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The liver plays a central role in glucose homeostasis. During the postabsorptive and fasting period, >90% of glucose production is derived from the liver. When glucose enters the blood following feeding, the liver switches from net glucose production to net glucose uptake to lessen the rise in blood glucose. Such switching is regulated by raised blood glucose per se and plasma insulin. Impaired suppression of hepatic glucose production and a defect in hepatic glucose uptake in response to the raise in plasma glucose and insulin are major pathogenesis in fasting and excessive postprandial hyperglycemia that are common feature in obesity and diabetes. Our laboratory is interested in the mechanism of the unresponsiveness of hepatic glucose flux to changes in blood glucose and plasma insulin in obesity and diabetes.
Glucokinase (GK) plays a critical role in determining net hepatic glucose flux by catalyzing glucose phosphorylation, the first step of glucose utilization by the liver, and by opposing glucose-6-phosphatase, which catalyze glucose de-phosphorylation, the last step of glucose production by the liver. GK activity is regulated allosterically by its regulatory protein (GKRP). GKRP binds to the allosteric site in GK and inhibits GK decreasing the apparent affinity of the enzyme for glucose. We found that in normal rats, GK, but not GKRP, translocated rapidly from the nucleus to the cytoplasm in response to physiological increases in plasma glucose and/or insulin while both proteins co-located in the nucleus in the presence of basal levels of plasma glucose and insulin. We also found that the unresponsiveness of hepatic glucose flux to the rise in plasma glucose and/or insulin seen in Zucker diabetic fatty rats, type 2 diabetes model with obesity, was associated with impaired trasnlocation of GK in the early stage of diabetes and abnormal localization of GKRP in the cytoplasm together with GK in the later stage of diabetes.
To understand pathogenic role for altered regulation of GK activity by GKRP in impaired hepatic glucose flux in obesity and diabetes, our laboratory focuses on 1) mechanism by which the subcellular localization of GK and GKRP is determined in normal animals, 2) the way in which the GK translocation is impaired in the early stage of diabetes, 3) the relationship between altered distribution of GKRP and impaired glucose phosphorylation by GK in later stage of diabetes, and 4) effect of increasing free (unbound) GK by transfecting GK gene to improve impaired responsiveness of hepatic glucose flux to the rise in plasma glucose and/or insulin and to reduce hyperglycemia in diabetic animals.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Chronic overeating impairs hepatic glucose uptake and disposition. Coate KC, Kraft G, Shiota M, Smith MS, Farmer B, Neal DW, Williams P, Cherrington AD, Moore MC (2015) Am J Physiol Endocrinol Metab 308(10): E860-7
    › Primary publication · 25783892 (PubMed) · PMC4587587 (PubMed Central)
  2. Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp. Farmer TD, Jenkins EC, O'Brien TP, McCoy GA, Havlik AE, Nass ER, Nicholson WE, Printz RL, Shiota M (2015) Am J Physiol Endocrinol Metab 308(3): E206-22
    › Primary publication · 25516552 (PubMed) · PMC4312835 (PubMed Central)
  3. ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD (2014) Mol Metab 3(5): 544-53
    › Primary publication · 25061559 (PubMed) · PMC4099508 (PubMed Central)
  4. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells. Leamy AK, Egnatchik RA, Shiota M, Ivanova PT, Myers DS, Brown HA, Young JD (2014) J Lipid Res 55(7): 1478-88
    › Primary publication · 24859739 (PubMed) · PMC4076085 (PubMed Central)
  5. Acyl-coenzyme A-binding protein regulates Beta-oxidation required for growth and survival of non-small cell lung cancer. Harris FT, Rahman SM, Hassanein M, Qian J, Hoeksema MD, Chen H, Eisenberg R, Chaurand P, Caprioli RM, Shiota M, Massion PP (2014) Cancer Prev Res (Phila) 7(7): 748-57
    › Primary publication · 24819876 (PubMed) · PMC4090029 (PubMed Central)
