Diabetes: regeneration of the pancreas in the zebrafish
1/6/16

How can we improve the treatment and quality of life of diabetic patients? One of the lines of the research studied involves the renewal of the beta cells of the pancreas which are responsible for the production of insulin. A team from GIGA at the University of Liege, led by Isabelle Manfroid and Marianne Voz, has just identified progenitor cells in the zebrafish which will make it possible to regenerate beta cells without the need for grafts or medicine.

Five hundred thousand diabetics in Belgium, more than 340 million in the world, more than 5 million deaths every year... Behind these frightening statistics, an entire community of researchers are actively studying the disease and working to find a solution to the problem. The members of the ZDDM laboratory (Zebrafish Development & Disease Models), are part of this community of researchers at the GIGA Research Institute at the University of Liege: "Our work focusses on diabetes: at the laboratory we have for many years been trying to understand how pancreatic beta cells are formed, these cells play a key role in the development of diabetes”, says Isabelle Manfroid, one of the heads of the ZDDM laboratory in the Development, Stem Cells and Regenerative Medicine Unit of GIGA.

Diabetes is characterised by the destruction of pancreatic beta cells which secrete insulin, the hormone responsible for lowering sugar levels in the blood. There are two main types of diabetes, types 1 and 2. Type 1 is caused by a deregulation of the immune system which destroys beta cells: patients then become hyperglycaemic and have to inject themselves insulin for the rest of their lives. Type 2 is the result of insulin resistance: the tissues targeted by this hormone (such as muscle, the liver and adipose tissue which should normally consume glucose in response to insulin) no longer respond, which in turn causes hyperglycaemia. In the long-term, the beta cells try to compensate for this resistance to insulin by trying to produce more of it but they become exhausted and die. The two main types of diabetes therefore involve hyperglycaemia and destruction of beta cells.

Other therapeutic options exist apart from the need for insulin injections for the life-span of the patient. "For serious cases, islets of Langerhans grafts are sometimes performed, but unfortunately, the life-span of the transplanted islets and the stabilisation of the disease are quite limited: at first, the patients concerned no longer need to inject themselves with insulin for a period of several months or even years, but then the graft no longer works and they become dependent on daily injections of insulin again. Another avenue of research that is currently in the development phase, aims to inject beta cells generated from human stem cells. All of these therapies have significant limitations and none of them actually cures the disease”, she continues.
zebrafish

Tissue regeneration

"Another therapeutic approach, which we have been actively working on, is to stimulate the regeneration of the patient’s beta cells”, she explains. “To do this, cells which are already present in vivo in the pancreas could be harnessed, these are pancreatic stem cells or progenitor cells capable of regenerating the beta cells. However, the existence of pancreatic stem cells in humans and even in mice (the traditional model used in laboratories) is shrouded in controversy because it is difficult to demonstrate their existence”.

How do pancreatic beta cells form in the zebrafish during embryonic development but also in the adult fish?  This is the question that has occupied the ZDDM laboratory for several years. The model of the zebrafish may seem exotic, yet it is very common in research circles. It is a freshwater fish of tropical origin, renowned for its ability to regenerate its own tissues. This latter property has particularly interested the team of GIGA researchers.

"This regeneration does not happen spontaneously in mice: they have to be injected with insulin, that takes up a lot of time and regeneration is incomplete. This ability is limited in humans too. We would like to understand how regeneration works in a successful system such as that of the zebrafish, if we can understand how it works we may be able to apply this to humans. This could take a long time of course. We really want to understand these regeneration mechanisms and, in time, learn to activate them in diabetic patients", she says hopefully.

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