Challenging Basic Science with a Human Application

Insulin controls energy use by all vertebrates. Changes in circulating insulin levels alert cells to alterations in available energy. When we eat, rising insulin levels direct storage cells such as liver and fat to stockpile energy, energy that they release back into the circulation when falling insulin levels indicate that we are fasting. In addition, insulin modulates cell growth and metabolism to match energy availability, and even plays a role in long-term energy balance by suppressing appetite when we overeat and accumulate excess energy stores. This reliance on a single molecule to direct such fundamental processes carries a risk: any defect in insulin production or function results in severe metabolic consequences that we recognize as diabetes.

The central focus of the German laboratory is the cells that produce insulin, the beta-cells. Beta-cells reside in the pancreas, in small clusters of endocrine cells called islets of Langerhans, and their loss, damage or dysfunction causes diabetes. Our group explores how the beta-cells arise during embryonic development, how they differentiate from the other pancreatic cell types, and what mechanisms control the turnover of the mature beta-cells. Ultimately, we believe that this knowledge will help us to understand where these processes break down in type 2 diabetes, and will yield novel strategies for curing diabetes (type 1 and 2).

All of the cells of the mature pancreas develop from a small pool of common progenitor cells in the early gut tube. But how do these unconstrained progenitor cells choose their ultimate cell fate and transform into mature cells? We have approached this problem by asking how these early progenitor cells change the genes that they express, since cellular differentiation can be viewed as a series of alteration in gene expression. Our general strategy has been to identify the transcription factors that regulate gene expression in progenitors and mature beta-cells. These factors and their genes are then used as tools to understand the process of beta-cell development by studying both how they regulate gene expression and development and how they are regulated themselves, both in mouse models and in vitro.

In parallel, we apply the accumulating information from these basic studies to the development and testing of methods for producing beta-cells for people with diabetes. We believe that the recapitulation of beta-cell genesis in the culture dish, or ultimately even in people, will eventually provide a cure for diabetes.