Regeneration Research in Diabetes: Basics

Beta cells and islets of Langerhans

The beta cells are the insulin-producing cells in the pancreas. They are not distributed throughout the tissue, but are grouped in specific regions of the organ – the islets of Langerhans, named after their discoverer, Paul Langerhans.

Beta cells make up 65 to 80 percent of the islets of Langerhans and are therefore sometimes referred to as islet cells. The remaining 20 percent of the islet cell mass also produce important neurotransmitters for the metabolism. Alpha cells produce the hormone glucagon, the antagonist of insulin. Glucagon promotes the release of glucose from the liver and thus causes the blood glucose level to rise.

The human pancreas contains about one million islets of Langerhans with about 4,000 beta cells each. However, only about 20 percent of beta cells are needed to produce enough insulin to regulate blood glucose levels. This is also the reason why type 1 diabetes only becomes apparent when large parts of the insulin-producing beta cells have already been destroyed by autoantibodies.

How does the beta-cell mass regulate itself?

[Translate to Englisch:] Menschliche Bauchspeicheldrüse unter dem Mikroskop
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It has been known for a few years that beta-cell function and beta-cell mass in the pancreas are dynamically regulated. With increasing body weight or during pregnancy, the functionally effective beta-cell mass increases. The cells enlarge and new beta cells are formed. Through a dynamic balance of growth and cell death, the beta cells adapt to the respective metabolic requirements. If this balance is skewed, this leads to a disturbed glucose metabolism.

In both type 1 diabetes and advanced type 2 diabetes, the absolute and functional beta-cell mass decreases as the disease progresses. The regeneration of beta cells therefore represents a promising research approach. This requires an understanding of how beta cell growth is regulated. A complex set of rules consisting of different hormones such as insulin, GLP-1 (glucagon-like peptide 1), growth factors (IGF-I and -II, PDGF, EGF), lactogens and glucose are involved.

The close connection between islet cells and blood vessels also plays an important role: The islets of Langerhans are crossed by a dense network of small blood vessels (capillaries). Each beta cell is in contact with at least one blood vessel endothelial cell. The beta cell is thus able to measure the blood glucose level directly and, depending on this, to release the appropriate amount of insulin into the blood stream.

The endothelial cells regulate the division, function and maturation of the beta cells and keep them in a differentiated stage. Mice that lack blood vessels in their islets of Langerhans can become diabetic.

Molecular switches for cell differentiation

The path from stem cell to mature tissue cell is long and is controlled by a variety of molecular mechanisms. Researchers at Helmholtz Zentrum München are intensively studying the formation of beta cells during embryonic development. Cell signals, gene regulators and molecules regulating morphogenesis are of great interest for deciphering disease mechanisms.

So-called pluripotent (from Latin 'plus', more, and 'potens', powerful, capable) stem cells have the ability to evolve into different tissue types. In order to turn them into beta cells, comprehensive knowledge of differentiation mechanisms and blueprints is required.

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Regenerative Therapies give opportunities for cure - for Type-1- and also for Type-2-Diabetes. Prof. Heiko Lickert, head of the Institute of Diabetes and Regeneration Research at Helmholtz Zentrum München, explains the different strategies in a video-interview. Length: 2.33 Minutes

Investigating the beta cell in detail

The beta-cell progenitors are able to evolve into different pancreatic cell types, such as pancreatic duct cells or different types of glands. Once embryonic development is complete, the function of the cells is determined and the cells lose the ability to develop into other cell types.

This means that a human being has to live with the once developed beta cells for a very long time. If too few beta cells are formed due to defects in embryonic development, the person is born with less beta-cell mass and has an increased risk of developing diabetes. However, researchers suspect that a small proportion of beta cells can continue to form from progenitor cells and that beta cells can also multiply by division. However, this division rate decreases sharply after early childhood development and is almost zero in a forty- or fifty-year-old person

Different approaches to regenerating beta cells

Regeneration research is not only searching for cellular properties that can be used to regulate growth and division, function and death of cells. Scientists are also searching for detailed functions of insulin-producing cells that can be used to treat diabetes.

