Altered regulation of insulin secretion in isolated islets of different sizes in aging rats

Kitahara, Akio; Adelman, Richard C.

doi:10.1016/s0006-291x(79)80035-2

Cited by 36 publications

(36 citation statements)

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“…The pattern of glucose‐stimulated insulin response detected in vivo by Gold et al 2 in portal vein blood of fasted, male Sprague‐Dawley rats aged two to 24 months is expressed in part in vitro when insulin secretion is stimulated by perifusion of isolated islets of different sizes from corresponding donor rats, as described by Kitahara and Adelman 13 . The insulin secretory response to 16.7 mmol (300 mg/100 mL) glucose by peri‐fused small (50–80 μm diameter) islets from fasted two‐month‐old rats is delayed by approximately two hours when assessing the identical islet population from fasted 24–month‐old rats.…”

Section: Altered Responsiveness To Glucose In Vitromentioning

confidence: 91%

“…Of those numerous factors that influence the observed patterns of insulin secretory response in vitro at different donor ages, the most noteworthy include physical size of the islets tested and response time at which insulin levels are measured. Magnitude and time course of insulin response to glucose by islets of heterogeneous sizes differ considerably at given donor ages 13 . Furthermore, the distribution of islet sizes changes as donors age 14–18 .…”

Section: Altered Responsiveness To Glucose In Vitromentioning

confidence: 99%

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Secretion of Insulin During Aging

Adelman

1989

J American Geriatrics Society

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ecognition of and response to environmental challenge are expressed in part by the availability and efficacy of circulating hormones for R the modulation of intermediary metabolism in target cells. One example of such adaptive capability that changes during aging is the impact of dietary glucose on its insulin-sensitive metabolism by liver and peripheral tissues. This paper provides a critical review of published research that addresses the pivotal role of insulin secretion in that adaptive sequence during aging.According to most, but not all, published reports, the regulation of insulin secretion by glucose changes during aging. However, interpretation of these data is complicated by numerous factors, most prominent of which include 1) the extent to which it is possible to evaluate insulin secretion in vivo by measurement of hormone levels in peripheral blood; 2) the distribution of functionally heterogeneous populations of pancreatic islets of Langerhans; 3) distinctions between growth, obesity, and aging; and 4) the frequent failure to acknowledge relevant, previously published literature. The present paper will examine these data both in the context of such complications and from the perspective of the pursuit of further insight into the fundamental biological processes of aging that are expressed in the absence of disease and inappropriate lifestyle. ALTERED RESPONSIVENESS TO GLUCOSE IN VIVOWhen the pancreas recognizes and responds to an increased level of blood glucose, insulin is secreted into the portal vein and through it is transported immediately to the liver. Within the liver insulin exerts certain of its hormonal actions and also is metabolized. The proportion of insulin molecules that escapes its hepatic metabolism is distributed throughout the peripheral circu-From the Institute of Gerontology, The University of Michigan, Ann Arbor, Michigan. Address correspondence and reprint requests to Richard C. Adelman, PhD, Institute of Gerontology, The University of Michigan, 300 N. Ingalls, Ann Arbor, MI 48109-2007.lation and tissues. Therefore, assessment of insulin secretion by the pancreas into the circulation can be approximated most accurately in portal vein blood.The concentration of insulin in portal vein blood is the net result of its secretion into the blood by the pancreas and its extraction from the blood by the liver at early points during the secretory response, although recirculation of secreted insulin complicates matters increasingly with the passage of time. However, the concentration of insulin in peripheral blood at any given time represents the far more complex net result of its pancreatic secretion, hepatic clearance, uptake and clearance through peripheral tissues, recirculation, and disposition within the blood. Therefore, consideration of peripheral blood insulin levels during aging in the context of the regulation of insulin secretion is excluded from this review, although previous work by Chen et al,' for example, is particularly relevant in this regard.The pattern of insulin respo...

