Beta Cell Physiology and Pathology

Group Leaders are Drs. Klaus Kaestner, Doris Stoffers, and Ali Naji
This Scientific focus area of the DRC is linked to the IDOM Type 1 Diabetes Unit.

Beta cell failure is the hallmark of type 1 diabetes and is also critical to the progression of type 2 diabetes. Studies of beta cell function have long been a major strength of the Penn DRC.  This topic includes strength in beta cell biology per se as well as complementary expertise in beta-cell immunology and islet/pancreas transplantation.  

Highlights From 2010-Present:
Penn DRC investigators have made major contributions to the understanding of beta cell physiology and pathophysiology, which includes the areas of beta cell development, gene regulation, insulin secretion, and immunology. The DRC supported Cores have been essential for this work, and will allow us to determine how beta cells develop, function, and survive or die.

Highlight one: Islet immunology and transplantation. Drs. Naji and Rickels have continued their collaboration to push the boundaries of islet transplantation as a treatment for Type 1 Diabetes, and to improve the quality of life for their patients. Through NIH-funded clinical trials, they have been able to show that glucose counter-regulation, or the body’s defense from hypoglycemic episodes, is restored in even long-standing Type 1 diabetics by islet transplantation (Rickels et al., Diabetes, 2015).  Strikingly, they also found that insulin sensitivity is improved following islet transplantation (Rickels et al., J Clin Endocrinolo Metab, 2013). Drs. Rickels, Naji and their colleagues are now in the process of applying for FDA approval for their optimized islet transplantation protocol, with the goal to obtain health insurance coverage for this promising treatment in order to help many more people with diabetes.

Highlight two: Understanding the molecular basis for genetic risk for Type 1 Diabetes.  Human genetic studies have identified numerous genes or loci that are associated with the inherited risk for developing Type 1 Diabetes. Some of these genes are active in the immune system, and thus their connection to autoimmunity is easy to rationalize. For many other genes, however, the molecular basis for how risk alleles contribute to pathogenesis is unknown.  Recently, seminal work by Dr. Stoffers and her fellow, Dr. Soleimanpour, demonstrated that the Type 1 Diabetes susceptibility gene CLEC16A is essential in controlling mitophagy in beta-cells, and thus beta-cell function (Soleimanpour et al., Cell 2014).  Thus, this pathway could be targeted in the future to prevent the onset of diabetes in susceptible people.

Highlight three: Increasing beta-cell mass.  Increasing functional beta-cell mass is critical to provide more cells for the treatment of Type 1 diabetics through transplantation, as the supply of islets from deceased organ donors suitable for treatment is very limited.  In a series of collaborative studies between Drs. Naji and Kaestner, the molecular and epigenetic properties of human beta-cells were mapped in great detail. These studies led to the discovery that pancreatic alpha-cells might be convertible to functional beta-cells (Bramswig et al., J. Clinical Invest. 2013), and that the targeting of specific pathways can be used to promote human beta-cell replication, resulting in new, functional beta-cells (Avrahami et al., J. Clinical Invest.  2014). Another joint study, between the Stoffers and Naji labs, led to the discovery that the microRNA Mir7 regulates proliferation of adult beta-cells through control of the mTOR pathway (Wang et al., Diabetes, 2013). These studies are a great example of the collaborative spirit within Penn’s diabetes research community, where discovery research and clinical science work hand in hand.

Beta Cell Physiology and Pathology Members

Youhai H. Chen Hank F. Kung James L. Riley
Diva D. De Leon Crutchlow Changhong Li Arthur H. Rubenstein
Nicolai M Doliba Franz M. Matschinsky Anil K. Rustgi
Hildegund C.J. Ertl David C. Metz Rebecca A. Simmons
Paul J Gadue Ali Naji Ben Z. Stanger
Wayne William Hancock Itzhak Nissim Charles A. Stanley
Robert O. Heuckeroth Michael A. Pack Doris A. Stoffers
Xianxin Hua Warren S. Pear David F. Wilson
Klaus H. Kaestner Michael R. Rickels Kenneth S. Zaret
Malek Kamoun

 

 


 

© Trustees of the University of Pennsylvania

 

Beta Cell Physiology and Pathology

Klaus Kaester

Klaus Kaestner, PhD

 

Doris Stoffers

Doris Stoffers, MD, PhD

 

Ali Naji

 

Ali Naji, MD