Inhibition of insulin degradation by nonsuppressible insulin-like activity.

Burghen, George A.; Duckworth, William C.; Kitabchi, Abbas E.; Solomon, Sidney; Poffenbarger, Phillip L.

doi:10.1172/jci108352

Cited by 22 publications

(9 citation statements)

References 17 publications

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“…Insulin protease, or insulinase as described originally by Mirsky (24), is a proteolytic enzyme which is found primarily in the soluble fraction of the cell (7,12,25). The general characteristics of the membrane enzyme, both liver (1,13,26) and kidney (27), closely resemble the properties described for insulin protease, but the presence of glutathione insulin transhydrogenase on the membrane has also been reported (23).…”

Section: Discussionmentioning

confidence: 90%

Insulin Degradation by Liver Cell Membranes*

Duckworth

1979

Endocrinology

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Liver cell membranes actively degrade insulin, but the mechanism for this process has not been established. Exposure of [ 125 I]iodoinsulin for various times to a liver cell membrane preparation enriched in blood sinusoidal surfaces resulted in the generation of labeled products of varying sizes.Separation of these products on a molecular sieve column demonstrated a progressive decrease in 125 I-labeled material eluting in the insulin peak and an increase in both larger and smaller molecular weight materials. The latter could be separated into at least three distinct peaks. In addition, the material eluting in the insulin peak had a decreased immunoprecipitability, suggesting that this peak was also heterogeneous. The l25 I-labeled material extracted from the membranes eluted from the molecular sieve column predominantly in the void volume and in the insulin peak. There was an increase with time in the larger molecular weight fraction.The liver membrane insulin-degrading activity was characterized by polyacrylamide gel electrophoresis after solubilization by Triton X-100. Only one area of insulin-degrading activity was found. This activity had a mobility identical with the mobility of purified insulin protease and distinctly different from that of purified glutathione insulin transhydrogenase. Furthermore, no glutathione insulin transhydrogenase activity could be demonstrated using an assay specific for that enzyme. Thus, the insulindegrading activity of liver cell membranes appears to be due to the proteolytic enzyme insulin protease. (Endocrinology 104: 1758, 1979)

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Section: Discussionmentioning

confidence: 90%

Insulin Degradation by Liver Cell Membranes*

Duckworth

1979

Endocrinology

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“…the isolated rat adipocyte, rat costal cartilage and human fibroblast systems respectively, is given in (Burghen et al, 1976;Kahn et al, 1976). Fig.…”

Section: Resultsmentioning

confidence: 99%

Insulin-like growth factor characteristics of an acidic non-suppressible insulin-like activity

Herington¹,

Kuffer²

1984

Biochemical Journal

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The biological activities of an acidic form of non-suppressible insulin-like activity (ILA pI 4.8) have been studied. ILA pI 4.8 was isolated from Cohn fraction IV-1 of human serum by pH 5.5 ion-exchange chromatography on SP-Sephadex. Carrier-bound ILA was eluted at pH 9.7 and then sequentially gel chromatographed in 1% formic acid on Sephadex G-75 and Bio-Gel P-30. The low-Mr (7000) active material was subjected to flat bed isoelectric focusing. Overall recovery was 87 munit of insulin equivalents/100 g of Cohn fraction IV-1, with a specific activity in the range 4-10 munit/mg of protein, representing a purity of 1-6%. This material has been tested in a variety of insulin-like growth factor (IGF)/somatomedin assay systems. It stimulated, in a dose-related manner, [14C]glucose conversion into lipid by isolated rat adipocytes, 35SO4(2-) incorporation into weanling rat costal cartilage and [3H]thymidine incorporation into DNA of cultured human fibroblasts. Like IGF-I and -II, ILA pI 4.8 was able to inhibit degradation of 125I-insulin by crude homogenates of rat liver. In addition, the biological activity of ILA pI 4.8 was completely suppressible by a recently described inhibitor of IGF-I and IGF-II. ILA pI 4.8 was able to compete, in a parallel manner, with 125I-IGF-I and 125I-IGF-II and, at higher doses, with 125I-insulin in a placental radioreceptor assay. No cross-reactivity was seen in a radioimmunoassay for IGF-I and -II C-peptides, but at higher concentrations parallel displacement was observed in a somatomedin C/IGF-I radioimmunoassay using two different antisera. These data indicate that ILA pI 4.8 does possess many of the biological activities previously reported for the IGFs. Since ILA pI 4.8 does occur naturally in serum, it would appear reasonable to tentatively include it as one of the IGF/somatomedin family.

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“…One of the lines of evidence strongly supporting this sequence of events-receptor binding, internalization, degradation-was the demonstration by autoradiography of uptake of 125 I-labeled insulin. This was first shown (10, 11) in cultured human lymphocytes, the I M-9 line, which has been used extensively to study insulin binding. At 15 C Ihe [ 125 I]insulin remained localized to the plasma membrane area, but at 37 C there was a shift of the autoradiographic grains to within the cell.…”

Section: A the Relationship Between Binding And Degradationmentioning

confidence: 88%

“…At 15 C Ihe [ 125 I]insulin remained localized to the plasma membrane area, but at 37 C there was a shift of the autoradiographic grains to within the cell. One group (11) found that the grains remained relatively close to the surface of the cell (10-15% of the radius of the cell) and did not appear to be preferentially localized to any subcellular organelle. The other study (10) found that the radioactivity appeared to localize to the nuclei.…”

Section: A the Relationship Between Binding And Degradationmentioning

confidence: 99%

“…From studies using various species of labeled insulin, insulin-receptor complexes cluster on the surface of the cell and are then internalized (11,20,(32)(33)(34)(35). The exact process varies from cell type to cell type, and the involvement of so-called "coated pits," which are important in the cellular uptake of other receptor bound ligands (36, 37), is controversial.…”

Section: A the Relationship Between Binding And Degradationmentioning

confidence: 99%

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