  6. Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity. Ueta K, O'Brien TP, McCoy GA, Kim K, Healey EC, Farmer TD, Donahue EP, Condren AB, Printz RL, Shiota M (2014) Am J Physiol Endocrinol Metab 306(11): E1225-38
    › Primary publication · 24714398 (PubMed) · PMC4042096 (PubMed Central)
  7. Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes. Egnatchik RA, Leamy AK, Noguchi Y, Shiota M, Young JD (2014) Metabolism 63(2): 283-95
    › Primary publication · 24286856 (PubMed) · PMC3946971 (PubMed Central)
  8. Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC (2013) Diabetes 62(12): 4144-53
    › Primary publication · 23630302 (PubMed) · PMC3837044 (PubMed Central)
  9. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, O'Brien RM (2013) Diabetes 62(5): 1547-56
    › Primary publication · 23274894 (PubMed) · PMC3636628 (PubMed Central)
  10. Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet. Coate KC, Smith MS, Shiota M, Irimia JM, Roach PJ, Farmer B, Williams PE, Moore MC (2013) Diabetes 62(3): 753-61
    › Primary publication · 23223020 (PubMed) · PMC3581200 (PubMed Central)
  11. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, Chen H, Clark JE, Alborn WE, Eisenberg R, Massion PP (2013) Clin Cancer Res 19(3): 560-70
    › Primary publication · 23213057 (PubMed) · PMC3697078 (PubMed Central)
  12. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Coate KC, Kraft G, Irimia JM, Smith MS, Farmer B, Neal DW, Roach PJ, Shiota M, Cherrington AD (2013) Diabetes 62(2): 392-400
    › Primary publication · 23028137 (PubMed) · PMC3554368 (PubMed Central)
  13. Measurement of glucose homeostasis in vivo: combination of tracers and clamp techniques. Shiota M (2012) Methods Mol Biol : 229-53
    › Primary publication · 22893411 (PubMed)
  14. Diabetes in Zucker diabetic fatty rat. Shiota M, Printz RL (2012) Methods Mol Biol : 103-23
    › Primary publication · 22893404 (PubMed)
  15. The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA, Piston DW, Hutton JC, Powell DR, O'Brien RM (2012) PLoS One 7(7): e40972
    › Primary publication · 22829903 (PubMed) · PMC3400647 (PubMed Central)
  16. Defective glycogenesis contributes toward the inability to suppress hepatic glucose production in response to hyperglycemia and hyperinsulinemia in zucker diabetic fatty rats. Torres TP, Fujimoto Y, Donahue EP, Printz RL, Houseknecht KL, Treadway JL, Shiota M (2011) Diabetes 60(9): 2225-33
    › Primary publication · 21771972 (PubMed) · PMC3161317 (PubMed Central)
  17. Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs. Torres TP, Sasaki N, Donahue EP, Lacy B, Printz RL, Cherrington AD, Treadway JL, Shiota M (2011) J Pharmacol Exp Ther 337(3): 610-20
    › Primary publication · 21363927 (PubMed) · PMC3207486 (PubMed Central)
  18. A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin. Winnick JJ, An Z, Moore MC, Ramnanan CJ, Farmer B, Shiota M, Cherrington AD (2009) Am J Physiol Endocrinol Metab 297(2): E358-66
    › Primary publication · 19470836 (PubMed) · PMC2724107 (PubMed Central)
  19. Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats. Torres TP, Catlin RL, Chan R, Fujimoto Y, Sasaki N, Printz RL, Newgard CB, Shiota M (2009) Diabetes 58(1): 78-86
    › Primary publication · 18952838 (PubMed) · PMC2606896 (PubMed Central)
  20. Hepatic glucose sensing: does flux matter? Shiota M, Magnuson MA (2008) J Clin Invest 118(3): 841-4
    › Primary publication · 18292804 (PubMed) · PMC2248806 (PubMed Central)
  21. Intraportal administration of neuropeptide Y and hepatic glucose metabolism. Nishizawa M, Shiota M, Moore MC, Gustavson SM, Neal DW, Cherrington AD (2008) Am J Physiol Regul Integr Comp Physiol 294(4): R1197-204
    › Primary publication · 18234742 (PubMed)
  22. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. Nagle CA, An J, Shiota M, Torres TP, Cline GW, Liu ZX, Wang S, Catlin RL, Shulman GI, Newgard CB, Coleman RA (2007) J Biol Chem 282(20): 14807-15
    › Primary publication · 17389595 (PubMed) · PMC2819346 (PubMed Central)
  23. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB (2004) Nat Med 10(3): 268-74
    › Primary publication · 14770177 (PubMed)