Insulin Biosynthesis and Secretion — A Still Unsettled Topic

Renold, Albert E.; Kanazawa, Yasunori; Lambert, André; Orci, Lelio; Burr, Ian M.; Balant, L; Beaven, D. W.; Grodsky, Gerold M.; Stauffacher, Werner; Jeanrenaud, B.; Roviller, Charles

doi:10.1056/nejm197001222820401

Cited by 58 publications

(31 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One recent finding published by Renold and his coworkers deserves consideration in this context (17). These investigators observed a paradoxical enhancement of tolbutamide action by 2-deoxy-D-glucose and D-mannoneptulose, two potent inhibitors of glucose-stimulated insulin release.…”

Section: Discussionmentioning

confidence: 96%

Kinetics of Insulin Release from the Perfused Rat Pancreas Caused by Glucose, Glucosamine, and Galactose

Landgraf

Matschinsky

1971

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

View full text Add to dashboard Cite

Under appropriate conditions, not only glucose but also glucosamine and galactose can serve as potent stimulants for insulin release from the isolated, perfused rat pancreas. Since galactose and, probably, glucosamine are not metabolized in the islets, and since these three compounds have in all likelihood common sites of action, it is postulated that a glucoreceptor of broad specificity is involved in the mechanism of insulin release, and that metabolism of glucose is not an essential part of the releasing action of this sugar.An important but deceptive question about the islets of Langerhans is how glucose stimulates insulin release. The question is important because it concerns a crucial aspect of normal function and of diabetes; it is deceptive because any specific releasing functions of glucose can be easily obscured by the more general role of glucose as a fuel. A promising approach to this difficulty is to compare the effects of glucose with its epimers (e.g., galactose), derivatives (e.g., glucosamine), and other closely related compounds, (e.g., mannoheptulose) and, in this way, to attempt to distinguish release and fuel functions. The perfused pancreas, although technically somewhat demanding (1), seemed an ideal system for such investigations.In this paper we describe the peculiar kinetics of insulin secretion observed when the perfused pancreas of the rat was stimulated by glucose, galactose, or glucosamine alone, by combinations of subthreshold levels of glucose with galactose or glucosamine, and also by combinations of stimulatory amounts of any of the three sugars with theophylline. MATERIALS AND METHODSAll reagents were analytical grade. Dextran The pancreas was isolated and perfused using the procedure described by Grodsky et al. (1) with minor modifications. The animals were fasted overnight, treated with atropine (0.1 mg/kg) intraperitoneal, and anesthetized with pentobarbital (45 mg/kg, intraperitoneal). The pancreas was removed together with the spleen, the stomach, and the proximal part of the duodenum. The celiac axis and the portal vein were cannulated and the organ complex was placed in an incubator at constant temperature (350C). Perfusate was not recycled.The perfusion fluid had the following composition: NaCl, 120 mM; KCl, 4.7 mM; MgSO4, 0.8 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; and NaHCO3, 25 mM. Dextran (8%) was added to provide a colloid osmotic pressure similar to that of serum. 1 hr prior to perfusion, the medium was warmed to 350C and equilibrated with Or-CO2 95:5. The resulting pH was 7.4. The pH changed less than 0.1 unit during one passage through the organ complex. The perfusion pressure varied between 40 and 80 mm of Hg. The average flow rate was 7.0 ml/min and was constant throughout the experiment, which usually lasted 1 hr.After the pancreas was perfused for 10 min with the same medium as used during the control periods of each experiment, the effluent was sampled. Usually three samples were taken as controls. At intervals, indicated in the figures, the perfusate ...

show abstract

Section: Discussionmentioning

confidence: 96%

Kinetics of Insulin Release from the Perfused Rat Pancreas Caused by Glucose, Glucosamine, and Galactose

Landgraf

Matschinsky

1971

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

View full text Add to dashboard Cite

show abstract

“…6). In 1970, Prof. Albert Renold published the article 'Insulin biosynthesis and secretion -a still unsettled topic' in The New England Journal of Medicine [107]. Although our understanding of insulin secretion has increased remarkably since that time, the title of the paper remains true.…”

Section: Discussionmentioning

confidence: 99%

Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea

2012

View full text Add to dashboard Cite

Clarification of the molecular mechanisms of insulin secretion is crucial for understanding the pathogenesis and pathophysiology of diabetes and for development of novel therapeutic strategies for the disease. Insulin secretion is regulated by various intracellular signals generated by nutrients and hormonal and neural inputs. In addition, a variety of glucose-lowering drugs including sulfonylureas, glinide-derivatives, and incretin-related drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are used for glycaemic control by targeting beta cell signalling for improved insulin secretion. There has been a remarkable increase in our understanding of the basis of beta cell signalling over the past two decades following the application of molecular biology, gene technology, electrophysiology and bioimaging to beta cell research. This review discusses cell signalling in insulin secretion, focusing on the molecular targets of ATP, cAMP and sulfonylurea, an essential metabolic signal in glucose-induced insulin secretion (GIIS), a critical signal in the potentiation of GIIS, and the commonly used glucoselowering drug, respectively.

show abstract

“…Since NADPH in islets is provided mainly through the metabolism of glucose-6--phosphate via the hexosemonophosphate shunt, interference with glucose phosphorylation, not surprisingly, also leads to inhibition of glucose-induced insulin release. The findings of Renold and coworkers (25) that inhibition of glucose phosphorylation by mannoheptulose or 2-deoxyglucose paradoxically potentiates tolbutamide-induced insulin release, despite blocking glucose-induced release, may be explained by shunting of glucose into sorbitol formation. Our finding that higher concentrations of Glt and (CH3)2Glt depress tolbutamide-induced release as well is consistent with the idea that sorbitol is required to "prime" or activate an element in the insulin release mechanism of the beta cell.…”

Section: Discussionmentioning

confidence: 99%