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588 results on '"Matschinsky, Franz M."'

105. Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets

Author

Li, Changhong, primary, Ackermann, Amanda M., additional, Boodhansingh, Kara E., additional, Bhatti, Tricia R., additional, Liu, Chengyang, additional, Schug, Jonathan, additional, Doliba, Nicolai, additional, Han, Bing, additional, Cosgrove, Karen E., additional, Banerjee, Indraneel, additional, Matschinsky, Franz M., additional, Nissim, Itzhak, additional, Kaestner, Klaus H., additional, Naji, Ali, additional, Adzick, N. Scott, additional, Dunne, Mark J., additional, Stanley, Charles A., additional, and De León, Diva D., additional

Published
2017
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106. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

Author

Zhu, Lu, primary, Almaça, Joana, additional, Dadi, Prasanna K., additional, Hong, Hao, additional, Sakamoto, Wataru, additional, Rossi, Mario, additional, Lee, Regina J., additional, Vierra, Nicholas C., additional, Lu, Huiyan, additional, Cui, Yinghong, additional, McMillin, Sara M., additional, Perry, Nicole A., additional, Gurevich, Vsevolod V., additional, Lee, Amy, additional, Kuo, Bryan, additional, Leapman, Richard D., additional, Matschinsky, Franz M., additional, Doliba, Nicolai M., additional, Urs, Nikhil M., additional, Caron, Marc G., additional, Jacobson, David A., additional, Caicedo, Alejandro, additional, and Wess, Jürgen, additional

Published
2017
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107. Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice.

Author

Lu Zhu, Rossi, Mario, Cohen, Amanda, Pham, Jonathan, Hongchao Zheng, Dattaroy, Diptadip, Taro Mukaibo, Melvin, James E., Langel, Jennifer L., Hattar, Samer, Matschinsky, Franz M., Appella, Daniel H., Doliba, Nicolai M., and Wess, Jürgen

Subjects
MUSCARINIC acetylcholine receptors, ALLOSTERIC regulation, GLUCOSE, BLOOD sugar, DRUG efficacy
Abstract

Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents. [ABSTRACT FROM AUTHOR]

Published
2019
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108. Glutamate dehydrogenase: role in regulating metabolism and insulin release in pancreatic ß-cells.

Author

Wilson, David F., Cember, Abigail T. J., and Matschinsky, Franz M.

Abstract

Regulation of insulin release and glucose homeostasis by pancreatic β-cells is dependent on the metabolism of glucose by glucokinase (GK) and the influence of that activity on oxidative phosphorylation. Genetic alterations that result in hyperactivity of mitochondrial glutamate dehydrogenase (GDH-1) can cause hypoglycemia-hyperammonemia following high protein meals, but the role of GDH-1 remains poorly understood. GDH-1 activity is strongly inhibited by GTP, to near zero in the absence of ADP, and cooperatively activated ( n = 2.3) by ADP. The dissociation constant for ADP is near 200 µM in vivo, but leucine and its nonmetabolized analog 2-amino-2-norbornane-carboxylic acid (BCH) can activate GDH-1 by increasing the affinity for ADP. Under physiological conditions, as [ADP] increases GDH-1 activity remains very low until ~35 µM (threshold) and then increases rapidly. A model for GDH-1 and its regulation has been combined with a previously published model for glucose sensing that coupled GK activity and oxidative phosphorylation. The combined model (GK-GDH-core) shows that GK activity determines the energy state ([ATP]/[ADP][Pi]) in β-cells for glucose concentrations > 5 mM ([ADP] < 35 µM). As glucose falls < 5 mM the [ADP]-dependent increase in GDH-1 activity prevents [ADP] from rising above ~70 µM. Thus, GDH-1 dynamically buffers β-cell energy metabolism during hypoglycemia, maintaining the energy state and the basal rate of insulin release. GDH-1 hyperactivity suppresses the normal increase in [ADP] in hypoglycemia. This leads to hypoglycemia following a high protein meal by increasing the basal rate of insulin release (β-cells) and decreasing glucagon release (α-cells). NEW & NOTEWORTHY A model of β-cell metabolism and regulation of insulin release is presented. The model integrates regulation of oxidative phosphorylation, glucokinase (GK), and glutamate dehydrogenase (GDH-1). GDH-1 is near equilibrium under physiological conditions, but the activity is inhibited by GTP. In hypoglycemia, however, GK activity is low and [ADP], a potent activator of GDH-1, increases. Reducing equivalents from GDH dynamically buffers the intramitochondrial [NADH]/[NAD+], and thereby the energy state, preventing hypoglycemia-induced substrate deprivation. [ABSTRACT FROM AUTHOR]

