In recent years, there has been a marked increase in the prevalence of obesity and insulin-resistant syndromes such as Type II Diabetes Mellitus and the metabolic syndrome. This increasing public health epidemic has dramatically emphasized the need to understand in more detail how insulin regulates metabolism and how this process gets perturbed during hyperinsulinemia. Work from the Principal Investigator as well as other scientists have contributed to unraveling a signaling pathway by which insulin regulates metabolism in liver, muscle and adipose tissue. Central to this signaling cascade is the serine/threonine protein kinase Akt, also known as Protein Kinase B. Previous work from the Principal Investigator's laboratory has demonstrated that each of the three Akt family members each has distinct roles in normal physiology. Thus, one of the major goals of this grant proposal understands the mechanism by which this isoform specificity is conferred. In particular, these studies focus on insulin action in the liver, where Akt appears to be an obligate intermediate in mediating many of insulin's metabolic outputs. The isoform specificity in hepatic metabolism is evident in liver, in that Akt2 deletion abrogates control of lipogenic gene expression, but insulin is still capable of regulating the genes encoding gluconeogenic proteins. Nonetheless, Akt2-deficient livers display insulin resistance in terms of glucose output in spite of the preserved transcriptional control. Thus, the second aim in these studies is to understand the mechanism by which insulin rapidly shuts off glucose output by the liver and how this process becomes defective in the absence of Akt2. Lastly, a paradoxical aspect of insulin resistant syndromes is that, even though the liver is alleged to be insensitive to the actions of insulin, its metabolic phenotype regarding lipids appears to be "hyper-responding" to insulin. The Principal Investigator and his laboratory favor the hypothesis that insulin resistance under pathological conditions is "selective", retaining the ability of insulin to regulate anabolic lipid pathways while losing suppression of hepatic glucose output. The phenotype of livers deficient in Akt2, which are protected from accumulation of fat in the liver, support this hypothesis.
The third aim of these studies understands mechanistically the requirement for Akt2 in the accumulation of neutral lipid in the mouse liver during pathological, insulin-resistant states. It is hoped that through these detailed investigations into the metabolic actions of insulin in the liver, it will be possible to arrive at new therapeutic targets to combat the ravages of Type II Diabetes Mellitus.

Public Health Relevance

Recent years have witnessed an increase in obesity and diabetes mellitus of epidemic proportions. One of the central abnormalities in these states is abnormal production of lipids in the liver, which contributes to the heart disease that is so often a major problem in Type II Diabetes Mellitus. It is the aim of these studies to understand why lipid metabolism is so disturbed in Type II Diabetes Mellitus and to identify novel targets to treat this aspect of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056886-15
Application #
8617268
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2000-02-15
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$414,871
Indirect Cost
$154,078
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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 23:1154-66
Wang, Qi; Yu, Wan-Ni; Chen, Xinyu et al. (2016) Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell 29:523-35
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
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
Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana et al. (2016) Akt-mediated foxo1 inhibition is required for liver regeneration. Hepatology 63:1660-74
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
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 160:745-58
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
Patel, Kashyap; Foretz, Marc; Marion, Allison et al. (2014) The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun 5:4535
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

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