Effect of a glucokinase inhibitor on energy production and insulin release in pancreatic islets

Sweet, Ian R.; Li, Guizhu; Najafi, Habiba; Berner, Donna K; Matschinsky, Franz M.

doi:10.1152/ajpendo.1996.271.3.e606

Cited by 54 publications

(58 citation statements)

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“…GK and Kir6.2 mRNA expression were less common in GE neurons than expected from previous studies (14,57) and studies in the ␤-cell (58 -60), although the Kir6.2 results must be interpreted with caution. In all, ϳ60% of GE neurons expressed GK, the proposed regulator of ␤-cell glucosensing (20,61,62). Also, Ͻ50% of GE neurons expressed Kir6.2 or Kir6.1 and even fewer expressed SUR-1 or -2 mRNA.…”

Section: Discussionmentioning

confidence: 93%

“…The control of both glycolysis (20,21) and glucose transport (22) have been proposed as regulators of ␤-cell glucosensing. In the pancreas, glucokinase (GK) (hexokinase IV, ATP: D-glucose 6-phosphotransferase) regulates glycolytic flux and intracellular ATP production in both ␤-and ␣-cells (23) and is a primary regulator of ATP production, K ATP channel activity, and insulin secretion in ␤-cells (24).…”

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confidence: 99%

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Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

et al. 2004

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To evaluate potential mechanisms for neuronal glucosensing, fura-2 Ca 2؉ imaging and single-cell RT-PCR were carried out in dissociated ventromedial hypothalamic nucleus (VMN) neurons. Glucose-excited (GE) neurons increased and glucose-inhibited (GI) neurons decreased intracellular Ca 2؉ ([Ca 2؉ ] i ) oscillations as glucose increased from 0.5 to 2.5 mmol/l. The Kir6.2 subunit mRNA of the ATP-sensitive K ؉ channel was expressed in 42% of GE and GI neurons, but only 15% of nonglucosensing (NG) neurons. Glucokinase (GK), the putative glucosensing gatekeeper, was expressed in 64% of GE, 43% of GI, but only 8% of NG neurons and the GK inhibitor alloxan altered [Ca 2؉ ] i oscillations in ϳ75% of GK-expressing GE and GI neurons. Insulin receptor and GLUT4 mRNAs were coexpressed in 75% of GE, 60% of GI, and 40% of NG neurons, although there were no statistically significant intergroup differences. Hexokinase-I, GLUT3, and lactate dehydrogenase-A and -B were ubiquitous, whereas GLUT2, monocarboxylate transporters-1 and -2, and leptin receptor and GAD mRNAs were expressed less frequently and without apparent relationship to glucosensing capacity. Thus, although GK may mediate glucosensing in up to 60% of VMN neurons, other regulatory mechanisms are likely to control glucosensing in the remaining ones. Diabetes 53:549 -559, 2004

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

et al. 2004

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“…It should be noted, however, that numerous transduction and effector steps are interposed between the metabolic signals and the end-responses. As has been pointed out, the fact that glucokinase is the ''glucose sensor'' does not detract from the possibility, indeed the likelihood, that these downstream steps could constitute targets for regulatory mechanisms or pathological disturbances in disease states such as diabetes mellitus (32).…”

Section: Discussionmentioning

confidence: 99%

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

Wang

Iynedjian

1997

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

126

142

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Insulinoma ␤-cells capable of overexpressing glucokinase under the control of a doxycycline-dependent transcriptional transactivator were established from parental INS-1 cells. Glucokinase could be maximally induced to a level more than 20 times the basal level after 36 h of culture with doxycycline. Intermediate levels of induction could be achieved by varying doses of, and time of culture with, the inducer. The rate of glycolysis was measured in cells with 3-, 5-, and 8-fold increment in glucokinase activity above the noninduced level. Proportionate increases in glycolytic f lux occurred in cells cultured at low physiological glucose concentration. At high glucose concentration, induction of glucokinase in excess of 2-fold above basal resulted in little additional increase in glycolysis. The consequences of graded increases of glucokinase on two physiological glucose effects were investigated. Increments in glucokinase activity were accompanied by a stepwise shift to the left of the doseresponse curve for the inductive effect of glucose on the L-type pyruvate kinase mRNA. Similarly, the insulin secretory response to glucose was shifted leftward in glucokinase-induced cells. The following conclusions are drawn: (i) glucokinase is the major rate-limiting enzyme for glycolysis in these cells; (ii) downstream metabolic steps become limiting at high extracellular glucose concentration with moderate increases in glucokinase over the wild-type level; (iii) within limits, glucokinase activity is a determining factor for two types of glucose responses of the ␤-cell, the induction of specific gene expression, and insulin release.The endocrine ␤-cell of the pancreas contains glucokinase, a hexokinase isoenzyme with distinctive kinetics, and tissue expression shared by only a few cell types in the body, including mostly the liver besides the endocrine pancreas (1-3). Halfsaturation of glucokinase with glucose occurs at a substrate concentration around 6 mM, close to the concentration of glucose in the extracellular fluids (4). Because glucose transport in the ␤-cell is not rate-limiting (5), the glucose concentration in the intracellular space is close to the extracellular concentration, physiologically around 5 mM. Thus, glucokinase operates in the cell under conditions close to halfsaturation with glucose, allowing changes in the extracellular glucose concentration to be translated into parallel changes in the rate of glucose phosphorylation, the first step of glucose metabolism. In addition, glucose phosphorylation appears to be the major rate-limiting step in the glycolytic pathway in the ␤-cell, because assayable glucokinase activity is the lowest of the activities of all glycolytic enzymes, and glucose utilization displays a glucose concentration dependency similar to that of glucokinase (6). Therefore, glucokinase is considered to be the enzyme that allows glucose to regulate its own rate of metabolism in the ␤-cell.Important physiological effects, including effects on the rate of specific gene transcriptio...

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“…As a result, changes in fuels resemble a ramp, a waveform that does not induce first phase insulin secretion (32).…”

Section: Retention Of Kic-stimulated Isr Despite Loss Of Glucose-stimmentioning

confidence: 99%

Control of Insulin Secretion by Cytochrome c and Calcium Signaling in Islets with Impaired Metabolism

Rountree

Neal

Lisowski

et al. 2014

Journal of Biological Chemistry

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Background: Intracellular calcium and metabolic signals mediate glucose-induced insulin secretion. Results: In metabolically compromised islets, calcium signaling was robust, whereas reduction and translocation of cytochrome c were diminished. Conclusion: Data are consistent with a rate-determining role at the level of cytochrome c for insulin secretion. Significance: Impairment of metabolic control preferentially affects cytochrome c versus calcium signaling.

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Effect of a glucokinase inhibitor on energy production and insulin release in pancreatic islets

Cited by 54 publications

References 0 publications

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

Modulation of glucose responsiveness of insulinoma β-cells by graded overexpression of glucokinase

Control of Insulin Secretion by Cytochrome c and Calcium Signaling in Islets with Impaired Metabolism

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