Published
2018
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109. Mechanisms of Bordetella Pertussis Adenylyl Cyclase Toxin (ACT) on Insulin Secretion and Insulin Promoter Activity of Pancreatic Β Cells

Author

GAO, ZHIYONG, XU, GANG, YOUNG, ROBERT A., HEWLETT, ERIK L., MATSCHINSKY, FRANZ M., and WOLF, BRYAN A.

Subjects
Physiological aspects, Pertussis toxin -- Physiological aspects, Adenylyl cyclase -- Physiological aspects, Insulin -- Physiological aspects, Adenylate cyclase -- Physiological aspects
Abstract

ACT is a bacterial exotoxin with adenylyl cyclase activity, which enters mammalian cells and converts ATP into cAMP in cells. The aim of this study is to investigate its effects [...]

Published
2000

110. Structural Model of Human Glucokinase in Complex With Glucose and ATP

Author

Mahalingam, Bhuvaneshwari, Cuesta-Munoz, Antonio, Davis, Elizabeth A., Matschinsky, Franz M., Harrison, Robert W., and Weber, Irene T.

Subjects
Hypoglycemia -- Causes of, Hyperglycemia -- Causes of, Health, Causes of
Abstract

Implications for the Mutants That Cause Hypo- and Hyperglycemia Mutations in human glucokinase are implicated in the development of diabetes and hypoglycemia. Human glucokinase shares 54% identical amino acid residues [...]

Published
1999

111. Glucose Regulation of Glutaminolysis and Its Role in Insulin Secretion

Author

Gao, Zhi-yong, Li, Guizhu, Najafi, Habiba, Wolf, Bryan A., and Matschinsky, Franz M.

Subjects
Pancreatic beta cells -- Physiological aspects, Glucose metabolism -- Physiological aspects, Health, Physiological aspects
Abstract

Leucine or the nonmetabolized leucine analog ± 2-amino-2-norbornane-carboxylic acid (BCH) (both at 10 mmol/l) induced biphasic insulin secretion in the presence of 2 mmol/l glutamine (Q2) in cultured mouse islets [...]

Published
1999

112. Characterization of Glucokinase Regulatory Protein Deficient Mice

Author

GRIMSBY, JOSEPH, COFFEY, JOHN W, DVOROZNIAK, MARK T, LI, GUIZHU, MATSCHINSKY, FRANZ M, SHIOTA, CHIYO, MAGNUSON, MARK A, and GRIPPO, JOSEPH F

Subjects
Diabetes -- Research, Health
Abstract

The physiological role of the glucokinase regulatory protein (GKRP) in controlling glucokinase (GK) activity was addressed using conventional gene targeting techniques to disrupt GKRP expression. Mice lacking GKRP are healthy, [...]

Published
1999

113. Mutations of Glucokinase (GK) in MODY-2 Cause Marked Changes of ATP Affinity

Author

CUESTA-MUNOZ, ANTONIO, DAVIS, ELIZABETH A, BUETTGER, CAROL W, WEBER, IRENE T, HARRISON, ROBERT W, MAHALINGAM, BHUVANESHWARI, MOATES, MICHAEL, MAGNUSON, MARK A, and MATSCHINSKY, FRANZ M

Subjects
Diabetes -- Research, Health
Abstract

Previous reports on kinetics of recombinant mutant GK in MODY-2 have usually explained diabetes by [k.sub.cat] and glucose [S.sub.0.5] changes of the enzyme (Pilkis et al, JBC 269:2195-2192, 1994). Reinvestigating [...]

Published
1999

115. Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets.

