Interleukin‐1β inhibits glucokinase activity in clonal HIT‐T15 β‐cells

Beggs, Mark; Beresford, Guy; Clarke, Jennifer N.; Mertz, Robert J.; Espinal, J.; Hammonds, Peter

doi:10.1016/0014-5793(90)80928-c

Cited by 15 publications

(7 citation statements)

References 30 publications

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“…Although glucokinase down-regulation may not be required for IL-1 to inhibit glucose-induced insulin secretion (9 -11), such inhibition would be an expected consequence of glucokinase down-regulation. It is of interest that culture of clonal HIT-T15 cells with IL-1 has been reported to reduce glucose-induced insulin secretion and to reduce both the glycolytic utilization of glucose and glucokinase activity in these cells (74), providing additional support for the possibility that IL-1 can down-regulate ␤-cell glucokinase levels under some conditions. IL-1-induced NO-dependent down-regulation of islet glucokinase mRNA content could reflect a reduction in gene transcription or in mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism

Landt

Bohrer

et al. 1997

Journal of Biological Chemistry

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Culture of rat pancreatic islets with interleukin-1 (IL-1) results in up-regulation of the inducible isoform of nitric oxide synthase and overproduction of nitric oxide (NO). This is associated with reversible inhibition of both glucose-induced insulin secretion and islet glucose oxidation, and these effects are prevented by the inducible nitric oxide synthase inhibitor N G -monomethylarginine. IL-1 also induces accumulation of nonesterified arachidonic acid in islets by an NO-dependent mechanism, and one potential explanation for that effect would involve an IL-1-induced enhancement of islet glycolytic flux. We have therefore examined effects of IL-1 on islet glycolytic utilization of glucose and find that culture of islets with IL-1 in medium containing 5.5 mM glucose results in suppression of islet glucose utilization subsequently measured at glucose concentrations between 6 and 18 mM. The IL-1-induced suppression of islet glucose utilization is associated with a decline in islet glucokinase mRNA content, as determined by competitive reverse transcriptase-polymerase chain reaction, and in glucokinase protein synthesis, as determined by immuoprecipitation experiments, and all of these effects are prevented by N G -monomethylarginine. These findings suggest that IL-1 can down-regulate islet glucokinase, which is the primary component of the islet glucose-sensor apparatus, by an NO-dependent mechanism. Because reductions in islet glucokinase levels are known to cause a form of type II diabetes mellitus, these observations raise the possibility that factors which increase islet NO levels might contribute to development of glucose intolerance.Culture of rat pancreatic islets with interleukin-1 (IL-1)

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Section: Discussionmentioning

confidence: 99%

Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism

Landt

Bohrer

et al. 1997

Journal of Biological Chemistry

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“…However, no decrease in ATP was seen in mouse islets treated with IL-ip (24). More critically, in HIT-T15 cells, IL-lp treatment did not induce a decrease in the ATP/ADP ratio (5), which is likely the essential parameter in closing K + -ATP channels (25). To our knowledge, there are no extant studies regarding guanine nucleotides in IL-ip-treated insulin-secreting cells.…”

mentioning

confidence: 83%

“…In particular, glucose-induced insulin secretion is markedly inhibited in a variety of insulin-producing cells (3)(4)(5)(6). Sensitivity to the different effects of IL-ip appears to be species and/or cell-line specific (e.g., rat islets are particularly sensitive to the cytotoxic effects of IL-ip, whereas mouse or human islets require a combination of cytokines for cytotoxicity) (7)(8)(9).…”

mentioning

confidence: 99%

“…Decreased glucose utilization has been demonstrated in HIT-T15 cells (5), providing a potential site of impairment of nucleotide synthesis or activation. Furthermore, Corbett et al (13), Welsh and Sandier (14), and Drapier and Hibbs (15) have shown a decrease in the activity of the mitochondrial enzyme aconitase and in the activity of the electron transport chain.…”

mentioning

confidence: 99%

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Dual Functional Effects of Interleukin-1β on Purine Nucleotides and Insulin Secretion in Rat Islets and INS-1 Cells

Meredith

Rabaglia²,

Corbett³

et al. 1996

Diabetes

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Interleukin-1beta (IL-1beta) has been shown to inhibit glucose-induced insulin secretion from rat islets and purified beta-cells, primarily through the generation of nitric oxide (NO). However, the mechanisms by which NO exerts its effects remain unclear. To examine the role of purine nucleotides, we cultured intact rat islets or INS-1 (glucose-responsive transformed rat) beta-cells for 18 h in the presence or absence of IL-1beta. In islets, the exposure to IL-1beta (100 pmol/l) inhibited subsequent glucose-induced insulin secretion by 91% with no significant effect on insulin content or basal insulin release. IL-1beta also diminished insulin secretion induced by pure mitochondrial fuels, 40 mmol/l K+, or a phorbol ester. Concomitantly, IL-1beta significantly decreased islet ATP (-45%), GTP (-33%), ATP/ADP (-54%), and GTP/GDP (-46%). These effects were totally reversed by provision of N(omega)-nitro-L-arginine methyl ester (NAME) in arginine-free media that inhibited NO production. In contrast, in INS-1 cells, IL-1beta (10 or 100 pmol/l) reduced both basal and glucose-induced insulin secretion by 50%, but insulin content was also reduced by 35%. Therefore, the INS-1 cells were still able to respond to glucose stimulation with a 1.8-2.0-fold increase in insulin release in either the presence or absence of IL-1beta. Concomitantly, in INS-1 cells, IL-1beta had no effect on ATP/ADP or GTP/GDP ratios, although it modestly decreased ATP (-25%) and GTP (-22%). As in islets, all effects of IL-1beta in INS-1 cells were prevented by NAME. Thus, in rat islets, IL-1beta (via the generation of NO) abolishes insulin exocytosis in association with large decreases in the ATP/ADP (and GTP/GDP) ratio, implying the impairment of mitochondrial function. Furthermore, IL-1beta inhibits cytosolic synthesis of new purine nucleotides (via the salvage pathway), as assessed by a decrease in their specific activity after labeling with [3H]hypoxanthine. In contrast, in INS-1 cells, IL-1beta appears to impair cytosolic synthesis of purine nucleotides and insulin biosynthesis selectively (both possibly reflecting decreased glycolysis) with little direct effect on insulin exocytosis itself.

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“…A larger amount of NO induces apoptosis, leading to cell death and the abolition of insulin release (12)(13)(14), but a relatively smaller concentration of NO induces a reversible deterioration of the cellular signal transduction system which suppresses insulin release. However, the identity of the sites disturbed by NO is controversial, and the enzymes including glucokinase (15)(16)(17), phosphofructokinase (18 -20), and aconitase in the Krebs cycle (21) are all candidates. It has been reported that NO inhibits phospholipase C activity (22), cAMP synthesis (23), and insulin mRNA synthesis (24), and increases the production of free radicals (25) that results in impaired insulin secretion.…”

mentioning

confidence: 99%

Heat Shock Restores Insulin Secretion after Injury by Nitric Oxide by Maintaining Glucokinase Activity in Rat Islets

Takeda

Tsuura

Fujita

et al. 2001

Biochemical and Biophysical Research Communications

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Interleukin‐1β inhibits glucokinase activity in clonal HIT‐T15 β‐cells

Cited by 15 publications

References 30 publications

Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism

Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism

Dual Functional Effects of Interleukin-1β on Purine Nucleotides and Insulin Secretion in Rat Islets and INS-1 Cells

Heat Shock Restores Insulin Secretion after Injury by Nitric Oxide by Maintaining Glucokinase Activity in Rat Islets

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