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

Abstract

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)

Studies of the Role of Group VI Phospholipase A2 in Fatty Acid Incorporation, Phospholipid Remodeling, Lysophosphatidylcholine Generation, and Secretagogue-induced Arachidonic Acid Release in Pancreatic Islets and Insulinoma Cells

“…De novo phospholipid synthesis from glucose requires glycolytic metabolism to triose phosphates and acylation of glycerol 3-phosphate and then lysophosphatidic acid to yield PA (24). Kinetic properties of the predominant islet glucose transporter and glucokinase cause islet glycolytic flux to rise severalfold as the medium glucose concentration increases from 5 to 20 mM (75), and this promotes islet de novo glycerolipid synthesis (60). Incorporation of [ 3 H]arachidonic acid into phospholipids was found not to be significantly affected by medium glucose concentration in control or BELtreated islets, although the latter exhibited greater incorporation at each glucose concentration (Table II, top).…”

Dynamic regulation of metabolism and respiration by endogenously produced nitric oxide protects against oxidative stress

“…2) at the expense of the NADPH production by the G6PDH pathway. A nitric oxide-mediated decline in glucose utilization following IL-1 induction of iNOS in pancreatic islets has been reported (34), and a decrease in gluconeogenesis, which resulted in an increased flow through phosphofructokinase and pyruvate kinase, has been reported after lipopolysaccharide (LPS)-mediated induction of hepatocyte NOS (35). The decrease in glucose utilization by the G6PDH pathway does appear to compromise the levels of reduced thiols in the eNOS-transfected cells and is not due to an inhibition of G6PDH activity.…”

Toll-like receptors, the NLRP3 inflammasome, and interleukin-1β in the development and progression of type 1 diabetes

“…IL1β may decrease insulin secretion in part by reducing levels of mRNA and protein for glucokinase, a key component of the glucose sensor in islet cells (31). Moreover, IL1β inhibits insulin release from previously docked granules in the β-cells of rats.…”