Diabetes is a polygenetic and chronic disease affecting approximately 346 million people worldwide. In 2004, an estimated 3.4 million people died from the consequences of high blood glucose. The World Health Organization projects that deaths caused by diabetes will double between 2005 and 2030. Uncontrolled diabetes results in hyperglycemia, which over time leads to serious damage to many organs. More than 90% of the diabetic population has type 2 diabetes mellitus (T2DM). The classic pathogenesis of T2DM involves insulin resistance and pancreatic beta cell dysfunction, marked by impaired, glucose-stimulated insulin secretion. Only 40-50% of individuals with insulin resistance progress to T2DM. The pivotal defect in those who progress is that pancreatic beta cells fail to compensate for insulin resistance, become dysfunctional, and eventually die. Thus, pancreatic beta cell dysfunction is a key step in the progression from metabolic impairments to a disease state. Most of the current efforts on anti-diabetes drug discovery focus on either protecting pancreatic beta cells from cell death or inducing beta cell proliferation. Only a few drugs have been developed to improve pancreatic beta cell function. It is well known that the same compound may have opposite effects on healthy and diseased cells, since different mechanisms may be involved in the regulation of cellular physiology versus pathophysiology. Therefore, a critical gap in anti-diabetes drug discovery is the lack of drugs rescuing human beta cell function in a diabetic condition. This deficit is mainly due to the lack of a high-throughput screening (HTS) platform to directly monitor human pancreatic beta cell function. In our preliminary studies, we created a luminescence-based HTS assay to identify compounds that rescue human pancreatic beta cell function in a diabetic condition. After completing a pilot screen using a library with more than 2,000 small molecules, we identified hit compounds that potentially rescue the impaired, glucose- stimulated insulin secretion of human pancreatic beta cells exposed to glucolipotoxicity. Here, we propose to perform a large-scale HTS using our established platform on multiple chemical libraries containing ~240,000 compounds, validate the hit compounds using follow-up assays, optimize lead compounds through simple structure activity relationship analyses, and evaluate the function of the identified chemical probes in diabetic-humanized mouse models. Finally, we will perform target identification and study the mechanism of action of the chemical probes. The identified chemical probes can be directly used for anti-diabetes drug development or serve to discover novel disease targets for future drug discovery.
Diabetes is a polygenetic and chronic disease affecting approximately 346 million people worldwide. Pancreatic beta cell dysfunction is a key step in the progression from metabolic impairments to a disease state. Here, we proposed to use a high throughput screening to identify the novel small molecules that rescue human pancreatic beta cell function in diabetes conditions. The identified compounds can not only be directly used for development of anti-diabetic drugs, but also used to identify novel target for drug discovery.
|Zhou, Ting; Kim, Tae Wan; Chong, Chi Nok et al. (2018) A hPSC-based platform to discover gene-environment interactions that impact human ?-cell and dopamine neuron survival. Nat Commun 9:4815|