Glucokinase as pancreatic beta cell glucose sensor and diabetes gene.

Matschinsky, Franz M.; Liang, Yin; Kesavan, Prabakaran; Wang, L; Froguel, P; Velho, Gilberto; Cohen, Daniel; Permutt, M. A.; Tanizawa, Yukio; Jetton, Thomas L.

doi:10.1172/jci116809

Cited by 277 publications

(222 citation statements)

References 44 publications

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“…It is generally acknowledged that GK plays the crucial role of "glucose sensor" in pancreatic β-cell, due to its specific kinetic properties that include low affinity and positive cooperativity for glucose and a lack of inhibition by its product glucose-6-phosphate. GK regulates GSIS by modulation of the glycolytic pathway and controlling the rate of its subsequent metabolism [26,27] . It is also deemed that GK is one of the downstream targets of the HNFs transcription regulatory circuit in pancreatic islets [9] .…”

Section: Discussionmentioning

confidence: 99%

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Wang¹,

Lu²,

Leng³

et al. 2008

WJG

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AIM:To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS: Primary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations (1, 3, 10 and 30 μmol/L) of berberine or 1 μmol/L Glibenclamide (GB) for 24 h. Glucose-stimulated insulin secretion (GSIS) assay was conducted and insulin was determined by radioimmunoassay. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha (HNF4α ) was determined by reverse transcription polymerase chain reaction (RT-PCR). Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase (GK) activity was measured by spectrophotometric method. RESULTS: Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION: Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas (SUs).

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Section: Discussionmentioning

confidence: 99%

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Wang¹,

Lu²,

Leng³

et al. 2008

WJG

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“…In yeast and higher plants, glucose repression does not require the glycolytic pathway, except for the first phosphorylation step by HXK. In mammals, glucose-mediated insulin secretion and insulin gene expression require glycolysis (German, 1993;Matschinsky et al, 1993;Mueckler, 1993;Grupe et al, 1995). In addition, insulin secretion has been shown to be enhanced by the overexpression of heterologous yeast YHXK2 (Epstein et al, 1992).…”

Section: Sugar Signaling Mediated Through Hxk 1s Uncoupled From Sugarmentioning

confidence: 99%

“…Although HXK is commonly known as the glycolytic enzyme that catalyzes the ATP-dependent conversion of hexoses to hexose 6-phosphates, it has been implicated as a glucose sensor in lower and higher eukaryotes, including yeast (Entian, 1980;Entian and Frolich, 1984;Entian et al, 1985;Rose et al, 1991) and mammals (German, 1993;Matschinsky et al, 1993;Mueckler, 1993;Grupe et al, 1995). Our previous studies (Jang and Sheen, 1994) suggested that sugar sensors might be evolutionary conserved in all eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Hexokinase as a sugar sensor in higher plants.

et al. 1997

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“…Through its unique kinetic character, GK plays a central role in blood glucose homeostasis by converting glucose to glucose-6-phosphate (G6P), enhancing glycogen synthesis, in hepatocytes (3), and sensing glucose for insulin secretion in pancreatic β-cells (4). Defect and mutations in GK are directly associated with type 2 diabetes and maturity-onset diabetes of the young type 2 (5, 6).…”

mentioning

confidence: 99%

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

Choi¹,

Seo²,

Kyeong³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 Å. GKRP binds to a super-open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver.hexokinase | sigmoidicity I conformational restriction | type 2 diabetes

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Glucokinase as pancreatic beta cell glucose sensor and diabetes gene.

Cited by 277 publications

References 44 publications

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Hexokinase as a sugar sensor in higher plants.

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

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