Tunable Insulin Resistance in a Drosophila Model of Diabetes

DESCRIPTION (provided by applicant): Diabetes has reached epidemic proportions in the United States resulting in expenditures of over 90B per year. The enormity of the potential market inspired many pharmaceutical companies to enter the field but success has proven difficult. The reason for this difficulty is that diabetes is a complicated disease affecting multiple organ systems including the kidneys, nervous system, and vascular system. The most severe effects of diabetes are related to long-term toxicity of high circulating glucose levels. Glucose toxicity and insulin resistance remain the greatest unmet need in the treatment of diabetes. Further, the chronic nature of diabetes requires that therapeutics present long-term safety profiles, a serious obstacle to clinical and market success. MEDROS' goal is to impact the field of diabetes by providing drugs that ameliorate the effects of insulin resistance using a different approach to drug discovery. MEDROS was founded on a proprietary platform optimized for high-throughput drug screening in situ by generating human diseases in the fruit fly Drosophila. Our whole-organism approach holds the promise of producing better safety and efficacy data than traditional pre-clinical modeling techniques with lower cost. MEDROS has licensed screening technology, from our academic collaborators at Washington University, regarding a diet-induced Drosophila model system for insulin resistance and Type-2 diabetes mellitus (T2DM). This model, achieved by feeding flies a high sugar diet, phenocopies important physiology observed in human patients with T2DM, namely hyperglycemia, hyperinsulinemia, and triglyceride accumulation, and also recapitulates the endpoint outcome- shortened lifespan. However, measurement of these endpoints is not conducive to high-throughput testing so modifications of this system are required for compound screening. At MEDROS we have successfully expanded on our founders' work and created a cancer fly model where flies die during a discreet point in their development by over-expressing oncogenes providing a rescue-from-lethality screening readout. The objective for this Phase I SBIR proposal is to apply this same approach to our diabetes research. In Aim 1 we will create transgenic fly lines with tunable expression levels of genes required for survival on a high sugar diet (i.e. insulin receptor, or Chico, etc) and optimize this system so that flies die during pupal development. In Aim 2 we will screen our compound collection in a 96-well format in search of molecules that yield adult flies. These compounds will be processed through our relevant secondary assays to quantify biochemical markers to establish relevance to the human disease. MEDROS' ultimate vision is to validate an entirely whole organism approach to diabetes drug discovery. PUBLIC HEALTH RELEVANCE: Diabetes has reached epidemic proportions in the United States, resulting in expenditures approaching 100 billion per year. Glucose toxicity and insulin resistance remain perhaps the greatest unmet need in the treatment of diabetes. MEDROS owns a proprietary Drosophila model that displays metabolic defects that mimic those in patients with T2DM: hyperglycemia, hyperinsulinemia, triglyceride accumulation, and shortened lifespan. MEDROS' goal is to impact the field of diabetes not only by putting better drugs into the clinic, but also by developing a different approach to drug discovery utilizing high-throughput whole-organism drug screens in fruit flies with human-like diseases.