Type II Diabetes Mellitus is one of the most common diseases in the Western world, with prevalence ranging from 10-50% in elderly populations. An integral component of Type II diabetes mellitus is insulin resistance, i.e. the inability of maximal concentrations of the hormone to stimulate appropriately muscle glucose transport, suppression of hepatic glucose output and other physiological responses. A plausible strategy leading to the development of novel insulin-sensitizing drugs begins with the systematic analysis of insulin signaling. After over 30 years of intensive research in the pursuit of relevant protein kinases, Akt/PKB has emerged as the only serine/threonine protein kinases definitively established as a mediator of insulin's regulation of important metabolic targets. The activity of Akt/PKB depends on the lipid products of phosphotidylinositol 3'- kinase, an enzyme known to be required for virtually all of the metabolic actions of insulin. The Akt/PKB kinases represent a family of three closely related proteins that have been implicated in the regulation of processes as diverse as apoptosis, cell growth, cell cycle progression, differentiation and angiogenesis as well as metabolism. Recent work has shown that mice deficient in Akt2/PKBbeta mimic several features of diabetes, including insulin resistance in liver, muscle and adipose tissue. Interestingly, Akt1/PKBalpha null mice are absolutely normal metabolically, but are about 20% reduced in size. The differences in phenotype between Akt1/PKBalpha and Akt2/beta knockout mice are due to both to isoform-speciflc patterns of expression as well as distinct signaling properties intrinsic to the proteins. The underlying rationale of these proposed studies is that by investigating the biochemical basis of the preferential ability of Akt2/PKBbeta to signal to glucose transport, significant progress will be made in understanding the fundamental mechanism of insulin action. Specificity will be approached using several related strategies: 1) the domains of Akt/PKB conferring isoform specific signaling will be mapped by the use of chimeric proteins; 2) the two isoforms will be analyzed for differences in intracellular localization; and 3) a search will be conducted for Akt2-specific substrates. It is anticipated that these studies will significantly extend the knowledge of physiological insulin-independent signaling and ultimately lead to the identification of potential targets for therapeutic intervention in diabetes mellitus.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Blondel, Olivier
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Quinn 3rd, William J; Wan, Min; Shewale, Swapnil V et al. (2017) mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion. J Clin Invest 127:4207-4215
Wang, Qi; Yu, Wan-Ni; Chen, Xinyu et al. (2016) Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell 29:523-535
Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana et al. (2016) Akt-mediated foxo1 inhibition is required for liver regeneration. Hepatology 63:1660-74
Chen, Qing; Lu, Mingjian; Monks, Bobby R et al. (2016) Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein. J Biol Chem 291:2371-8
Perry, Rachel J; Borders, Candace B; Cline, Gary W et al. (2016) Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism. J Biol Chem 291:12161-70
Titchenell, Paul M; Quinn, William J; Lu, Mingjian et al. (2016) Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production. Cell Metab 23:1154-1166
Perry, Rachel J; Camporez, João-Paulo G; Kursawe, Romy et al. (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745-758
Titchenell, Paul M; Chu, Qingwei; Monks, Bobby R et al. (2015) Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat Commun 6:7078
Feng, Daorong; Youn, Dou Yeon; Zhao, Xiaoping et al. (2015) mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC). PLoS One 10:e0126240
Koral, Kelly; Li, Hui; Ganesh, Nandita et al. (2014) Akt recruits Dab2 to albumin endocytosis in the proximal tubule. Am J Physiol Renal Physiol 307:F1380-9

Showing the most recent 10 out of 69 publications