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Diabetes Genome Anatomy Project

Joslin Diabetes Center Harvard Medical School Dana-Farber Cancer Institute Children's Hospital Boston Whitehead Institute UMASS Medical School

Mission

The Diabetes Genome Anatomy Project (DGAP) represents a unique, multidimensional initiative whose goal is to unravel the interface between insulin action, insulin resistance and the genetics of type 2 diabetes. The project was developed in conjunction with NIDDK in response to the report of the Diabetes Research Working Group and represents the efforts of investigators from five institutions. There are six projects and four cores that form a highly interactive matrix and also serve as a scaffold on which to build future projects or interactions with related projects and grants.

The overall goal of the project is to identify the sets of the genes and gene products involved in insulin action and the predisposition to type 2 diabetes, as well as the secondary changes in gene expression that occur in response to the metabolic abnormalities present in diabetes. There are five major and one pilot project involving human and rodent tissues that are designed to:

  1. Create a database of the genes expressed in insulin-responsive tissues, as well as accessible tissues, that are regulated by insulin, insulin resistance and diabetes.
  2. Assess levels and patterns of gene expression in each tissue before and after insulin stimulation in normal and genetically-modified rodents; normal, insulin resistant and diabetic humans, and in cultured and freshly isolated cell models.
  3. Correlate the level and patterns of expression at the mRNA and/or protein level with the genetic and metabolic phenotype of the animal or cell.
  4. Generate genomic sequence from a panel of humans with type 2 diabetes focusing on the genes most highly regulated by insulin and diabetes to determine the range of sequence and expression variation in these genes and the proteins they encode, which might affect the risk of diabetes or insulin resistance.

The resultant information will be used to create a highly annotated and interactive public database, standardized protocols for gene expression and proteomic analysis, and ultimately diabetes-specific and insulin action-specific DNA chips for investigators in the field. In this manner, the DGAP project will define:

  • the normal anatomy of gene expression, i.e. basal levels of expression and response to insulin.
  • the morbid anatomy of gene expression, i.e., the impact of diabetes on expression patterns and the insulin response.
  • the extent to which genetic variability might contribute to the alterations in expression or to diabetes itself.
Normal Anatomy
  • What is the normal gene/protein expression program induced by insulin in muscle, fat and liver of rodents and humans and in differentiating cultured adipocytes?
  • What elements are regulated in all target tissues and which are specific to each tissue?
  • Can functional sub-programs of insulin regulated gene/protein expression be identified related to distinct branches of insulin action or specific compartments of the cell?
  • Are expression profiles reproducible and does array analysis detect the majority of insulin-regulated genes or is subtraction cloning more sensitive?

Normal vs. Morbid Anatomy

Genetic Variation
  • How variable are the sequences of insulin and diabetes-responsive genes?
  • Do these sequence variabilities contribute to altered expression or function?
  • Do these sequence variabillities contribute to diabetes?
Morbid Anatomy
  • How are the gene/protein expression programs altered in diabetes and insulin resistant states?
  • Which changes are related to the insulin resistance of type 2 diabetes or obesity, which to the insulin deficiency of type 1 diabetes, and which to the metabolic alterations of both forms of diabetes?
  • Can expression profiles be defined that allow metabolic staging of the disease?
  • Will array analysis detect the majority of diabetes-regulated genes or are other approaches more sensitive?

This project and the resultant database will aid investigators in the quest to unravel the complexity of insulin action and its alterations in diabetes, and ultimately help develop more effective and specific modes for classification, metabolic staging and therapy of the disease.


Structure of DGAP


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