Physical and biological properties of guinea pig insulin

Zimmerman, Arthur E.; Kells, David I. C.; Yip, Cecil C.

doi:10.1016/0006-291x(72)90769-3

Cited by 31 publications

(13 citation statements)

References 10 publications

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“…Therefore the ISG matrix may be more refractory to expanding concomitantly with the surrounding membrane than the matrix of other granules. Notably, guinea pig ISGs, the insulin of which does not crystallise [20], display only a thin halo [21]. Similar observations were made in mice lacking prohormone convertase 1/3, which is mainly responsible for converting proinsulin into insulin [22].…”

Section: Discussionmentioning

confidence: 87%

Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling

et al. 2012

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Aims/hypothesisKnowledge of number, size and content of insulin secretory granules is pivotal for understanding the physiology of pancreatic beta cells. Here we re-evaluated key structural features of rat beta cells, including insulin granule size, number and distribution as well as cell size.MethodsElectron micrographs of rat beta cells fixed either chemically or by high-pressure freezing were compared using a high-content analysis approach. These data were used to develop three-dimensional in silico beta cell models, the slicing of which would reproduce the experimental datasets.ResultsAs previously reported, chemically fixed insulin secretory granules appeared as hollow spheres with a mean diameter of ∼350 nm. Remarkably, most granules fixed by high-pressure freezing lacked the characteristic halo between the dense core and the limiting membrane and were smaller than their chemically fixed counterparts. Based on our analyses, we conclude that the mean diameter of rat insulin secretory granules is 243 nm, corresponding to a surface area of 0.19 μm2. Rat beta cells have a mean volume of 763 μm3 and contain 5,000–6,000 granules.Conclusions/interpretationA major reason for the lower mean granule number/rat beta cell relative to previous accounts is a reduced estimation of the mean beta cell volume. These findings imply that each granule contains about twofold more insulin, while its exocytosis increases membrane capacitance about twofold less than assumed previously. Our integrated approach defines new standards for quantitative image analysis of beta cells and could be applied to other cellular systems.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2438-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 87%

Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling

et al. 2012

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“…In contrast to bovine and human insulin which bind zinc, guinea pig (hystricomorph) insulin exists as a monomeric species even in the presence of zinc (Zimmerman et al ., , ; Zimmerman and Yip, ). Differences in physical properties between guinea pig and bovine/humulin insulin may contribute to differences in their metabolic activities (Zimmerman et al ., , ; Zimmerman and Yip, ; King et al ., ; Chan et al ., ). Interestingly, hystricomorph insulins appear to exert these metabolic activities via a receptor that recognizes PDGF and not via insulin receptors (King et al ., ; Chan et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons

Gao

Lieu

et al. 2019

British J Pharmacology

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Background and Purpose Acute insulin administration hyperpolarized, with concomitant decrease of firing rate, a subpopulation of arcuate proopiomelanocortin (POMC) and neuropeptide Y/agouti‐related peptide cells. This rapid effect on cellular activity has been proposed as a cellular correlate of insulin effects on energy balance and glucose homoeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin‐induced inhibition of arcuate POMC neurons, while guinea pig insulin, which fails to bind zinc, activates POMC neurons in mice. Here, we tested the effects of zinc and insulin formations on arcuate POMC neurons. Experimental Approach Effects of zinc and insulin formulations were assessed through whole‐cell patch clamp recordings on transgenic mice in vitro. Key Results Insulin formulations containing zinc hyperpolarized POMC neurons. Zinc also hyperpolarized arcuate POMC neurons, albeit at much higher concentration than found in various insulin formulations. Chelation of zinc inhibited the zinc‐induced hyperpolarization of POMC neurons, whereas effects of insulin on POMC cellular activity were unchanged after chelation. Zinc‐free insulin also hyperpolarized arcuate POMC neurons. Insulin failed to hyperpolarize POMC neurons deficient for insulin receptors, suggesting that insulin receptors are required for these effects. Activation of POMC neurons by guinea pig insulin was independent of insulin receptors but was inhibited by PDGF receptor antagonism or loss of TRPC5 channel subunits. Conclusions and Implications Together, these findings suggest that insulin inhibited arcuate POMC neurons independent of zinc and highlights a possible role of putative PDGF receptors in the acute effects of guinea pig insulin.

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“…We did not use insulin concentrations "which are all supersaturating with respect to receptor binding;" in fact, saturation of a small percentage of the sites induces significant cooperativity (32). Zimmerman et al have not "failed to demonstrate dimerization" of guinea pig insulin due to the low insulin concentration used in sedimentation equilibrium studies (39); in a more recent study they have indeed clearly demonstrated that guinea pig insulin remains monomeric even at concentrations of 3 mg/ml (40); Cuatrecasas and Hollenberg are apparently unaware of the publication of this more complete study. Finally, Pekar and Frank (34) did not report a dissociation constant for dimerization of 7 X lo-' M; they reported an equilibrium constant of 1.4 X lo5 l/mole, which yields a dissociation constant of -7 X lop6 M. This agrees well with the value reported by Goldman and Carpenter (43) (not quoted by Cuatrecasas and Hollenberg) and is consistent with the fall in cooperative effect observed in our studies.…”

Section: Ligand-ligand Interactionsmentioning

confidence: 95%

“…(c) Nondimerizing insulin species, tetra (nitrotyrosine)-insulin (37) and guinea pig insulin (38)(39)(40)(41) induce the accelerated dissociation in strict correlation with their relative ability to bind to the insulin receptor sites (32,36). Since they do not dimerize, no fall in effect is observed at high concentrations.…”

Section: Ligand-ligand Interactionsmentioning

confidence: 99%

Cooperative properties of hormone receptors in cell membranes

Meyts

1976

J Supramol Struct

164

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The binding of many polypeptide hormones to cell surface receptors does not appear to follow the law of mass action. While steady-state binding data are consistent in many cases with either heterogeneous populations of binding sites or interactions of the type known as negative cooperativity, study of the kinetics of dissociation of the type known as negative cooperativity, study of the kinetics of dissociation of the hormone receptor complex allows an unambiguous demonstration of cooperative interactions. Negative cooperativity, which seems to be wide-spread among hormone receptors, provides exquisite sensitivity of the cell at low hormone concentrations while buffering against acutely elevated hormone levels. The molecular mechanisms underlying the cooperativity are still largely unknown. Cooperativity may stem from a conformational transition in individual receptors or involve receptor aggregation in the fluid membrane (clustering) or more extensive membrane phenomena. Thus, new models of hormone action must be considered which integrate the progress in our knowledge of both the complex mechanisms regulating hormone binding to their surface receptors, and the dynamic properties of the cell membrane.

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Physical and biological properties of guinea pig insulin

Cited by 31 publications

References 10 publications

Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling

Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling

Acute effects of zinc and insulin on arcuate anorexigenic proopiomelanocortin neurons

Cooperative properties of hormone receptors in cell membranes

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