The American Diabetes Association in 2008 determined that type 2 diabetes (T2D) has reached the status of "public health crisis" costing the United States at least $174 billion a year. The pathogenesis of T2D is characterized by a combination of factors that ultimately lead to the loss of glycemic control. Approximately 60% of diabetics do not achieve their target blood sugar levels with their current treatment regimen. In addition, no existing agent reverses disease progression and all exhibit reduced efficacy over time. Chronic low-grade inflammation has emerged as a central mechanism that underlies both insulin resistance in the periphery and b-cell dysfunction and apoptosis in the pancreas. The NLRP3 inflammasome is a sensor of metabolic dysregulation that triggers the maturation and secretion of proinflammatory cytokines IL-1b and IL-18. Implicated as a critical driver of the progression from obesity to T2D, the inflammasome has emerged as an attractive target, though an incompletely understood one. Recently, glyburide has been shown to inhibit the NLRP3 inflammasome, and its insulin secretagogue activity is not responsible for these actions. In fact, glyburide's secretagogue activity is undesirable since it puts patients at risk for hyperinsulinemic hypoglycemia and contributes to b-cell dysfunction and apoptosis. We propose to optimize glyburide's inflammasome activity while designing out its secretagogue actions to produce potent and selective inhibitors. We will demonstrate that these compounds suppress IL-1b secretion in our macrophage and islet models while preserving islet function. This work will be a first step towards developing a new class of oral agents for T2D;NLRP3 inflammasome inhibitors.

Public Health Relevance

The American Diabetes Association in 2008 determined that type 2 diabetes (T2D) has reached the status of "public health crisis" costing the United States at least $174 billion a year. The International Diabetes Federation predicts that by 2025, the cost will exceed $302.5 billion. The pathogenesis of T2D is characterized by a combination of factors that ultimately lead to loss of glycemic control. Approximately 60% of diabetics do not achieve their target blood sugar levels with their current treatment regimen. In addition, no existing agent reverses disease progression and all exhibit reduced efficacy over time. We seek to create and develop oral therapies for T2D that address the chronic low-grade inflammation that drives disease progression. Our efforts represent significant steps towards the development of a novel, oral treatment to improve glycemic control in type 2 diabetics with the unique potential to modify disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43DK094627-01
Application #
8253234
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (10))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2012-09-18
Project End
2013-08-31
Budget Start
2012-09-18
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$184,776
Indirect Cost
Name
Metafold Therapeutics, Inc.
Department
Type
DUNS #
809743490
City
San Francisco
State
CA
Country
United States
Zip Code
94110