Author

Changhong Li, Ackermann, Amanda M., Boodhansingh, Kara E., Bhatti, Tricia R., Chengyang Liu, Schug, Jonathan, Doliba, Nicolai, Bing Han, Cosgrove, Karen E., Banerjee, Indraneel, Matschinsky, Franz M., Nissim, Itzhak, Kaestner, Klaus H., Naji, Ali, Adzick, N. Scott, Dunne, Mark J., Stanley, Charles A., De León, Diva D., Li, Changhong, and Liu, Chengyang

Subjects
METABOLOMICS, SYSTEMS biology, HYPERINSULINISM, CONGENITAL disorders, HYPOGLYCEMIA, ALANINE metabolism, CALCIUM metabolism, POTASSIUM metabolism, RNA metabolism, GLUCOSE metabolism, BIOCHEMISTRY, ELECTRON microscopy, FLOW cytometry, GABA, GENE expression, GLUTAMINE, GLYCINE, GLYCOLYSIS, IMMUNOHISTOCHEMISTRY, INSULIN, ISLANDS of Langerhans, ISOTOPES, GENETIC mutation, PANCREATECTOMY, POTASSIUM, RESEARCH funding, SERINE, OXYGEN consumption, CASE-control method, SEQUENCE analysis, MEMBRANE transport proteins, GENETICS
Abstract

Loss-of-function mutations of β-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium ([Ca2+] i ), insulin secretion, oxygen consumption, and [U-13C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal [Ca2+] i and insulin secretion were higher in KATPHI islets compared with controls. Unlike controls, insulin secretion in KATPHI islets increased in response to amino acids but not to glucose. KATPHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-13C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in 13C enrichment of alanine in KATPHI islets, suggesting increased rates of glycolysis. KATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KATPHI islets had low γ-aminobutyric acid (GABA) levels and lacked 13C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KATPHI β-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KATPHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition. [ABSTRACT FROM AUTHOR]

Published
2017
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121. Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.

Author

UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Gloyn, Anna L, Odili, Stella, Zelent, Dorothy, Buettger, Carol, Castleden, Harriet A J, Steele, Anna M, Stride, Amanda, Shiota, Chyio, Magnuson, Mark A, Lorini, Renata, d'Annunzio, Giuseppe, Stanley, Charles A, Kwagh, Jae, Van Schaftingen, Emile, Veiga da Cunha, Maria, Barbetti, Fabrizio, Dunten, Pete, Han, Yi, Grimsby, Joseph, Taub, Rebecca, Ellard, Sian, Hattersley, Andrew T, Matschinsky, Franz M, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Gloyn, Anna L, Odili, Stella, Zelent, Dorothy, Buettger, Carol, Castleden, Harriet A J, Steele, Anna M, Stride, Amanda, Shiota, Chyio, Magnuson, Mark A, Lorini, Renata, d'Annunzio, Giuseppe, Stanley, Charles A, Kwagh, Jae, Van Schaftingen, Emile, Veiga da Cunha, Maria, Barbetti, Fabrizio, Dunten, Pete, Han, Yi, Grimsby, Joseph, Taub, Rebecca, Ellard, Sian, Hattersley, Andrew T, and Matschinsky, Franz M

Abstract

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.

Published
2005

122. Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

Author

Sarabu, Ramakanth, primary, Bizzarro, Fred T., additional, Corbett, Wendy L., additional, Dvorozniak, Mark T., additional, Geng, Wanping, additional, Grippo, Joseph F., additional, Haynes, Nancy-Ellen, additional, Hutchings, Stanley, additional, Garofalo, Lisa, additional, Guertin, Kevin R., additional, Hilliard, Darryl W., additional, Kabat, Marek, additional, Kester, Robert F., additional, Ka, Wang, additional, Liang, Zhenmin, additional, Mahaney, Paige E., additional, Marcus, Linda, additional, Matschinsky, Franz M., additional, Moore, David, additional, Racha, Jagdish, additional, Radinov, Roumen, additional, Ren, Yi, additional, Qi, Lida, additional, Pignatello, Michael, additional, Spence, Cheryl L., additional, Steele, Thomas, additional, Tengi, John, additional, and Grimsby, Joseph, additional

Published
2012
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124. Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics

Author

Doliba, Nicolai M., primary, Qin, Wei, additional, Najafi, Habiba, additional, Liu, Chengyang, additional, Buettger, Carol W., additional, Sotiris, Johanna, additional, Collins, Heather W., additional, Li, Changhong, additional, Stanley, Charles A., additional, Wilson, David F., additional, Grimsby, Joseph, additional, Sarabu, Ramakanth, additional, Naji, Ali, additional, and Matschinsky, Franz M., additional

