Vanderbilt University School of
Shiota, Masakazu , D.V.M., Ph.D.
Associate Professor of Molecular Physiology and Biophysics
Phone Number: 615-936-1092
762 Robinson Research Building
762 Robinson Research Building 0615
Diabetes, Obesity, Metabolism, Liver, Carbohydrate, Lipid, Glucokinase
Hepatic Glucose Flux Regulation in Obesity and Type 2 Diabetes.
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.
Pino, MF, Kim, KA, Shelton, KD, Lindner, J, Odili, S, Li, C, Collins, HW, Shiota, M, Matschinsky, FM, Magnuson, MA. Glucokinase thermolability and hepatic regulatory protein binding are essential
factors for predicting the blood glucose phenotype of missense mutations. J Biol Chem, 282(18), 13906-16, 2007.
Shin, JS, Torres, TP, Catlin, RL, Donahue, EP, Shiota, M. A defect in glucose-induced dissociation of glucokinase from the regulatory
protein in Zucker diabetic fatty rats in the early stage of diabetes. Am J Physiol Regul Integr Comp Physiol, 292(4), R1381-90, 2007.
Brissova, M, Shostak, A, Shiota, M, Wiebe, PO, Poffenberger, G, Kantz, J, Chen, Z, Carr, C, Jerome, WG, Chen, J, Baldwin, HS, Nicholson, W, Bader, DM, Jetton, T, Gannon, M, Powers, AC. Pancreatic islet production of vascular endothelial growth factor--a is essential
for islet vascularization, revascularization, and function. Diabetes, 55(11), 2974-85, 2006.
Fujimoto, Y, Torres, TP, Donahue, EP, Shiota, M. Glucose toxicity is responsible for the development of impaired regulation
of endogenous glucose production and hepatic glucokinase in Zucker diabetic fatty rats. Diabetes, 55(9), 2479-90, 2006.
Fujitani Y, Fujitani S, Boyer DF, Gannon M, Kawaguchi Y, Ray M, Shiota M, Stein RW, Magnuson MA, Wright CV. Targeted deletion of a cis-regulatory region reveals differential gene dosage
requirements for Pdx1 in foregut organ differentiation and pancreas formation. Genes Dev, 20(2), 253-66, 2006. PMCID:1356115
Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J, Hasegawa Y, Gao J, Kaneko K, Iwasaki H, Ishihara H, Sasano H, Inukai K, Mizuguchi H, Asano T, Shiota M, Nakazato M, Oka Y. Neuronal pathway from the liver modulates energy expenditure and systemic insulin
sensitivity. Science, 312(5780), 1656-9, 2006.
Brissova M, Blaha M, Spear C, Nicholson W, Radhika A, Shiota M, Charron MJ, Wright CVE, Powers AC. Reduced PDX-1 Expression Impairs Islet Response to Insulin Resistance and Worsens
Glucose Homeostasis. Am J Physiol Endocrinol Metab, 288, E707-E714, 2005.
Fowler M, Virostko J, Chen Z, Poffenberger G, Radhika A, Brissova M, Shiota M, Nicholson WE, Shi Y, Hirshberg B, Harlan DM, Jansen ED, Powers AC. Assessment of pancreatic islet mass after islet transplantation using in vivo
bioluminescence imaging. Transplantation, 79(7), 768-76, 2005.
Jones JR, Barrick C, Kim KA, Lindner J, Blondeau B, Fujimoto Y, Shiota M, Kesterson RA, Kahn BB, Magnuson MA. Deletion of PPARgamma in adipose tissues of mice protects against high fat
diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A, 102(17), 6207-12, 2005. PMCID:556131
Shiota C, Rocheleau JV, Shiota M, Piston DW, Magnuson MA. Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea
receptor. Am J Physiol Endocrinol Metab, 289(4), E570-7, 2005.
Shiota M, Galassetti P, Igawa K, Neal DW Cherrington AD. Inclusion of Low Amounts of Fructose With an Intraportal Glucose Load Increases
Net Hepatic Glucose Uptake in the Presence of Relative Insulin Deficiency in Dog. Am J Physiol Endocrinol Metab, 288, E1160-E1167, 2005.
An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB.. Hepatic expression of Malonyl CoA decarboxylase reverses in muscle, liver and whole-animal insulin resistance in rats with diet-induced obesity. Nature Med, 10, 268-274, 2004.
Brissova M, Fowler M, Wiebe P, Shostak A, Shiota M, Radhika A, Lin PC, Gannon M, Powers AC. Intraislet endothelial cells contribute to revascularization of transplanted
pancreatic islets. Diabetes, 53(5), 1318-25, 2004.
