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Islet group research

The insulin-producing beta cells in the Islets of Langerhans of the pancreas play a key role in all types of diabetes mellitus. The islets of Langerhans are the main focus of both clinical and basic research projects. The Islet group started in 2006 when a human islet isolation laboratory was established in the Leiden University Medical Center followed by a clinical islet transplantation program in 2007. This enabled the establishment of basic and clinical research programs involving human islet cells. Basic research focuses on human islet cell identity, islet survival and function, and strategies in order to generate new insulin-producing cells. Clinical research is focused on improvement of current human islet isolation and beta cell replacement therapy, and on assessment of islet function and damage in patients with severe beta cell failure (in particular type 1 diabetes). The following topics are key areas of research:

Human islet isolation and clinical beta-cell replacement therapy
Diabetes due to loss and/or failure of the insulin-producing beta cells (in particular type 1 diabetes, but also severe forms of chronic pancreatitis (cystic fibrosis), or pancreatectomy) requires administration of exogenous insulin and is usually associated with instable glycemic control compared to patients with substantial residual beta cell function. Patients with severe beta cell failure due to type 1 diabetes often develop this disease at a young age ( Beta-cell replacement is the only therapeutic modality to restore normal sugar levels without the risk of hypoglycemia side effects. In the LUMC beta cell replacement is an integrated program consisting of pancreas transplantation (since 1984) and islet transplantation (since 2007).
Our research focuses on improvement of human islet isolation and transplantation outcome. Areas of research include pancreas preservation strategies and new techniques to isolate human islets. Preclinical studies on human islets are performed to improve islet survival. And novel immunosuppressive regimes and peritransplant strategies are tested. In collaboration with the group of Aart van Apeldoorn (University of Maastricht) preclinical studies are performed using scaffolds in order to create alternative transplantation sites and improve islet function and survival. This work was also part of the Diabetes Cell Therapy Initiative, a Dutch consortium focused on improvement of islet transplantation, coordinated by our group.

Marten Engelse
Michiel Nijhoff
Bas Uitbeijerse
Merel Ruissen
Jason Doppenberg
Eelco de Koning

Alternative sources of beta cells

Beta cell replacement therapy is an attractive treatment option but the procedure is limited to a small number of patients with severe beta cell failure due to the need for an alternative source of insulin-producing cells and the scarcity of organ donors. In collaboration with the De Koning group at the Hubrecht Institute in Utrecht, we investigate the use of adult human pancreatic tissue for regenerative purposes. Human duct cells can be isolated from the islet-depleted pancreatic tissue after islet purification. These cells are an attractive source of islet progenitors as ductal tissue is involved in islet neogenesis in vivo. Two key issues that are relevant for clinical application need to be optimized: the maintenance and expansion of the adult pancreatic cells and the reprogramming of expanded cells towards functionally active beta-cells. Since 2017 our group coordinates the diabetes project in the Dutch consortium for regenerative medicine RegMedXB. The diabetes project in this consortium is focused on advanced beta-cell replacement therapy using alternative cell sources and immunoevasive devices in patients with severe beta-cell failure.

Anja Steffen
Aniela Skrzypczyk
Françoise Carlotti
Marten Engelse
Eelco de Koning

Beta-cell mass and function

The insulin producing beta cells are essential to maintain blood glucose levels within a narrow range. When the demand for insulin is chronically increased by physiological or pathological changes, beta-cells can adapt by enhancing insulin secretion (increased function) and/or enhancing beta-cell number (increased mass). Inadequate adaptation leads to the development of hyperglycemia and eventually to diabetes. Therefore, insight into the mechanisms and signalling pathways that control beta-cell adaptation and survival is important for developing therapies that can preserve or enhance beta-cell mass. We investigate pathways relevant for islet survival. In addition we explore the function of residual beta cells in patients with type 1 diabetes and markers of beta cell dysfunction both in vitro and in vivo.

