The Metabolism of Proinsulin and Insulin by the Liver

Rubenstein, Arthur H.; Pottenger, Lawrence A.; Mako, Mary E.; Getz, Godfrey S.; Steiner, D F

doi:10.1172/jci106886

Cited by 159 publications

(75 citation statements)

References 45 publications

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“…Being weakly extracted by specific receptors, circulating HPI is essentially cleared by the kidneys [33][34][35]. Actually, scintigraphic images obtained after injection of 123 I-HPI are very similar to those obtained after injection of 123 I-insulin into rats whose receptor compartment has been fully occupied by "cold'" ligand or blocked by specific anti-receptor antibodies [19,31].…”

Section: Discussionmentioning

confidence: 95%

Scintigraphic distribution of 123 I labelled proinsulin, split conversion intermediates and insulin in rats

et al. 1988

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Summary. Insulin, biosynthetic human proinsulin and 2 human proinsulin conversion intermediates, des (64, 65) human proinsulin and des (31, 32) human proinsulin, were labelled with 123 I and the derivatives monosubstituted on Tyr A14 were purified by reverse phase high performance liquid chromatography. The four tracers were injected into anaesthetized rats via a jugular or a portal vein and time activity curves were generated for the liver and kidneys using a gamma camera and an online computer. Liver extraction coefficients varied in the order insulin (38%), des (64, 65) human proinsulin (11.7%), des (31, 32) human proinsulin (3.2%), human proinsulin (1.6%); whereas half-life of hepatic activity varied in the reverse order, from 6 rain for insulin, to 45 min for human proinsulin. As expected for a non-receptor mediated process, kidney extraction varied conversely to liver extraction, being highest for human proinsulin and lowest for insulin. It is concluded that the kinetics of human proinsulin conversion intermediates depends upon the site of cleavage and deletion and is intermediate between those of insulin and intact human proinsulin.Key words: Biosynthetic human proinsulin, conversion intermediates, 123-I-labelling, scintillation scanning.Most of proinsulin is converted to insulin inside the B cells of the pancreas, a process resulting from the interplay of several endopeptidases, different from trypsin itself [1][2][3]. Recently, two distinct site-specific endopeptidases regulated by calcium concentration and pH were identified in a B granule fraction of rat insulinoma [4]. During proinsulin processing, conversion intermediates are formed, in particular the split products des (64, 65) human proinsulin (HPI) and des (31, 32) HPI. These intermediates and intact HPI have been found in human sera [5], in insulin producing islet cell tumours [6-81 and in familial hyperproinsulinaemia [9-111. Conversion to intermediates or insulin does not seem to occur after proinsulin enters the blood stream; partial conversion to intermediates might occur in the skin after subcutaneous injection [121.From the standpoint of biological activity, proinsulin has remarkable characteristics. Compared to insulin, HPI has a low biological potency, a low avidity for insulin receptors and a prolonged half-life [13][14][15][16][17]. Moreover, the proinsulin conversion intermediates have been shown to exhibit greater biological activity than proinsulin itself, and this is particularly true for the conversion intermediate in which the C peptide/A chain bond has been cleaved. Peavy et al. demonstrated that cleavage and/or dibasic amino acid deletions in the connecting peptide region of proinsulin enhance the receptor binding and hypoglycaemic activities of these compounds. In these studies, C peptide/A chain split products exhibited greater receptor affinity and hypoglycaemic activity than B chain C peptide split intermediates [18]. These observations prompted us to investigate the hepatic extraction and processing of HPI and its conver...

