Glucoreceptor mechanisms and the control of insulin release and biosynthesis

Ashcroft, S. J. H.

doi:10.1007/bf01228295

Cited by 287 publications

(194 citation statements)

References 72 publications

(95 reference statements)

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…It appears furthermore plausible that disturbances in either of these two mechanism may be of aetiological significance for the manifestations of diabetes. The regulation of the rapid insulin response has recently been the subject of several reviews [42][43][44][45][46]. In this article I would like to draw attention to the more long-term adaptive changes, with special regard to growth in B-cell number and mass.…”

Section: Long-term Adaptation Of the B Cell To Changing Functional Loadsmentioning

confidence: 99%

The life story of the pancreatic B cell

Hellerström

1984

Diabetologia

115

View full text Add to dashboard Cite

Summary. Most research on the pancreatic B cell has so far focussed on the regulation and molecular biology of insulin biosynthesis and release. The present review draws attention to some additional areas of islet research which have become accessible to investigation by recent methodological progress and which may advance our understanding of the role of the B cell in diabetes. There is now evidence to suggest that B cells arise from a pool of undifferentiated precursor cells in the fetal and newborn pancreas. These ceils may contribute to islet growth and, if inappropriately stimulated, also to early islet hyperplasia. In the postnatal state, B-cell function is finely tuned by a complex set of incoming signals, one of which is the nutrient supply provided by the blood. Recent studies indicate that a disproportionately high fraction of pancreatic blood is diverted to the islets and that the islet blood flow is increased by glucose. An acute stimulus to insulin release may thus be accompanied by a process which enhances the distribution of the hormone to the target cells. Long-term adjustments of B-cell function are made by changes in B-cell number and total mass. Adaptive growth responses to an increased insulin demand occur in a number of hereditary diabetic syndromes in animals, but in some of these there is an inherited restriction on the capacity for B-cell proliferation leading to further deterioration of the glucose tolerance. Some evidence suggests that a similar mechanism may operate also in human non-insulin-dependent diabetes. A critical appraisal of this hypothesis requires, however, that human B cells should be tested for their growth characteristics. Studies of B-cell proliferation in experimental animals have shown that the B cell passes through the cell cycle at a relatively high rate but that the fraction of proliferating cells is low. Regulation of growth of the total B-cell mass seems to take place by changes in the number of B cells passing through the cell cycle rather than by changes in the rate of the cycle. The number of proliferating B cells also shows a marked decrease with age. It is at present uncertain to what extent these regulatory mechanisms apply also to the human B cell but it can be anticipated that further technical developments will elucidate this problem.

show abstract

Section: Long-term Adaptation Of the B Cell To Changing Functional Loadsmentioning

confidence: 99%

The life story of the pancreatic B cell

Hellerström

1984

Diabetologia

115

View full text Add to dashboard Cite

show abstract

“…Insulin secretion from the pancreatic ␤-cell is tightly regulated by stimulatory signals generated during the intracellular metabolism of glucose and by neurohumoral agonists operative at the cell membrane (1)(2)(3)(4)(5). Most recently an additional layer of complexity has been added by reports suggesting that insulin exerts an autocrine stimulatory effect on insulin secretion from the ␤-cell (6,7).…”

mentioning

confidence: 99%

Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets

Zawalich

2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Isolated perifused rat islets were stimulated with glucose, exogenous insulin, or carbachol. C-peptide and, where possible, insulin secretory rates were measured. Glucose (8 -10 mM) induced dose-dependent and kinetically similar patterns of C-peptide and insulin secretion. The addition of 100 nM bovine insulin had no effect on C-peptide release in response to 8 -10 mM glucose stimulation. The addition of 100 nM bovine insulin or 500 nM human insulin together with 3 mM glucose had no stimulatory effect on C-peptide secretion rates from perifused rat islets. Stimulation with carbachol plus 7 mM glucose enhanced both C-peptide and insulin secretion, and the further addition of 100 nM bovine insulin had no inhibitory effect on C-peptide secretory rates under this condition. Perifusion studies using pharmacologic inhibitors (genistein and wortmannin) of the kinases thought to be involved in insulin signaling potentiated 10 mM glucose-induced secretion. The results support the following conclusions. 1) C-peptide release rates accurately reflect insulin secretion rates from collagenase-isolated, perifused rat islets. 2) Exogenously added bovine insulin exerts no inhibitory effect on release to several agonists including glucose. 3) In the presence of 3 mM glucose, exogenously added bovine or human insulin do not stimulate endogenous insulin secretion.Insulin secretion from the pancreatic ␤-cell is tightly regulated by stimulatory signals generated during the intracellular metabolism of glucose and by neurohumoral agonists operative at the cell membrane (1-5). Most recently an additional layer of complexity has been added by reports suggesting that insulin exerts an autocrine stimulatory effect on insulin secretion from the ␤-cell (6, 7). This concept was based primarily on amperometric measurements using ␤-cells preincubated in 5-hydroxytryptamine (5HT).1 Because 5HT exposure exerts inhibitory effects on insulin release (8 -10), the precise physiologic significance of findings made with 5HT-preloaded ␤-cells is unclear. Moreover, previous studies exploring the potential role of insulin on stimulated secretion showed no effect (11) or supported the concept that insulin exerts a negative, not positive, feedback on its own secretion (12-15).There are at least three major issues that must be addressed in attempting to establish the impact of exogenously added insulin on endogenous insulin secretory rates. The first is technical; it is difficult to accurately measure endogenous insulin release rates in the presence of exogenous insulin. The second relates to concentration of insulin necessary to establish an effect of exogenously added hormone on the ␤-cell. Considering that the ␤-cell continually releases insulin into a small volume of interstitial fluid, the level of insulin bathing the ␤-cell may be quite high. For example, calculations based on islet cell volume, the insulin diffusion constant and insulin secretory rates, suggest that these levels may exceed 100 nM during glucose stimulation (16). Even at rest, levels o...

show abstract

“…It is currently thought that the process through which glucose is identified in the pancreatic B-cell as a stimulus for both proinsulin biosynthesis and insulin release strictly depends on the integrity of glucose metabolism in the islet cells [ 1,2]. However, the mechanism by which the glycolytic and oxidative flux is increased in response to a rise in the extracellular concentration of glucose is not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%