Type 2 diabetes mellitus (T2DM) is reaching epidemic proportions in United States, creating a significant adverse effect on both its health and financial stability. One of the earliest events in the development of T2DM is insulin resistance, i.e. an inability of the hormone to suppress hepatic glucose output and to stimulate the uptake of glucose into muscle. Few drugs are available to treat the insulin resistance of T2DM and other related metabolic diseases. The most commonly prescribe drug, metformin, has been available for 50 years and still is useful in reducing blood sugar in diabetic individuals. However, many patients cannot tolerate metformin, and, even when efficacious, it usually needs to be eventually supplemented with other classes of therapeutics. The mechanism by which metformin reduces glucose production by the liver is poorly defined and remains controversial. The rationale underlying these studies is that by understanding the biochemical steps that metformin utilizes to educe beneficial effects on liver glucose and lipid metabolism, we will identify promising new drug targets. The initial approach to examining metformin's action is based on a novel experimental system that utilizes stable isotopes to map out the flux of simple precursors into glucose and fatty acids. These experiments will be performed in primary hepatocytes isolated form mouse, as these are likely to offer the best reflection of physiological events. The approach will be to challenge hepatocytes with varying concentrations of metformin and to monitor the flux of 13C-precursors though metabolic intermediates into glucose and lipid. These experiments should indicate the biochemical steps modulated by metformin. Putative regulatory sites will be validated by targeted mutagenesis of the responsible enzymes. To address one known candidate for an intermediate in metformin action, we will assess the ability of metformin to carry out its actions in liver cells deficient for the AMPK-activated protein kinase (AMPK). We will ascertain whether AMPK is a reasonable target to which to develop drugs that mimic the beneficial effects of metformin. Through these experiments we will identify targets for the development of novel therapeutic agents for the treatment of T2DM.

Public Health Relevance

These studies are designed to devlop new strategies for the development of drugs to treat diabetes mellitus, a disease now affecting 30 million individuals in the United States. The approach will be to study a drug, metformin, that lowers blood sugar by reducing glucose produced by liver. By understanding how metformin works, we will indentify new biochemcial targets to use in the development of novel, more effective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK049210-17
Application #
8502646
Study Section
Special Emphasis Panel (ZDK1-GRB-9)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
17
Fiscal Year
2013
Total Cost
$303,504
Indirect Cost
$113,814
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Juliana, Christine A; Yang, Juxiang; Cannon, Corey E et al. (2018) A PDX1-ATF transcriptional complex governs ? cell survival during stress. Mol Metab 17:39-48
Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705
Kim, Yong Hoon; Marhon, Sajid A; Zhang, Yuxiang et al. (2018) Rev-erb? dynamically modulates chromatin looping to control circadian gene transcription. Science 359:1274-1277
Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752
Juliana, Christine A; Yang, Juxiang; Rozo, Andrea V et al. (2017) ATF5 regulates ?-cell survival during stress. Proc Natl Acad Sci U S A 114:1341-1346
Ediger, Benjamin N; Lim, Hee-Woong; Juliana, Christine et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic ? cells. J Clin Invest 127:215-229
Jang, Jessica C; Li, Jiang; Gambini, Luca et al. (2017) Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114:E10399-E10408
Carr, Rotonya M; Dhir, Ravindra; Mahadev, Kalyankar et al. (2017) Perilipin Staining Distinguishes Between Steatosis and Nonalcoholic Steatohepatitis in Adults and Children. Clin Gastroenterol Hepatol 15:145-147
Park, Hyeong Kyu; Kwak, Mi Kyung; Kim, Hye Jeong et al. (2017) Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med 32:239-247
Ackermann, Amanda M; Zhang, Jia; Heller, Aryel et al. (2017) High-fidelity Glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting. Mol Metab 6:236-244

Showing the most recent 10 out of 220 publications