Basic and Translational Research in Diabetes
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About the Lab
Diabetes is fundamentally due to a mismatch of insulin supply with the body’s insulin requirement. In type 1 diabetes, the cells that produce insulin are destroyed by an autoimmune process. Type 2 diabetes becomes manifest when the insulin-secreting beta cells fail to adequately respond to rising insulin resistance, the loss of the ability of target tissues to respond normally to insulin. Thus, insulin resistance and its concomitant metabolic alterations constitute a fundamental predisposing event. Predisposition to diabetes is inherited and type 2 diabetes is more likely to occur in those who are obese, but there is more to be learned about both type 1 and type 2 diabetes. The fundamental questions addressed by the basic research laboratories in the the Diabetes Unit are:
- What are the genetic foundations of type 2 diabetes and insulin resistance?
- What are the mechanisms involved in beta cell destruction?
- What are the limitations of the beta cell regenerative capacity?
- Why does obesity cause insulin resistance?
- How can genetics aid in the identification and validation of new drug targets?
A better understanding of the molecular, cellular and genetic underpinnings of insulin resistance and beta cell failure and how these lead to diabetes will lead to novel prevention strategies and new treatments. Present treatments for type 2 diabetes remain unsatisfactory for a variety of reasons, and as the incidence of this disease continues to rise, concomitant with the prevalence of obesity, improved therapy is greatly needed.
The Genetics of Diabetes
Today, scientists know little more than that there is an inherited component to the risk of getting diabetes and on the subsequent development of complications. It appears that diabetes is caused by the combined action of many weakly acting genetic causes. Clearly, variations in these genes must explain the predisposition to diabetes but the identification of the predisposing genes has, until now, been an insurmountable challenge.
The Human Genome Project has provided a basic map of over 90% of the DNA comprising human chromosomes. This map enables scientists to better understand the genetic basis for our differences. In most cases, very few differences are found when comparing the same gene between two different individuals. When there are differences, they tend to affect only one or a few of the basic building blocks of genes, called nucleotides. Nevertheless, since we have so many genes, these few differences per gene add up to many thousands of variations in total.
Current Research Projects
Jose Florez, MD, PhD
Jose C. Florez, MD, PhD, Professor of Medicine at Harvard Medical School and Chairman of the Department of Medicine at Massachusetts General Hospital, is engaged in translating new genetic findings from type 2 diabetes research into the clinical arena. He and his group help generate and analyze emerging genetic data in order to:
- Provide a more refined understanding of type 2 diabetes, both by dissecting its clinical heterogeneity and illuminating novel mechanistic pathways
- Offer a “proof of concept” for the role of selected genetic variants significantly associated with diabetes or related glycemic traits, by showing that behavioral or pharmacological manipulation of a particular gene pathway alters specific phenotypes in humans
- Contribute to ushering in the era of genomic medicine, in which the practical utility of known genetic variation may be rigorously tested in the prediction of disease, prognosis of its clinical course, response to preventive or therapeutic options and individual susceptibility to side effects
To achieve these goals, Dr. Florez and his group have participated in the evaluation of specific variants in candidate genes that encode drug targets with type 2 diabetes. He and his team have contributed to the performance and analysis of high-throughput genome-wide association and sequencing studies in type 2 diabetes and related traits, in the Diabetes Genetics Initiative, the Framingham Heart Study, and other international consortia such as MAGIC, GENIE, DIAGRAM, T2D-GENES and SIGMA, where he plays management roles. Dr. Florez leads the genetic research efforts of the Diabetes Prevention Program, where the effects of genetic variants on the development of diabetes can be examined prospectively, and their impact on specific behavioral and pharmacological preventive interventions can be assessed. He is the Principal Investigator of the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), and also conducts other pharmacogenetic studies at Mass General. His laboratory at the Broad Institute explores the molecular mechanisms by which common variants in the genes SLC16A11 and IGF2 increase risk of type 2 diabetes in Latinos.
Vamsi Mootha, MD
Vamsi Mootha, MD is a Professor of Systems Biology and of Medicine at Harvard Medical School. His laboratory is based in the Department of Molecular Biology and Center for Human Genetic Research at Massachusetts General Hospital and at the Broad Institute of MIT and Harvard. His laboratory uses a blend of genomics, computation, and biochemical physiology to systematically study mitochondrial biology. Dr. Mootha's work has led to the discovery of over one dozen monogenic mitochondrial disease genes, as well as to the discovery that mitochondrial dysfunction is associated with the common form of type 2 diabetes mellitus. His work has also led to the development of generic, computational strategies that have now been applied successfully to other human diseases.
Alexander Soukas, MD, PhD
Alexander Soukas MD, PhD is an Assistant Professsor of Medicine at Harvard Medical School. His laboratory studies the molecular genetics of obesity and diabetes. The lab uses a multidisciplinary approach to study metabolic disease, uniting C. elegans genetics and genomics with vertebrate genetics and physiology. Disease mechanisms are studied in C. elegans and conserved findings are brought to mammalian systems through the use of human cell culture models and the development of mouse models. The Soukas lab houses the infrastructure to complete high-throughput screening of C. elegans, including automated microscopy, facilities for genome-wide RNAi screening, and a lifespan machine for longevity analysis. The Soukas lab, together with the Avruch lab also supports sophisticated equipment for detailed metabolic phenotyping of mouse models of obesity and diabetes, including an EchoMRI-100H for body composition analysis, a 16-cage Sable Systems Promethion for analysis of energy expenditure, and 4 CMA Microdialysis dual syringe setups for conducting insulin clamp studies.
The Soukas lab has three major projects:
- Identification of ancient, starvation defense pathways involved in metabolic disease through unbiased genomics.
Through genome-wide RNAi screening in C. elegans for fat-regulatory genes, the lab has identified nearly 500 fat-regulatory genes. The lab uses genetic approaches in C. elegans, mice and human cells to determine the biological mechanisms by which the 500 fat-regulatory genes regulate starvation defenses and fat metabolism. - Identification of how the mTOR pathway regulates aging, metabolism and starvation defenses.
The target of rapamycin (mTOR) pathway is a critical part of the insulin pathway regulating metabolism, lifespan, and stress resistance. The Soukas group discovered that mTOR complex 2 acts through the kinase serum and glucocorticoid-induced kinase (Sgk) to regulate metabolism, growth, and lifespan, and this regulation is conserved to mammals. The lab uses genomic, epigenomic, and proteomic approaches to determine how mTOR and Sgk regulate glucose and lipid metabolism and lifespan in C. elegans and mouse models. - Identification of conserved response pathways for the antidiabetic drug metformin.
Metformin is the most commonly prescribed drug for type 2 diabetes worldwide, and yet its molecular mode of action remains unclear. Together with the Florez lab, the Soukas lab is using the worm as a model to identify metformin response pathways, and interfacing our data with human genetic studies of metformin response genes.
The Soukas lab’s unique combination of invertebrate and vertebrate genetics to approach obesity and diabetes allows science and discovery to move at a much faster pace and permits important findings to be brought much more quickly to mammalian systems and ultimately to improve human health.