Generation of beta-cells from hepatocytes
Type I diabetes is classified as a chronic disease because affected individuals can manage the condition by repeated insulin injection. However, a large number of patients eventually suffer from serious, life-threatening complications of their diabetic state, including blindness, kidney failure, amputation of limbs, heart disease, and stroke. Our goal is finding a cure for type I (and a severe form of type II) diabetes.
Recent transplantation of islets cells isolated from human cadavers into individuals with type 1 diabetes has shown that these patients became free from insulin-dependency for a significant period of time, raising the possibility that someday the disease may be cured by transplanting healthy, exogenous islet cells. However, the cadaver approach is hampered by severe limitations associated with the sourcing of sufficient tissue for the large pool of patients in need. We will never come close to obtaining enough islet cells to meet the demands of the over 1.5 million type 1 diabetics in the US using the present isolation methods. What is now required is an essentially unlimited supply of physiologically competent human islet cells.
Naturally, the current focus of diabetes research is directed towards generating replacement cells that can mimic the function of normal pancreatic b-cells. An approach attempted by many scientists has been to convert stem cells directly into b-cells in vitro. Despite efforts to date, the protocols currently available for driving the differentiation of ES cells into a pancreatic lineage are inefficient. In order to explore an alternative approach, we attempt to leverage the close developmental relatedness of liver and pancreas in designing a two-stage process to transform ES cells into b-cells. Since differentiating ES cells into liver cells appears to be somewhat simpler, human ES cells will be steered into the liver lineage first, and then to pancreas via directed expression of particular genes specific to pancreatic development.
This approach has several advantages. First, available methods for differentiating ES cells into liver are simpler and more efficient that those for pancreatic differentiation. Second, we have identified molecular factors involved whose activities show promise in assisting an in vitro conversion of liver to pancreas. Lastly, recently published pieces of evidence support the notion that a method including generation of b-cells from liver holds promise. If we are successful in our two-stage approach beginning with ES cells, we may even be able to identify liver cells within the body capable of being changed into insulin-producing cells. The significance of being able to use a diabetic’s own liver tissue to generate b-cells for transplantation is that this would not only eliminate the risk of transplant rejection, but also alleviate concerns over potential tumor formation from use of ES cells.
Diabetes is the leading cause of the blindness, kidney failure, non-traumatic amputations in adults, and contributes significantly to rates of heart disease and stroke. Because the disease affects millions of people in so many different ways due to diabetic complications, diabetes is increasingly being referred to as the epidemic of the New Millennium. The disease (type I and type II) affects over 17 million people nationwide, with approximately 2 million of these in California, based on a 1992 report. Approximately 95% of the overall diabetic population suffers from type II diabetes with the remaining 5% having type I. The total number of diabetics in California is expected to double by the year 2020.
The adverse effects of diabetes disproportionately burden the elderly, women, and people of color, stemming from poor economic circumstances, genetic background, or both. Numbers In all groups are expected to rise in the future. The occurrence of juvenile diabetes (type I) is also increasing, with type I diabetes expected to strike 1 out of every 200 children by 2010. Therefore, for many of Californians, the question is not whether they will develop the disease, but when its symptoms will begin to have major negative impacts on their lives.
The diabetes-related costs to the nation in terms of medical expenses, disability payments, lost work, and premature mortality is currently more than $100 billion, with California’s share of this cost at approximately $12 billion. There are over 300,000 diabetes-related hospitalizations in California each year, at annual cost of $3.4 billion (data from Diabetes Prevention and Control Program). Clearly, diabetes has a major negative impact on California’s economy. A cure for diabetes would allow physicians to radically improve the quality of patients’ lives while significantly relieving stress upon the economy by simultaneously reducing medical costs and improving productivity at the work place. The overall positive effects from a cure for diabetes upon society are immeasurable.