Basic and Translational Research in Diabetes

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

Joseph Avruch, MD

Joseph Avruch, MD, Professor of Medicine at Harvard Medical School, studies signal transduction initiated by the insulin receptor and related receptor tyrosine kinases. Many of the components also participate in mitogenic and cell differentiation programs. Two areas currently under study are:

• MTOR is a giant protein kinase that responds to nutrient sufficiency and insulin/IGF-1 (and other mitogens) to control the growth/size of all cells (e.g., pancreatic beta cells) and occasionally their proliferation or migration. TOR also negatively regulates insulin signaling in a feedback loop. TOR functions in two physically separate complexes (mTOR complexes 1 and 2). The activity of mTORC1 is controlled interdependently by insulin and by amino acids especially leucine, and current effort is focused on elucidating leucine regulation of mTORC1. Downstream of MTOR, the lab studies the mechanisms by which MTOR regulates the RNA binding protein IMP2, encoded by a candidate T2DM locus, and especially IMP control of the translation of the IGF2 mRNA
• The Mst1 and Mst2 protein kinases are the mammalian orthologs of the “Hippo” kinase, a central element in an anti-proliferative developmental pathway defined in Drosophila. In liver and intestinal epithelia, as in Drosophila, Mst1 and Mst2 act as redundant tumor suppressors, largely through inhibition of the YAP transcriptional coactivator. In contrast, Mst1 deficiency in man results in a combined immunodeficiency; Mst1 and Mst2 in T cells are regulated by chemokine and T cell antigen receptors through the small GTPase Rap1 to control migration and the commitment to a primary immune response. The mechanisms underlying these diverse Mst1/2 outputs are under investigation.

Jose Florez, MD, PhD

Jose C. Florez, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Chief of the Diabetes Unit 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.

Joel Habener, MD

The laboratory of Joel Habener, MD, Professor of Medicine at Harvard Medical School, is exploring approaches to obtaining an understanding of the pathogenesis of diabetes mellitus. The team seeks discoveries of disease mechanisms that will enable the development of effective treatments to restore insulin-sensitivity, insulin production, and nutrient homeostasis in individuals who suffer from diabetes.

Dr. Habener and his team are pursuing two lines of investigation relevant to the discovery of effective treatments for diabetes:

• Explorations of the efficacies and mechanisms of action of newly-discovered nona- and pentapeptides, derived from the glucoincretin hormone glucagon-like peptide-1 (GLP-1), and that have anti-oxidant, insulin-sensitizing actions on insulin-resistant tissues in vitro and in obese, insulin-resistant mice in vivo
• Examination of the chemokine, stromal-cell-derived factor-1 (SDF-1), as an effector produced by injured beta cells that promotes their regeneration by the recruitment and differentiation of progenitor cells

Future goals include studies of the GLP-1-derived nona- and pentapeptides as a treatment for type 2 diabetes and the metabolic syndrome and studies of SDF-1 and GLP-1 in the regeneration of new beta cells.

Amit Majithia, MD

Amit R. Majithia, MD is an Instructor in Medicine at Harvard Medical School, a practicing endocrinologist and an Associated Scientist at the Broad Institute of Harvard/MIT. His goal is to identify genes causing insulin resistance in humans in order to find new therapeutic targets for diabetes treatment. Dr. Majithia's approach to discovery is grounded in human genetics, clarified through systematic, high-throughput experimentation in human cells, and calibrated by its relevance to clinical disease. His group uses massively parallel genome engineering to re-create mutations identified in patients and develop high-throughput assays to interrogate function in human adipocytes. They apply bioinformatics and statistics to make sense of this data integrating:

• Human mutations
• Cellular function
• Metabolic/glycemic phenotypes of the individuals who harbor them

Using this approach, Dr. Majithia's group has discovered novel missense mutations that greatly increase risk for type 2 diabetes. As a complementary aim towards precision medicine, they develop tools for clinical genome interpretation powered by high-throughput experimental data.

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.