Effects of alloxan on glucose-stimulated insulin secretion, glucose metabolism, and cyclic adenosine 3?, 5?-monophosphate levels in rat isolated islets of Langerhans

Abstract

Insulin secretion was stimulated and cyclic adenosine 3', 5'-monophosphate (cAMP) levels were elevated in isolated rat islets by 27.5 mmol/l glucose. Alloxan caused a dose-dependent decrease in both variables with complete obliteration of insulin release at a concentration of 1.25 mmol/l. D-glucose, in the presence or absence of extracellular calcium, or 3-0-methyl-D-glucose (both at 27.5 mmol/l) protected completely against the effects of alloxan on both glucose-induced insulin release and cAMP Levels. 3-0-Methylglucose did not stimulate insulin secretion or elevate cAMP and did not interfere with glucose-stimulated secretion or elevation of cAMP. When glucose-stimulated insulin release was abolished by alloxan, the metabolism of glucose, determined by the rate of 3H2O formation from [5-3H] glucose, was depressed by 20%. It is concluded that alloxan altered the adenylate cyclase system such that it could no longer be stimulated by glucose. Glucose-stimulated insulin secretion or elevation of cAMP did not appear essential for glucose to protect against alloxan. Protection by 3-0-methylglucose did not appear to be mediated through an alteration of cAMP metabolism. Alloxan did not inhibit glucose-induced insulin secretion by grossly altering glycolysis.

Alloxan: history and mechanism of action

“…Half maximal concentrations of glucose for protection of glucose-induced insulin secretion [51] and pancreatic B cell glucokinase [41, 43,49] are approximately 10 mmol/l. 6.3-O-Methylglucose also protects glucose-induced insulin secretion against alloxan inhibition [59][60][61][62][63]. But unlike glucose, this non-metabolisable sugar does not achieve this by direct protection through binding to the sugar binding site of the glucokinase [43], but protects the glucokinase in the intact cell [41,43] and, thus, glucose-induced insulin secretion against alloxan inhibition through inhibition of alloxan uptake into the B cell [64,65].…”

“…Data were derived from [49] ing metabolism of glucose or mannose to keep the SH groups in a reduced state and to inactivate alloxan [66] apparently also does not participate in the protective action of these two nutrient insulin secretagogues. The structural requirements of the sugar binding site of glucokinase [47,49] are far more strict than those of the glucose transporter [63] in the pancreatic B cell plasma membrane, where no single OH group is essential for binding to the carrier as depicted by the ability of the carrier to transport 3-O-methylglucose or 2-deoxyglucose [63]. Thus, the glucokinase inhibition theory of alloxan action [41], as presented here, is compatible with the view that the glucose transporter in the B cell membrane is not the primary site where alloxan accomplishes its inhibitory action on glucose-induced insulin secretion and its B cell toxic action [85].…”

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

“…Islet Glucose Utilization-As in previously described procedures (20,25), triplicate batches of 10 islets per incubation condition were placed into Microfuge tubes (0.5 ml). Medium was then removed, and radioactive mixture (15 l) was added.…”

Glucose but not Arginine Prevents the Inhibitory Effect of Vincristine on Glucose-induced Insulin Release

“…15 ' 16 In these studies, simultaneous treatment of isolated pancreatic islets with alloxan and glucose prevented the inhibition of insulin release seen with alloxan alone.…”