Welcome to the Sweet Laboratory
Fundamental mechanisms regulating insulin secretion by the pancreas. A primary determinant of developing diabetes is the ability of specific cells in the pancreas to secrete insulin. When these cells (called beta cells) do not respond to rises in blood glucose by secreting the appropriate amount of insulin, blood sugar levels can remain high commonly requiring treatment with injected insulin or oral medications. In order to understand why the function of beta cells becomes impaired, our laboratory studies the biochemical mechanisms that mediate the sensing of glucose levels by beta cells and the intracellular signaling that tells the beta cells how much insulin to secrete. One such signal that is calcium, a cation that enters the cells upon glucose stimulation, and is essential for the release of insulin. However, how calcium interacts with intracellular proteins to promote the release of insulin is not understood, making it difficult to know what is going wrong during the development of diabetes, and how to correct it pharmacologically. Our laboratory has recently discovered unique features of an additional signaling molecule, called cytochrome c. This protein has long been established to be involved with the generation of energy needed for maintenance of cell function, however we have found that changes in its configuration and movement from one part of the cell to another, may operate in conjunction with calcium to regulate the appropriate amount of insulin release. Importantly we have recently found that a lack of signaling by cytochrome c can result in decreased insulin secretion, demonstrating the proof of principle that impairment of this signal could be a cause of diabetes. Present work is focused on factors that control the configuration of cytochrome c and how this could be contributing to the risk of diabetes. The research is being supported by the American Diabetes Association.
Replacement of beta cells. During the progression of Type 1 diabetes, beta cells are destroyed by what is believed to be an autoimmune process. An important and promising clinical goal is replacement of the destroyed beta cells with cells that are generated from stem cells. In conjunction with the Diabetes Stem Cell Program, we are using our expertise in beta cell biochemistry to evaluate cells that have been differentiated to beta cells. We surmise that transplantation of cells will successfully lead to insulin independence when differentiated stem cells will have proper glucose sensing and signaling in addition to the ability to synthesize and secrete insulin. This work is being supported by the Washington State Life Science Discovery Fund
Cystic Fibrosis results in high incidence of diabetes. With improvements in care of patients with cystic fibrosis, average life span has increased from less than 10 years of age to over 40. Unfortunately with the increased life span, the incidence of developing Type 2 diabetes (termed Cystic Fibrosis Related Diabetes, or CFRD) has risen to more than 50%. The Sweet Laboratory has been addressing the question of whether the impaired secretory capacity is due to intrinsic defects in beta cells caused by the mutation in the protein that is caused Cystic Fibrosis (the CFTR), or whether beta cells are damaged due to the general conditions they are exposed to in patients suffering from the disease. This work is supported by the National Institute of Health.
Drug toxicity testing. Although the major goal of pharmaceuticals are to treat of prevent symptoms, very often it is the side effects that determine whether a drug will ultimately be suitable for widespread use. Since both pharmaceutical companies and patients desire getting drugs to market, there is an exigent need to improve and speed up drug toxicity testing methodologies. Our laboratory is using ultra sensitive methods to resolve small changes in mitochondrial function in response to low levels of drugs, far below the levels that can be tested with standard methods. We predict that the approach will make the drug testing process more efficient and improve the probability of drugs making it to market with less toxic side effects. This research is being supported by the University of Washington Commercialization Gap Fund.
Our laboratory was the recipient of the 2013 Gail Patrick Innovation Award from the American Diabetes Association. In honor of Gail Patrick, the first National Chair of the ADA Board of Directors and legendary Motion Picture actress, this award is granted to Innovation award applications to the ADA that receive the highest priority score in a given year. Prestigious awardees receive $50,000 per year for two years to support an innovative idea that advances the Association’s efforts to prevent, treat and cure diabetes and to improve the lives of all people affected by the disease. Dr. Sweet’s project entitled, “Role of cytochrome c translocation in insulin release”, will test whether the movement of cytochrome c is necessary and sufficient to stimulate insulin secretion in the face of elevated calcium signaling.
Ian Sweet, PhD, Principal Investigator, Research Associate Professor of Medicine.My career has been devoted to the understanding of the biochemical mechanisms mediating and regulating insulin secretion and function of other cells important to diabetes. As a bioengineer/chemical engineer, my approaches have centered round the fabrication of powerful methods to study these processes in intact cells. Development of these technologies has supported many research groups that I have collaborated with through the Cellular Functional Analysis Core of the Diabetes Research Center that I have directed for the last 15 years. Based on our technology, I have published with more than 15 research groups in the last 5 years alone, and applied the methods to various fundamental and clinically important research areas including the differentiation of stem cells, drug toxicity testing and the understanding of various diseases. Click here for full bio and publication list. Kelly Kernan, BS, Research Interests: use of molecular biology tools to assess physiologic and pathophysiological roles of specific proteins by genetically altering their levels. Adam Neal, BS, Research Scientist, Research interests: Hepatotoxicity Testing, Metabolic Function of Stem Cells; Homeostasis of Redox State and Insulin Secretion. Austin Rountree, BS, Research Scientist. Research Interests: Functional Analysis of Retina, Mechanisms of Metabolic Impairment of Pancreatic Islets.
Diabetes and Obesity Center of Excellence
Department of Pathology
University of Washington School of Medicine
South Lake Union Campus
850 Republican Street Rm S281
Seattle, WA 98109-8055
Fax: (206) 543-3567
Ian Sweet: (206) 685-4775
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