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Section: Altered Responsiveness To Glucose In Vitromentioning

confidence: 91%

Section: Altered Responsiveness To Glucose In Vitromentioning

confidence: 99%

Secretion of Insulin During Aging

Adelman

1989

J American Geriatrics Society

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“…The variety of p-cell locations is suggestive for heterogeneity in functions. Occurrence as isolated single cells or as units in aggregates of variable size and composition may be related to different states of activity (1,27). A localization in the dorsal part of the pancreas appears associated with stronger secretory responses than one in the ventral part (28).…”

Section: Functional Diversity In Situmentioning

confidence: 99%

Heterogeneity in Pancreatic β-cell Population

Pipeleers

1992

Diabetes

176

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All pancreatic beta-cells are identified by specific morphological characteristics. Similarity in microscopic features is not necessarily associated with identity in functional properties. In vitro studies on isolated rat beta-cells have indicated intercellular differences in the threshold for glucose-induced shifts in metabolic redox state. The cellular heterogeneity in glucose sensitivity results in a dose-dependent recruitment of glucose-exposed beta-cells into biosynthetic and secretory activities. The molecular basis of this diversity is not known. Indirect evidence supports the concept that the in situ pancreatic beta-cell population is also composed of functionally diverse subpopulations. The heterogeneity in glucose responsiveness is expected to create subpopulations of beta-cells with either constant, fluctuating, or occasional glucose-dependent functions; whether any subpopulation is preferentially responsive to other regulatory factors and/or committed to other activities is unknown. Morphological markers may help identify beta-cell subpopulations in situ and quantify their size in conditions known to affect total beta-cell mass or function. The concept of a functionally heterogeneous beta-cell population influences views on the role of pancreatic beta-cells in health and disease.

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“…The second consideration in interpreting these pulse-chase experiments is that while all insulin-specific immunoprecipitable radioactivity after a 30-min pulse is proinsulin, most of the secreted insulin during the chase is insulin; thus, a correction had to be made to take into account the loss of radioactivity in secreted C-peptide, which is not immunoprecipitated in the assay system. Samples of secreted [3H]leucine-labeled material from 7 and 24 mo islets were taken after a 120-min chase and fractionated by HPLC; in general, they showed a 10-20% ratio of label in proinsulin vs. insulin, which is similar to values for islets from young animals (20). Gold et al (27) have also reported that young and old islets secrete similar ratios of labeled proinsulin and insulin in pulse-chase experiments at 25 mM glucose.…”

Section: Secretion Ofnewly Made Insulinmentioning

confidence: 99%

“…Similarly, the glucose intolerance of aging, which is primarily due to a postreceptor defect in insulin-mediated glucose disposal (2)(3)(4)(5), and accompanied by a decrease in insulin clearance (6), has been shown to be associated with defectiveness in the primary B cell function, glucose-stimulated insulin secretion (7)(8)(9)(10). In particular, the Reavens and their collaborators have shown in rats that insulin secretion per B cell decreases with age, even ifthe animals are prevented from becoming obese by exercise or caloric restriction (8).…”

Section: Introductionmentioning

confidence: 99%

Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

Wang

Halban²,

Rowe³

1988

J. Clin. Invest.

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Abstracttransducing the glucose stimulus into the wide range of B cell responses to glucose. Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma membrane, and exocytosis. We have examined the influence of age at three stages along this pathway: preproinsulin mRNA levels, proinsulin synthesis, and secretion of newly made and preformed insulin, using Fischer rats, a widely studied rodent model of aging. Pancreatic weights and total insulin contents, islet sizes, and mean insulin content per islet were the same in young adult (4-5 mo) and senescent (21-22 mo) animals. There was no effect of age on preproinsulin mRNA levels in whole pancreata offed animals, or in isolated islets cultured for 16 h in 5.5 mM glucose. Proinsulin biosynthesis and the secretion of newly made insulin were compared in isolated islets preincubated in 5.5 mM glucose. After a pulse label at 16.7 mM glucose, proinsulin synthesis, assayed by immunoprecipitation, was decreased 16% in 7 mo islets and 39% in 21-22 mo islets, compared with 4-5 mo islets, though total protein synthesis was not reduced. When chased at 2.8 mM glucose, 4-5 month and 21-22 mo islets showed no difference in release of preformed or newly made insulin. When chased at 16.7 mM glucose, there was a significant decrease in the secretion of newly made insulin in the old islets compared with the young islets. There was preferential release of newly made insulin over preformed insulin in both young and old islets. However, since secretion of preformed insulin was decreased much more than secretion of newly made insulin in senescent islets, these displayed a two-to threefold increase in the proportion of newly made insulin relative to total immunoreactive insulin released compared with young adult islets. The differential effects of aging on these steps in the insulin synthesis-secretion pathway may be due to varying impairments in signals

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Altered regulation of insulin secretion in isolated islets of different sizes in aging rats

Cited by 36 publications

References 10 publications

Secretion of Insulin During Aging

Secretion of Insulin During Aging

Heterogeneity in Pancreatic β-cell Population

Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

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