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Section: Discussionmentioning

confidence: 95%

Scintigraphic distribution of 123 I labelled proinsulin, split conversion intermediates and insulin in rats

et al. 1988

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“…This phenomenon in thyrotoxic patients was observed in the fasting state and also during both oral and IV glucose tolerance tests. Thus, in hyperthyroidism it could be argued that the pancreatic B cell has an increased capacity to secrete proinsulin compared with the euthyroid state, and proinsulin is circulating in high concentrations because of the relatively slow rate of proinsulin removal [15,16]. In contrast to insulin independent diabetes, where the fasting proinsulin concentration is also increased [17], the concentration of proinsulin in thyrotoxicosis is frequently so high that it is in the range which is considered characteristic of patients with insulinomas [14,18].…”

Section: Discussionmentioning

confidence: 99%

Hypersecretion of proinsulin in thyrotoxicosis

Sestoft

Hedïng

1981

Diabetologia

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Summary. The plasma insulin, C-peptide and proinsulin concentrations were investigated in thyrotoxic patients and in normal controls after an overnight fast, during a 36 h fasting period, an intravenous glucose tolerance test and an oral glucose tolerance test. The main finding was a significantly raised concentration of proinsulin in plasma of patients with thyrotoxicosis. After an overnight fast the plasma proinsulin was 0.048 + 0.005 pmol/ml in 15 thyrotoxic patients compared with 0.023 _ 0.012 pmol/ml in 15 euthyroid controls. A twofold rise of plasma proinsulin concentration was also found in thyrotoxic patients during a prolonged fast, and during intravenous and oral glucose tolerance tests. The immunoreactivity of proinsulin in the insulin radioimmunoassay gave rise to slightly elevated concentrations of immunoreactive insulin in thyrotoxic patients in all the conditions investigated. When insulin values were corrected for proinsulin crossreactivity, they were similar in euthyroid controls and thyrotoxic patients. The concentration of plasma Cpeptide was not significantly altered in thyrotoxic patients during intravenous and oral glucose tolerance tests.

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“…However, the liver is the main site of insulin clearance, removing approximately 75% of the insulin during the first portal passage [23]. Few reports have been published concerning the functional regulation of IDE in the liver or in liver cells [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

et al. 2009

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Aims/hypothesis Hepatic insulin degradation decreases in type 2 diabetes. Insulin-degrading enzyme (IDE) plays a key role in insulin degradation and its gene is located in a diabetes-associated chromosomal region. We hypothesised that IDE may be regulated by insulin and/or glucose in a liver cell model. To validate the observed regulation of IDE in vivo, we analysed biopsies of human adipose tissue during different clamp experiments in men. Methods Human hepatoma HepG2 cells were incubated in normal (1 g/l) or high (4.5 g/l) glucose medium and treated with insulin for 24 h. Catalytic activity, mRNA and protein levels of IDE were assessed. IDE mRNA levels were measured in biopsies of human subcutaneous adipose tissue before and at 240 min of hyperinsulinaemic, euglycaemic and hyperglycaemic clamps. Results In HepG2 cells, insulin increased IDE activity under normal glucose conditions with no change in IDE mRNA or protein levels. Under conditions of high glucose, insulin increased mRNA levels of IDE without changes in IDE activity. Both in normal and high glucose medium, insulin increased levels of the catalytically more active 15a IDE isoform compared with the 15b isoform. In subcutaneous adipose tissue, IDE mRNA levels were not significantly upregulated after euglycaemic or hyperglycaemic clamps. Conclusions/interpretation Insulin increases IDE activity in HepG2 cells in normal but not in high glucose conditions. This disturbance cannot be explained by corresponding alterations in IDE protein levels or IDE splicing. The loss of insulin-induced regulation of IDE activity under hyperglycaemia may contribute to the reduced insulin extraction and peripheral hyperinsulinaemia in type 2 diabetes.

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The Metabolism of Proinsulin and Insulin by the Liver

Cited by 159 publications

References 45 publications

Scintigraphic distribution of 123 I labelled proinsulin, split conversion intermediates and insulin in rats

Scintigraphic distribution of 123 I labelled proinsulin, split conversion intermediates and insulin in rats

Hypersecretion of proinsulin in thyrotoxicosis

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

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