Chu CA, Fujimoto Y, Igawa K, Grimsby J, Grippo JF, Magnuson MA, Cherrington AD, Shiota M. Rapid Translocation of Hepatic Glucokinase in Response to Intraduodenal Glucose Infusion and Changes in Plasma Glucose and Insulin in Conscious Rats. Am J Physiol Gastrointest Liver Physiol, 286, G627-G634, 2004.
Fujimoto Y, Donahue EP, Shiota M. Defect in glucokinase translocation in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab, 287(3), E414-23, 2004.
Wang XL, Herzog B, Waltner-Law M, Hall RK, Shiota M, Granner DK. The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic
phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300. J Biol Chem, 279(33), 34191-200, 2004.
Brissova M, Nicholson WE, Shiota M, Powers AC. Assessment of insulin secretion in the mouse. Methods Mol Med, 83, 23-45, 2003.
Magnuson MA, She P, Shiota M. Gene-altered mice and metabolic flux control. J Biol Chem, 278(35), 32485-8, 2003.
Nishizawa M, Moore MC, Shiota M, Gustavson SM, Snead WL, Neal DW, Cherrington AD. Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. Am J Physiol Endocrinol Metab, 284(5), E1027-36, 2003.
She P, Burgess SC, Shiota M, Flakoll P, Donahue EP, Malloy CR, Sherry AD, Magnuson MA. Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation. Diabetes, 52(7), 1649-54, 2003.
Wu L, Nicholson W, Wu C-Y, Xu M, McGaha A, Shiota M, Powers AC. Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagon-like peptide 1 receptor. Gene Ther, 10(19), 1712-20, 2003.
Brissova M, Shiota M, Nicholson WE, Gannon M, Knobel SM, Piston DW, Wright CVE, Powers AC. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem, 277(13), 11225-32, 2002.
Igawa K, Mugavero M, Shiota M, Neal DW, Cherrington AD. Insulin sensitively controls the glucagon response to mild hypoglycemia in the dog. Diabetes, 51(10), 3033-42, 2002.
Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren P-O, Magnuson MA. Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem, 277(40), 37176-83, 2002.
Shiota M, Moore MC, Galassetti P, Monohan M, Neal DW, Shulman GI, Cherrington AD. Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog. Diabetes, 51(2), 469-78, 2002.
Flattem, N, Igawa, K, Shiota, M, Emshwiller, M G, Neal, D W, Cherrington, A D. Alpha- and beta-cell responses to small changes in plasma glucose in the conscious dog. Diabetes, 50(2), 367-75, 2001.
Jetton, T L, Shiota, M, Knobel, S M, Piston, D W, Cherrington, A D, Magnuson, M A. Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition. Int J Exp Diabetes Res, 2(3), 173-86, 2001. PMCID:2478546
Postic, C, Shiota, M, Magnuson, M A. Cell-specific roles of glucokinase in glucose homeostasis. Recent Prog Horm Res, 56, 195-217, 2001.
Sherck, S M, Shiota, M, Saccomando, J, Cardin, S, Allen, E J, Hastings, J R, Neal, D W, Williams, P E, Cherrington, A D. Pancreatic response to mild non-insulin-induced hypoglycemia does not involve extrinsic neural input. Diabetes, 50(11), 2487-96, 2001.
Shiota, M, Postic, C, Fujimoto, Y, Jetton, T L, Dixon, K, Pan, D, Grimsby, J, Grippo, J F, Magnuson, M A, Cherrington, A D. Glucokinase gene locus transgenic mice are resistant to the development of obesity-induced type 2 diabetes. Diabetes, 50(3), 622-9, 2001.
She, P, Shiota, M, Shelton, K D, Chalkley, R, Postic, C, Magnuson, M A. Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Mol Cell Biol, 20(17), 6508-17, 2000. PMCID:86125
Shiota, M, Jackson, P, Galassetti, P, Scott, M, Neal, D W, Cherrington, A D. Combined intraportal infusion of acetylcholine and adrenergic blockers augments net hepatic glucose uptake. Am J Physiol Endocrinol Metab, 278(3), E544-52, 2000.
Lu, J T, Son, Y J, Lee, J, Jetton, T L, Shiota, M, Moscoso, L, Niswender, K D, Loewy, A D, Magnuson, M A, Sanes, J R, Emeson, R B. Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development. Mol Cell Neurosci, 14(2), 99-120, 1999.
Postic, C, Shiota, M, Niswender, K D, Jetton, T L, Chen, Y, Moates, J M, Shelton, K D, Lindner, J, Cherrington, A D, Magnuson, M A. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem, 274(1), 305-15, 1999.
Galassetti, P, Shiota, M, Zinker, B A, Wasserman, D H, Cherrington, A D. A negative arterial-portal venous glucose gradient decreases skeletal muscle glucose uptake. Am J Physiol, 275(1 Pt 1), E101-11, 1998.