Published
2012
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125. Mutational analysis of allosteric activation and inhibition of glucokinase

Author

Zelent, Bogumil, primary, Odili, Stella, additional, Buettger, Carol, additional, Zelent, Dorothy K., additional, Chen, Pan, additional, Fenner, Deborah, additional, Bass, Joseph, additional, Stanley, Charles, additional, Laberge, Monique, additional, Vanderkooi, Jane M., additional, Sarabu, Ramakanth, additional, Grimsby, Joseph, additional, and Matschinsky, Franz M., additional

Published
2011
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128. Discovery, Structure−Activity Relationships, Pharmacokinetics, and Efficacy of Glucokinase Activator (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675)

Author

Haynes, Nancy-Ellen, primary, Corbett, Wendy L., additional, Bizzarro, Fred T., additional, Guertin, Kevin R., additional, Hilliard, Darryl W., additional, Holland, George W., additional, Kester, Robert F., additional, Mahaney, Paige E., additional, Qi, Lida, additional, Spence, Cheryl L., additional, Tengi, John, additional, Dvorozniak, Mark T., additional, Railkar, Aruna, additional, Matschinsky, Franz M., additional, Grippo, Joseph F., additional, Grimsby, Joseph, additional, and Sarabu, Ramakanth, additional

Published
2010
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129. Clinical Heterogeneity in Monogenic Diabetes Caused by Mutations in the Glucokinase Gene (GCK-MODY)

Author

Cuesta-Muñoz, Antonio L., primary, Tuomi, Tiinamaija, additional, Cobo-Vuilleumier, Nadia, additional, Koskela, Hanna, additional, Odili, Stella, additional, Stride, Amanda, additional, Buettger, Carol, additional, Otonkoski, Timo, additional, Froguel, Philippe, additional, Grimsby, Joseph, additional, Garcia-Gimeno, Maria, additional, and Matschinsky, Franz M., additional

Published
2009
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131. Functional pancreatic beta-cell line from SV40 T-antigen transgenic mice

Author

Gilligan, Ann, Jewett, Lorraine, Simon, Daniela, Damjanov, Ivan, Matschinsky, Franz M., Weik, Heather, Pinkert, Carl, and Knowles, Barbara B.

Subjects
Cell lines -- Models, Pancreatic beta cells -- Models, Health, Models
Abstract

Cell line IgSV195, derived from a pancreatic tumor that arose in an SV40 T-antigen transgenic mouse, retains certain morphological and physiological characteristics of pancreatic β-cells throughout in vitro and in [...]

Published
1989

140. Glucokinase

Author

Bell, Graeme I., primary, Cuesta‐Munoz, Antonio, additional, and Matschinsky, Franz M., additional

Published
2002
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144. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.

Author

Szlyk, Benjamin, Braun, Craig R, Ljubicic, Sanda, Patton, Elaura, Bird, Gregory H, Osundiji, Mayowa A, Matschinsky, Franz M, Walensky, Loren D, and Danial, Nika N

Subjects
GLUCOKINASE, INSULIN, HYPOGLYCEMIA, ENZYMES, GLUCOSE
Abstract

Glucokinase (GK) is a glucose-phosphorylating enzyme that regulates insulin release and hepatic metabolism, and its loss of function is implicated in diabetes pathogenesis. GK activators (GKAs) are attractive therapeutics in diabetes; however, clinical data indicate that their benefits can be offset by hypoglycemia, owing to marked allosteric enhancement of the enzyme's glucose affinity. We show that a phosphomimetic of the BCL-2 homology 3 (BH3) α-helix derived from human BAD, a GK-binding partner, increases the enzyme catalytic rate without dramatically changing glucose affinity, thus providing a new mechanism for pharmacologic activation of GK. Remarkably, BAD BH3 phosphomimetic mediates these effects by engaging a new region near the enzyme's active site. This interaction increases insulin secretion in human islets and restores the function of naturally occurring human GK mutants at the active site. Thus, BAD phosphomimetics may serve as a new class of GKAs. [ABSTRACT FROM AUTHOR]

Published
2014
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