The following approaches are conceivable:

     

  • The stimulation of growth and the proliferation of beta cells. In older people, however, this is almost impossible.
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  • Reversing loss of beta cell function: In both type 1 and type 2 diabetes, there is evidence that beta cells can lose their maturity status and regress to a non-functional progenitor stage. From this state, it is possible that the cells recover and return to their function. This would explain, for example, the rapid success of blood glucose control after bariatric surgery such as sleeve gastrectomy (reduction of the size of the stomach). Even after many years of type 1 diabetes, functional beta cells are still found in the pancreas. A low self-production of insulin may still be detectable. It is the task of science to better understand the processes in the cells in order to stimulate the cells to function again.
  •  

  • The formation of beta cells from progenitor cells for other tissues (for example, the pancreatic duct) is also discussed.
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  • The conversion of alpha cells into beta cells: However, this will be difficult to implement in clinical practice.
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In brief:

After eating, the glucose level in the blood rises and stimulates the release of insulin. There is an amplifier mechanism for the glucose effect: Various neurotransmitters occupy receptors on the surface of the beta cells. These transmit signals into the cell interior and improve the uptake of glucose into the beta cell.

Receptors and the insulin enigma

The release of insulin from beta cells is subject to a complex regulatory mechanism. At present not all mechanisms are known. The most important trigger of insulin secretion is the increased glucose level in the blood after a meal. Fine regulation is additionally mediated by a number of neurotransmitters. These neurotransmitters dock to certain receptors on the surface of the beta cells. Glucose does not use these receptors.

What is going on here in detail?

An answer was provided by experiments with knockout mice in which these neurotransmitter receptors were inactivated. It was found that the secretion of insulin in these animals is disturbed at an early stage and that they develop diabetes mellitus. How does this happen? When the beta cell receives the glucose signal, insulin secretion is initiated and the aforementioned neurotransmitters are released along with the insulin. These then dock to the receptors on the cell surface and thereby improve the uptake of glucose into the beta cell. It is a kind of amplifying mechanism.

But what happens if the receptors for the neurotransmitters are missing or the signaling chain started by them in the cell is interrupted? The amplifying mechanism is not activated, which means that glucose can no longer trigger the secretion of insulin. Therefore, the glucose level in the blood remains elevated. If it were possible to use this receptor-mediated mechanism specifically, insulin secretion could be improved.

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References

  • Tritschler, S. et al.: Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. In: Mol Metab., 2017, 6(9):974-990. doi: 10.1016/j.molmet.2017.06.021. eCollection 2017 Sep. Review.
  • Bastidas-Ponce, A. et al.: Cellular and molecular mechanisms coordinating pancreas development. In: Development. 2017 Aug 15;144(16):2873-2888. doi: 10.1242/dev.140756.
  • Bastidas-Ponce, A.: Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. In: Mol Metab., 2017, 6(6):524-534. doi: 10.1016/j.molmet.2017.03.007. eCollection 2017 Jun.
  • Lickert, H., Kaestner, K.H.: Islet biology. In: Mol Metab., 2017, 6(9):vi. doi: 10.1016/j.molmet.2017.06.005. eCollection 2017 Sep 
  • Kleinert, M. et al.: Animal models of obesity and diabetes mellitus. In: Nat Rev Endocrinol., 2018, 14(3):140-162. doi: 10.1038/nrendo.2017.161.
  • Wang, X. et al: Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. In: Mol Metab., 2018, 9:57-68. doi: 10.1016/j.molmet.2018.01.011.
  • Wang, X. et al.: Generation of a human induced pluripotent stem cell (iPSC) line from a patient with family history of diabetes carrying a C18R mutation in the PDX1 gene. In: Stem Cell Res., 2016, 17(2):292-295. doi: 10.1016/j.scr.2016.08.005.
  • Wang, X. et al: Generation of a human induced pluripotent stem cell (iPSC) line from a patient carrying a P33T mutation in the PDX1 gene. In: Stem Cell Res., 2016, 17(2):273-276. doi: 10.1016/j.scr.2016.08.004. Epub 2016 Aug 5.
  • Roscioni, S.S. et al.: Impact of islet architecture on β-cell heterogeneity, plasticity and function. In: Nat Rev Endocrinol., 2016, 12(12):695-709. doi: 10.1038/nrendo.2016.147. Epub 2016 Sep 2.
  • Migliorini, A. et al.: Targeting insulin-producing beta cells for regenerative therapy. In: Diabetologia. 2016 Sep;59(9):1838-42. doi: 10.1007/s00125-016-3949-9.
  • Bader, E. et al: Identification of proliferative and mature β-cells in the islets of Langerhans. In: Nature. 2016 Jul 21;535(7612):430-4. Epub 2016 Jul 11.
  • Willmann S.J. et al.: The global gene expression profile of the secondary transition during pancreatic development. In: Mech Dev. 2016 Feb;139:51-64. doi: 10.1016/j.mod.2015.11.004. 

Scientific advice: Prof. Dr. Heiko Lickert

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December, 13, 2018

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