Kimura, K, Moriyama, M, Nishisako, M, Kannan, Y, Shiota, M, Sakurada, K, Musashi, M, Sugano, T. Modulation of platelet activating factor-induced glycogenolysis in the perfused rat liver after administration of endotoxin in vivo. J Biochem (Tokyo), 123(1), 142-9, 1998.
Kimura, K, Moriyama, M, Nishisako, M, Kannan, Y, Shiota, M, Sugano, T. Endotoxin modulates arachidonic acid-induced glycogenolysis in the perfused rat liver. Horm Metab Res, 30(4), 178-81, 1998.
Shiota, M, Galassetti, P, Monohan, M, Neal, D W, Cherrington, A D. Small amounts of fructose markedly augment net hepatic glucose uptake in the conscious dog. Diabetes, 47(6), 867-73, 1998.
Jackson, P A, Pagliassotti, M J, Shiota, M, Neal, D W, Cardin, S, Cherrington, A D. Effects of vagal blockade on the counterregulatory response to insulin-induced hypoglycemia in the dog. Am J Physiol, 273(6 Pt 1), E1178-88, 1997.
Niswender, K D, Postic, C, Shiota, M, Jetton, T L, Magnuson, M A. Effects of altered glucokinase gene copy number on blood glucose homoeostasis. Biochem Soc Trans, 25(1), 113-7, 1997.
Niswender, K D, Shiota, M, Postic, C, Cherrington, A D, Magnuson, M A. Effects of increased glucokinase gene copy number on glucose homeostasis and hepatic glucose metabolism. J Biol Chem, 272(36), 22570-5, 1997.
Okuno, A, Ikeda, K, Shiota, M, Fujiwara, T, Yoshioka, S, Sugano, T, Horikoshi, H. Acute effect of troglitazone on glucose metabolism in the absence or presence of insulin in perfused rat hindlimb. Metabolism, 46(6), 716-21, 1997.
Shiota, M, Jackson, P A, Bischoff, H, McCaleb, M, Scott, M, Monohan, M, Neal, D W, Cherrington, A D. Inhibition of glycogenolysis enhances gluconeogenic precursor uptake by the liver of conscious dogs. Am J Physiol, 273(5 Pt 1), E868-79, 1997.
Kimura, K, Hamada, M, Moriyama, M, Kannan, Y, Shiota, M, Sakurada, K, Musashi, M, Sugano, T. Phorbol ester, but not endotoxin, desensitizes mannan-induced glycogenolysis in the perfused rat liver. J Biochem (Tokyo), 120(3), 488-93, 1996.
Moriyama, M, Makiyama, I, Shiota, M, Uesugi, K, Kannan, Y, Ohta, M, Kimura, K, Sugano, T. Decreased ureagenesis from alanine, but not from ammonia and glutamine, in the perfused rat liver after partial hepatectomy. Hepatology, 23(6), 1584-90, 1996.
Shiota, M, Green, R, Colburn, C A, Mitchell, G, Cherrington, A D. Inability of hyperglycemia to counter the ability of glucagon to increase net glucose output and activate glycogen phosphorylase in the perfused rat liver. Metabolism, 45(4), 481-5, 1996.
Kimura, K, Okamoto, Y, Sashiwa, H, Saimoto, H, Shigemasa, Y, Moriyama, M, Shiota, M, Sugano, T. Partially deacetylated chitin and hyaluronan induce glycogenolysis in perfused rat liver. J Biochem (Tokyo), 118(5), 953-8, 1995.
Shiota, M, Chinzei, F, Moriyama, M, Kimura, K, Sugano, T. Effects of an increase in perfusion pressure and of the direction of flow on carbohydrate metabolism in the perfused rat liver. J Biochem (Tokyo), 117(5), 958-64, 1995.
Shiota, M, Inagami, M, Fujimoto, Y, Moriyama, M, Kimura, K, Sugano, T. Cold acclimation induces zonal heterogeneity in gluconeogenic responses to glucagon in rat liver lobule. Am J Physiol, 268(6 Pt 1), E1184-91, 1995.
Shiota, M, Fujimoto, J, Takenaga, M, Satoh, H, Ichinohasama, R, Abe, M, Nakano, M, Yamamoto, T, Mori, S. Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry. Blood, 84(11), 3648-52, 1994.
Shiota, M, Hiramatsu, M, Fujimoto, Y, Moriyama, M, Kimura, K, Ohta, M, Sugano, T. The capacity of the malate-aspartate shuttle differs between periportal and perivenous hepatocytes from rats. Arch Biochem Biophys, 308(2), 349-56, 1994.
Matsui, Y, Ishibashi, H, Kimura, K, Shiota, M, Ohta, M, Sugano, T. Responses to catecholamines in perfused livers of hypothalamic-lesioned rats. Am J Physiol, 265(1 Pt 2), R117-23, 1993.
