Biomedical Research Education & Training
Faculty Member

Shiota, Masakazu, D.V.M., Ph.D.
Associate Professor of Molecular Physiology and Biophysics

Lab Url: N/A

Phone Number: 615-936-1092

Email Address: masakazu.shiota@Vanderbilt.Edu

Shiota, Masakazu's picture
Academic history
Ph.D., University of Osaka Prefecture, Osaka, Japan
B. Vet. Sci., Rakuno Gakuen University, Hokkaido, Japan
D.V.M., The Ministry of Agriculture and Forestry of Japan, Japan
M.S., University of Osaka Prefecture, Osaka, Japan
Postdoctoral Training, Cedars-Sinai Medical Center, CA, U.S.A.

Office Address   Mailing Address

762 Robinson Research Building

762 Robinson Research Building 0615

Research Keywords
Diabetes, Obesity, Metabolism, Liver, Carbohydrate, Lipid, Glucokinase

Research Specialty
Hepatic Glucose Flux Regulation in Obesity and Type 2 Diabetes.

Research Description
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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