Diabetes mellitus is a huge health burden due to decreased quality of life and the escalating cost of treatment. In the United States alone, ~8% of the population is diabetic and nearly one-third of adults are now estimated to be at risk to develop the disease. Obesity, insulin resistance and metabolic abnormalities in liver, adipose, and muscle are important factors in disease. Yet, most of the gene loci recently found associated with type 2 diabetes encode proteins that enable insulin production from pancreatic cells. Nutrients and hormones regulate not only insulin secretion but also the capacity of cells to continue to produce insulin. In this proposal we focus on mechanisms of action of nutrients and agents that enhance insulin production in cells. The overarching goals are to elucidate mechanisms that can be manipulated to improve -cell function and overcome the physiological changes in cells that occur during prolonged hyperglycemia, contributing to inadequate insulin release.
In aim 1 we will determine the functions of the taste receptor complex (T1R1/T1R3) in pancreatic cells. This dimeric G protein-coupled receptor (GPR) is involved in amino acid-sensing. This receptor, identified in gustatory neurons, binds to a variety of amino acids, but has not been studied on cells. We find that stable knockdown of T1R3 reduces insulin secretion, and insulin content, and causes events associated with autophagy. We will explore the bases for these phenotypic changes and we will also examine the underlying signaling mechanisms. In the second aim we will examine molecular mechanisms of action of small molecules that enhance beta-cell function. These molecules stimulate insulin production by cells, improve oral glucose tolerance of db/db mice, and restore insulin production by human islets in long term culture. We have identified a number of changes that take place in cells treated with these drugs, including epigenetic alterations, and changes in concentrations of key transcription factors. We will evaluate candidates that may mediate the actions of these drugs identified by drug-affinity chromatography. Finally, we will continue to investigate ERK1/2-dependent signaling events that control insulin gene transcription by focusing on mechanisms of recruitment of the coactivator p300. These studies should provide new understanding of how amino acids regulate insulin production, stability and release and will exploit a new pharmacological tool to identify mechanisms to enhance insulin production and insulin transcription in normal and failing islets.
Type 2 diabetes mellitus is now found not only in adults but also in children in the United States. These studies will explore new mechanisms to enhance insulin production in diabetes focusing on a nutrient sensing receptor and a novel small molecule that enhances insulin production from poorly functioning islets.
|Kalwat, Michael A; Hwang, In Hyun; Macho, Jocelyn et al. (2018) Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic ? cells. J Gen Physiol 150:1747-1757|
|Guerra, Marcy L; Kalwat, Michael A; McGlynn, Kathleen et al. (2017) Sucralose activates an ERK1/2-ribosomal protein S6 signaling axis. FEBS Open Bio 7:174-186|
|Kalwat, Michael A; Cobb, Melanie H (2017) Mechanisms of the amplifying pathway of insulin secretion in the ? cell. Pharmacol Ther 179:17-30|
|Kalwat, Michael A; Wichaidit, Chonlarat; Nava Garcia, Alejandra Y et al. (2016) Insulin promoter-driven Gaussia luciferase-based insulin secretion biosensor assay for discovery of ?-cell glucose-sensing pathways. ACS Sens 1:1208-1212|
|Kalwat, Michael A; Huang, Zhimin; Wichaidit, Chonlarat et al. (2016) Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in ?-Cells. ACS Chem Biol 11:1128-36|
|Wauson, Eric M; Guerra, Marcy L; Dyachok, Julia et al. (2015) Differential Regulation of ERK1/2 and mTORC1 Through T1R1/T1R3 in MIN6 Cells. Mol Endocrinol 29:1114-22|
|Lawrence, Michael C; Borenstein-Auerbach, Nofit; McGlynn, Kathleen et al. (2015) NFAT targets signaling molecules to gene promoters in pancreatic ?-cells. Mol Endocrinol 29:274-88|
|Guerra, Marcy L; Wauson, Eric M; McGlynn, Kathleen et al. (2014) Muscarinic control of MIN6 pancreatic ? cells is enhanced by impaired amino acid signaling. J Biol Chem 289:14370-9|
|Chamberlain, Chester E; Scheel, David W; McGlynn, Kathleen et al. (2014) Menin determines K-RAS proliferative outputs in endocrine cells. J Clin Invest 124:4093-101|
|Osborne, Jihan K; Guerra, Marcy L; Gonzales, Joshua X et al. (2014) NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas. Mol Biol Cell 25:1782-92|
Showing the most recent 10 out of 32 publications