Dextran-linked insulin: A soluble high molecular weight derivative with biological activity invivo and invitro

Armstrong, Kenneth J.; Noall, Matthew W.; Stouffer, John E.

doi:10.1016/0006-291x(72)90720-6

Cited by 33 publications

(12 citation statements)

References 7 publications

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“…The biological activity of these derivatives has now been amply confirmed in our own and other (10) laboratories. Moreover, strong and specific physical interaction of fat cells with insulin beads has recently been directly demonstrated by Katzen and colleagues (11), and large, soluble insulin-dextran polymers have now been shown to be biologically active (12). Furthermore, the conclusions are completely consistent with a large body of other information which has since accumulated concerning insulin receptors.…”

mentioning

confidence: 53%

Humerus of Robust Australopithecus

Butcher

Crofford

Gammeltoff

et al. 1973

Science

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mentioning

confidence: 53%

Humerus of Robust Australopithecus

Butcher

Crofford

Gammeltoff

et al. 1973

Science

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“…1). However, when further experimental evidence accumulated together with studies on the effects of other hormones, we found that this simple model is inaccurate and should be discarded [2]- [26]. The basis for this denunciation is in sections IIA and IIB.…”

Section: Identification Of the Problemmentioning

confidence: 91%

“…Intravascular agonists that are 100 times the size of their natural agonists have a lower action speed and potency. Unexpectedly, their effects being either: coronary tone, inotropism, dromotropism, spontaneous ventricular rhythm, bradycardia, skeletal muscle vascular tone, and enhanced glucose consumption; they act as fast and potent as the smallsize agonist [2]- [19], [23]- [25]. The fact that intravascular large-size agonists and their smaller counterparts behave equally suggests that both act at the same site and at the same speed because they do not diffuse across the endothelial wall.…”

Section: A Lack Of Hormone-free Exchange Between Circulatory and Interstitial Compartments Diffusional Studies 1) Agonists Either Large Omentioning

confidence: 99%

The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach

Rubio

2021

EJMED

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In 1849, the first list of endocrine hormones was discovered and proposed that the synthesizing gland delivers it to the circulation. The circulatory hormone reaches the target organ, physically unimpeded acts directly on the parenchymal cells. Such a simplistic view persists despite new knowledge of an endothelial wall barrier and implications for every parenchymal cell in the body. This misconception leads to inadequate interpretations of data, wrong diagnosis and therapeutic expectations, erroneous hypotheses, and misleads further research work. The quest of this review is to play down this misconception by pointing out key overlooked findings of the vascular endothelial wall: 1) The selective endothelial barrier physically separates two same-hormone-containing compartments; the endocrine and the interstitial autocrine hormone compartments, 2) the hormone concentrations values in these compartments are independent of each other, 3) in each compartment the hormone acts solely on the receptors of that particular compartment, 4) multiple intravascular endocrine hormones act solely on their corresponding luminal endothelial membrane receptor (LEMR), without directly acting on the parenchymal cells, 5) Agonist-activation of LEMR triggers the release of specific paracrine endothelial agents that in conjunction with autocrine interstitial hormone modulate parenchymal function(s) and perhaps the turnover of the interstitial autocrine hormone, 6) these hormone compartments, functionally interact via paracrine exchange signaling, and the integrated intercourse of all these events result in the final hormonal organ effect. The present challenges to achieving more rationale therapeutic effects are to design agonists or antagonists that exclusively gain access to a target compartment and have high specificity for the receptor of the cells in that compartment.

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“…This finding can hardly be generalized, but it has an interesting parallel in the reported high biological activity of dextran-linked insulin [4]. Cuatrecasas reported a highly active Sepharose derivative of the same polypeptide hormone [1,28] but the findings became the subject of a recent controversy [29] due to the possible presence of soluble insulin in such Sepharose conjugates.…”

Section: Chromatography Experiments With Agarose-conjugated Pep Tide mentioning

confidence: 99%

“…Insoluble peptide conjugates with Sepharose or Sephadex are used in affinity chromatography of macromolecules such as receptors of peptide hormones [l], antibodies directed against peptide antigens [2] or proteolytic enzymes [3]. Soluble peptide-polysaccharide conjugates may be used in studies of the interaction of peptides on a cellular level or in vivo, as recently shown with insulin, bound to soluble dextran of high molecular weight [4]. In peptide hormones, essential biological information may be encoded in the amino-acid sequence near the N-termiAbbreviations.…”

mentioning

confidence: 99%

Preparation of Soluble and Insoluble Polysaccharide Conjugates of Peptides with a Free α‐Amino Group

Jost

Yaron

1974

European Journal of Biochemistry

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Synthetic peptides were covalently attached to Sepharose and water-soluble dextran of high molecular weight. In these polysaccharide conjugates, the bound peptides bear a free a-amino group. The interaction of leucine aminopeptidase with its peptide ligands Thr-Phe-Pro (substrate) or Thr-(But)-Phe-Pro (competitive inhibitor) was strikingly different in soluble dextran conjugates and insoluble Sepharose conjugates of these ligands. The affinity of the enzyme to its inhibitor Thr(Bu')-Phe-Pro was decreased by more than 100-fold upon insolubilization of the peptide on Sepharose. When the peptide was coupled to dextran ofweight-average molecular weight z 500000, the potency of the inhibition was not impaired.Leucine aminopeptidase failed to hydrolyze the Sepharose-bound substrate Thr-Phe-Pro to a measurable extent, but it released N-terminal threonine from the soluble dextran conjugate of this peptide to an extent of at least 38 % of the theory.The interference, caused by the insoluble matrix was hardly overcome, when a new type of spacer, consisting of > 80 m-alanyl residues, was inserted between matrix and ligand. The spacer which is several enzyme subunit diameters in length, gave rise to a small fraction (about 5%) of accessible ligand but did not improve specific interaction to a sufficient extent in order to enable specific binding of leucine aminopeptidase to inhibitor-, or substrate-substituted Sepharoses.

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Dextran-linked insulin: A soluble high molecular weight derivative with biological activity invivo and invitro

Cited by 33 publications

References 7 publications

Humerus of Robust Australopithecus

Humerus of Robust Australopithecus

The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach

Preparation of Soluble and Insoluble Polysaccharide Conjugates of Peptides with a Free α‐Amino Group

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