Shiota, M, Fujimoto, Y, Inagami, M, Hiramatsu, M, Moriyama, M, Kimura, K, Ohta, M, Sugano, T. Adaptive changes in zonation for gluconeogenic capacity in liver lobules of cold-exposed rats. Am J Physiol, 265(4 Pt 1), E559-64, 1993.
Kimura, K, Shiota, M, Mochizuki, K, Ohta, M, Sugano, T. Different preparations of zymosan induce glycogenolysis independently in the perfused rat liver. Involvement of mannose receptors, peptide-leukotrienes and prostaglandins. Biochem J, 283 ( Pt 3), 773-9, 1992. PMCID:1130953
Shiota, M, Kurano, Y, Mochizuki, Y, Kimura, K, Ohta, M, Sugano, T. Effects of nerve stimulation and zymosan on glycogenolysis in perfused livers from cold-exposed rats. Am J Physiol, 263(3 Pt 1), G353-9, 1992.
Hamatani, Y, Inoue, M, Kimura, K, Shiota, M, Ohta, M, Sugano, T. Effects of calmodulin antagonists on hydrogen-translocating shuttles in perfused rat liver. Am J Physiol, 261(3 Pt 1), E325-31, 1991.
Noda, K, Shiota, M, Tanizawa, O, Inoue, M, Tenjin, Y, Sugishita, T, Yakushiji, M, Miyoshi, T, Nozawa, S, Sakuma, T. [Clinical significance of serum sialyl Tn antigen in patients with gynecological cancer. STN Study Group. Gan To Kagaku Ryoho, 18(8), 1287-96, 1991.
Kobayashi, T, Iwai, H, Uchimoto, R, Ohta, M, Shiota, M, Sugano, T. Gluconeogenesis in perfused livers from dexamethasone-treated chickens. Am J Physiol, 256(4 Pt 2), R907-14, 1989.
Shiota, M, Masumi, S. Effect of norepinephrine on consumption of oxygen in perfused skeletal muscle from cold-exposed rats. Am J Physiol, 254(4 Pt 1), E482-9, 1988.
Sugano, T, Nishimura, K, Sogabe, N, Shiota, M, Oyama, N, Noda, S, Ohta, M. Ca2+-dependent activation of the malate-aspartate shuttle by norepinephrine and vasopressin in perfused rat liver. Arch Biochem Biophys, 264(1), 144-54, 1988.
Yamada, T, Shiota, M, Sugano, T. Effects of cold exposure on inhibition by isoproterenol of release of alanine in the rat. J Appl Physiol, 64(3), 906-12, 1988.
Yamano, T, Yorita, K, Fujii, H, Uchimoto, R, Shiota, M, Ohta, M, Sugano, T. Gluconeogenesis in perfused chicken kidney. Effects of feeding and starvation. Comp Biochem Physiol B, 91(4), 701-6, 1988.
Yorita, K, Yamano, T, Ikeda, K, Kobayashi, T, Shiota, M, Sugano, T. Distribution of glycolysis and gluconeogenesis in perfused chicken kidney. Am J Physiol, 253(5 Pt 2), R679-86, 1987.
Shiota, M, Sugano, T. Characteristics of rat hindlimbs perfused with erythrocyte- and albumin-free medium. Am J Physiol, 251(1 Pt 1), C78-84, 1986.
Shiota, M, Sugano, T. [Mechanisms involved in metabolic responses to cold exposure. Seikagaku, 57(1), 36-47, 1985.
Shiota, M, Tanaka, T, Sugano, T. Effect of norepinephrine on gluconeogenesis in perfused livers of cold-exposed rats. Am J Physiol, 249(3 Pt 1), E281-6, 1985.
Shiota, M, Golden, S, Katz, J. Lactate metabolism in the perfused rat hindlimb. Biochem J, 222(2), 281-92, 1984. PMCID:1144177
Sugano, T, Shiota, M, Khono, H, Shimada, M. Intracellular redox state and control of gluconeogenesis in perfused chicken liver. J Biochem (Tokyo), 91(6), 1917-29, 1982.
Sugano, T, Shiota, M, Khono, H, Shimada, M. Stimulation of gluconeogenesis by glucagon and norepinephrine in the perfused chicken liver. J Biochem (Tokyo), 92(1), 111-20, 1982.
Sugano, T, Shiota, M, Khono, H, Shimada, M, Oshino, N. Effects of calcium ions on the activation of gluconeogenesis by norepinephrine in perfused rat liver. J Biochem (Tokyo), 87(2), 465-72, 1980.
Sugano, T, Shiota, M, Tanaka, T, Miyamae, Y, Shimada, M, Oshino, N. Intracellular redox state and stimulation of gluconeogenesis by glucagon and norepinephrine in the perfused rat liver. J Biochem (Tokyo), 87(1), 153-66, 1980.
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