cell wall and are also found on insulin-producing beta cells. They are the starting point of some signaling cascades, i.e. they transfer the effect of stimulants and neurotransmitters to the cell. At the beta cells, they are thus part of the signaling chain that causes the cell to secrete insulin.

But cilia are also involved in regulating blood glucose beyond the beta cell: Muscle cells, which absorb about 80 percent of the glucose from the blood, also possess such cilia. The cellular components required for glucose uptake appear to be localized in the cilia. Scientists assume that in type 2 diabetes, both the cilia of the beta cells and the cilia of the muscle cells are defective.

In addition, the cilia also appear to influence the overall metabolism of the cells. Scientists are currently investigating the relationship between ciliary function and the mitochondria, the cells' so-called power plants. Mitochondrial energy production is essential for all cell functions.

Stop age-related beta cell loss

Researchers at the Stanford University School of Medicine have succeeded in finding a key molecular signaling pathway that causes beta cell growth to decline with age. The scientists hope to someday be able to control this signaling pathway in humans in such a way that beta cell function is preserved despite the aging process.

An important role is played by the growth factor PDGF, the formation of which decreases over time in both mice and humans. When the PDGF receptor signaling pathway is artificially activated, the number of beta cells in the pancreas increases without causing hypoglycemia.

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References

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Wissenschaftliche Beratung: Prof. Dr. Heiko Lickert

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13. Dezember 2018

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