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 #
5P01DK049210-18
Application #
8663229
Study Section
Special Emphasis Panel (ZDK1-GRB-9)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
18
Fiscal Year
2014
Total Cost
$307,114
Indirect Cost
$115,168
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ahima, Rexford S (2016) Editorial: Unlocking Therapeutic Potential of Brown Fat. Mol Endocrinol 30:275-7
Iwafuchi-Doi, Makiko; Donahue, Greg; Kakumanu, Akshay et al. (2016) The Pioneer Transcription Factor FoxA Maintains an Accessible Nucleosome Configuration at Enhancers for Tissue-Specific Gene Activation. Mol Cell 62:79-91
Shearin, Abigail L; Monks, Bobby R; Seale, Patrick et al. (2016) Lack of AKT in adipocytes causes severe lipodystrophy. Mol Metab 5:472-9
Carr, Rotonya M; Ahima, Rexford S (2016) Pathophysiology of lipid droplet proteins in liver diseases. Exp Cell Res 340:187-92
Yang, Yizeng; Katz, Jonathan P (2016) KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions. Cancer Biol Ther 17:422-9
Jang, Cholsoon; Oh, Sungwhan F; Wada, Shogo et al. (2016) A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22:421-6
Jang, Jessica C; Chen, Gang; Wang, Spencer H et al. (2015) Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden. PLoS Pathog 11:e1004579
Soleimanpour, Scott A; Ferrari, Alana M; Raum, Jeffrey C et al. (2015) Diabetes Susceptibility Genes Pdx1 and Clec16a Function in a Pathway Regulating Mitophagy in β-Cells. Diabetes 64:3475-84
Park, Hyeong-Kyu; Ahima, Rexford S (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64:24-34
Blanchet, Emilie; Van de Velde, Sam; Matsumura, Shigenobu et al. (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149-57

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