Glucokinase Is an Integral Component of the Insulin Granules in Glucose-Responsive Insulin Secretory Cells and Does Not Translocate During Glucose Stimulation

Arden, Catherine; Harbottle, Andrew; Baltrusch, Simone; Tiedge, Markus; Agius, Loranne

doi:10.2337/diabetes.53.9.2346

Cited by 47 publications

(49 citation statements)

References 39 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been argued that acute glucose exposure mediates association of mitochondria with glucokinase (39). While such a process is consistent with the ⌬⌿ fuel response observed here, it has not been corroborated in other studies (40). Recently, a specific plant hexokinase (HXK1), mutated to lack catalytic activity, was shown to still support various signaling functions, thus uncoupling its glucose sensing and subsequent signaling from glucose metabolism (41).…”

Section: Discussionsupporting

confidence: 66%

β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels

Wikström

Katzman²,

Mohamed³

et al. 2007

Diabetes

105

View full text Add to dashboard Cite

OBJECTIVE-␤-Cell response to glucose is characterized by mitochondrial membrane potential (⌬⌿) hyperpolarization and the production of metabolites that serve as insulin secretory signals. We have previously shown that glucose-induced mitochondrial hyperpolarization accompanies the concentration-dependent increase in insulin secretion within a wide range of glucose concentrations. This observation represents the integrated response of a large number of mitochondria within each individual cell. However, it is currently unclear whether all mitochondria within a single ␤-cell represent a metabolically homogenous population and whether fuel or other stimuli can recruit or silence sizable subpopulations of mitochondria. This study offers insight into the different metabolic states of ␤-cell mitochondria. RESULTS-Weshow that mitochondria display a wide heterogeneity in ⌬⌿ and a millivolt range that is considerably larger than the change in millivolts induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased ⌬⌿ heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in ⌬⌿ of individual mitochondria, ATP-hydrolyzing mitochondria, and uncoupling protein 2 are not significant contributors to ⌬⌿ heterogeneity. We identified BAD, a proapoptotic BCL-2 family member previously implicated in mitochondrial recruitment of glucokinase, as a significant factor influencing the level of heterogeneity.CONCLUSIONS-We suggest that mitochondrial ⌬⌿ heterogeneity in ␤-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target. Diabetes

show abstract

Section: Discussionsupporting

confidence: 66%

β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels

Wikström

Katzman²,

Mohamed³

et al. 2007

Diabetes

105

View full text Add to dashboard Cite

show abstract

“…GK Activity Assay-GK activity was determined from the difference in glucose phosphorylating activity at 0.5 and 100 mM glucose, representing low K m and total hexokinase activity, respectively, using a previously described method (36).…”

Section: Glucose Oxidation and Oxygen Consumption-[u-mentioning

confidence: 99%

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Ronnebaum

Joseph

Ilkayeva

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60 -80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to ␤-cells suppressed [ 14 C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

show abstract

“…Rizzo et al (69) showed that high glucose released GK from insulin granules to the cytoplasm in ␤TC3 cells. In MIN6 cells, however, GK association with components of the granule membrane of dense insulin granules and low-density organelles was not affected by glucose (42). In ␤TC3 cells, the interaction between GK and insulin granules proved to be dependent on the generation of nitric oxide (NO), and GK was also associated with neuronal NO synthase, thereby regulating NO synthesis in insulin-secreting cells (70).…”

Section: Glucokinase Regulation In Pancreatic ␤-Cellsmentioning

confidence: 99%

“…By the use of cell imaging techniques and subcellular fractioning of primary ␤-cells and insulin-producing cell lines, it could be demonstrated that GK binds to insulin secretory granules (42,(67)(68)(69)(70). This explains the punctate pattern of GK and a costaining with insulin in ␤-cells (69).…”

Section: Glucokinase Regulation In Pancreatic ␤-Cellsmentioning

confidence: 99%

Glucokinase Regulatory Network in Pancreatic β-Cells and Liver

Baltrusch

Tiedge

2006

Diabetes

Self Cite

View full text Add to dashboard Cite

The low-affinity glucose-phosphorylating enzyme glucokinase (GK) is the flux-limiting glucose sensor in liver and ␤-cells of the pancreas. Furthermore, GK is also expressed in various neuroendocrine cell types. This review describes the complex network of GK regulation, which shows fundamental differences in liver and pancreatic ␤-cells. Tissue-specific GK promoters determine a higher gene expression level and glucose phosphorylation capacity in liver than in pancreatic ␤-cells. The second hallmark of tissue-specific GK regulation is based on posttranslational mechanisms in which the high-affinity regulatory protein in the liver undergoes glucose-and fructose-dependent shuttling between cytoplasm and nucleus. In ␤-cells, GK resides outside the nucleus but has been reported to interact with insulin secretory granules. The unbound diffusible GK fraction likely determines the glucose sensor activity of insulin-producing cells. The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) has been identified as an activating binding partner of ␤-cell GK, increasing the V max value of the enzyme, while the GLUCOKINASE AND ITS EXCEPTIONAL ROLE IN THE HEXOKINASE GENE FAMILYThe glucose-phosphorylating enzyme glucokinase (GK) (hexokinase type IV) has unique characteristics compared with the ubiquitously expressed hexokinase isoforms type I-III. The smaller 50-kDa size of the GK protein distinguishes it from the 100-kDa hexokinase isoforms (1). From a historical point of view, several kinetic preferences allowed this enzyme to act as a metabolic glucose sensor: 1) its low affinity for glucose, in the physiological concentration range between 5 and 7 mmol/l, 2) a cooperative behavior for glucose with a Hill coefficient (n Hill ) between 1.5 and 1.7, and 3) a lack of feedback inhibition by glucose-6-phosphate within the physiological concentration range (2-4). A further characteristic of the GK enzyme is its exceptional sensitivity to sulfhydryl group oxidizing compounds, although the pattern of cysteine residues does not differ between GK and high-affinity hexokinase isoforms (5).GK activity could be predominantly demonstrated in hepatocytes and pancreatic ␤-cells, both cell types that have to couple physiological glucose concentrations to metabolism. Pioneered by the work of Matschinsky's group (2-4), GK proved to be the flux-limiting glucose sensor in pancreatic ␤-cells within the scenario of metabolic stimulus-secretion coupling.Sequence comparisons revealed a high homology between the 50-kDa mammalian GK and the 100-kDa mammalian hexokinases, which apparently developed by gene duplication of a so far unknown common ancestral 50-kDa hexokinase gene (1,6). Notably, the homology of GK to the 50-kDa yeast hexokinase is much lower, in the range of 30% (6). This evolution of hexokinase isoenzymes was of particular interest to solve the structure of GK. While crystallization of yeast hexokinase (Fig. 1A) and the 100-kDa hexokinases resulted in three-dimensional structures of enzymes in which t...

show abstract

Glucokinase Is an Integral Component of the Insulin Granules in Glucose-Responsive Insulin Secretory Cells and Does Not Translocate During Glucose Stimulation

Cited by 47 publications

References 39 publications

β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels

β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism

Glucokinase Regulatory Network in Pancreatic β-Cells and Liver

Contact Info

Product

Resources

About