Françoise Carlotti
Bas Uitbeijerse
Eelco de Koning

Beta-cell plasticity:

Mature human beta-cells are typically considered as terminally differentiated cells that do not change phenotype. However we and others recently showed an unexpected plasticity (i.e. capacity to change identity) of pancreatic endocrine cells. Loss of beta-cell identity has been associated with loss of beta-cell function, which may lead to diabetes. We are currently investigating the mechanisms involved in the endocrine cell conversion. Ultimately this knowledge could help us defining novel protective and regenerative therapeutic strategies for diabetes.

Françoise Carlotti
Nathalie Groen
Javier Triñanes Ramos
Floris Leenders
Eelco de Koning

RECENT KEY PUBLICATIONS:

  1. A Single-Cell Transcriptome Atlas of the Human Pancreas. Muraro MJ*, Dharmadhikari G*, Grün D, Groen N, Dielen T, Jansen E, van Gurp L, Engelse MA, Carlotti F, de Koning EJ*, van Oudenaarden A*. Cell Syst. 2016 Sep 28.
  2. Glycemic Stability Through Islet-After-Kidney Transplantation Using an Alemtuzumab-Based Induction Regimen and Long-Term Triple-Maintenance Immunosuppression. Nijhoff MF, Engelse MA, Dubbeld J, Braat AE, Ringers J, Roelen DL, van Erkel AR, Spijker HS, Bouwsma H, van der Boog PJ, de Fijter JW, Rabelink TJ, de Koning EJ. Am J Transplant. 2016 Jan;16(1):246-53.
  3. Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits. Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, Koster AJ, Rabelink TJ, Hansen BC, Clark A, Carlotti F, de Koning EJ. Diabetes. 2015 Aug;64(8):2928-38
  4. Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice. Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Am J Physiol Endocrinol Metab. 2014 Mar 1;306(5):E552-E558
  5. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Ellenbroek JH, Töns HA, Westerouen van Meeteren MJ, de Graaf N, Hanegraaf MA, Rabelink TJ, Carlotti F, de Koning EJ. Diabetologia. 2013 Sep;56(9):1980-6.
  6. Conversion of mature human β-cells into glucagon-producing α-cells. Spijker HS, Ravelli RB, Mommaas-Kienhuis AM, van Apeldoorn AA, Engelse MA, Zaldumbide A, Bonner-Weir S, Rabelink TJ, Hoeben RC, Clevers H, Mummery CL, Carlotti F, de Koning EJ. Diabetes. 2013 Jul;62(7):2471-80.

ISLET GROUP IN THE MEDIA:
Television
2015 Tijd voor Max (Dutch)
2014 RTL Toekomstmakers – Diabetes (Dutch)
2013 NTR – Over leven met ….diabetes (Dutch)
2007 TELEAC – Wetenschap is beterschap (Dutch)

Website videos
2016 Leiden University MOOC Clinical kidney transplantation – Lecture 2.7: Simultaneous kidney pancreas and islet transplantation (English)
2016 Leiden University MOOC MOOC Clinical kidney transplantation – Lecture 4.4: Late challenges after pancreas and islet transplantation (English)
2015 Bontius Stichting (LUMC) – Eilandjes transplantatie bij type 1 diabetes (Dutch)
2014 Ééndiabetes – Interview Eelco de Koning (Dutch)
2012 Diabetes Fonds – Stamcellen voor diabetes in kader van prijsvraag (Dutch)

Other news items
2015 LUMC – Dr. F. Gerritzen prijs voor Rianne Ellenbroek (Dutch)
2014 LUMC – LUMC ontvangt grote subsidies voor diabetesonderzoek (Dutch)
2014 Diapedia – Islet transplantation (English)
2012 Inaugural lecture Eelco de Koning (Dutch)

Former group members:
Cindy Loomans, PhD (post-doc)
Rianne Ellenbroek-den Doelder, PhD (post-doc)
Siebe Spijker, MD (PhD student)
Maaike Roefs, MSc (PhD student)
Jeetindra Balak. MD (PhD student)
Nerys Williams, MSc (PhD student)
Matthias Roost, MSc (shared PhD student)
Tim Dielen (Technician)
Jeroen Sijtsma (Technician)