Studies on the biological activity of porcine proinsulin

Lazarus, Norman R.; Penhos, J. C.; Tanese, Tomio; Michaels, L.; Gutman, R.; Recant, Lillian

doi:10.1172/jci106258

Cited by 41 publications

(20 citation statements)

References 18 publications

(20 reference statements)

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“…The results obtained are in quite close agreement, indicating a biological potency between 2 and 5% that of insulin. This agrees well with relative potency estimations previously reported in studies in vitro (Steele, Brown & Stone, 1970;Kitabchi, 1970;Toomey et al, 1970), but is somewhat lower than the 12-15% found in vivo (Lazarus et al, 1970;Stoll et al, 1971). It seems probable that this biological action is inherent in the proinsulin molecule since Lazarus et al (1970) failed to find evidence for the conversion of proinsulin into insulin after intravenous administration to rats or incubation with rat hemidiaphragms in vitro.…”

Section: Discussionsupporting

confidence: 90%

“…The opportunity has been taken in the present study to compare the biological potencies of human insulin and porcine proinsulin in relation to their hypoglycaemic effects, since there have been conflicting reports on the biological potency of proinsulin (Toomey, Shaw, Reid & Young, 1970;Kitabachi, 1970;Lazarus, Penhos, Tanese, Michaels, Gutman & Recant, 1970;Fineberg & Merimee, 1970).…”

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confidence: 99%

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A Comparative Study on the Metabolism of Human Insulin and Porcine Proinsulin in Man

et al. 1973

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1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16-21 6 punitslml (insulin) and 4-2-42.8 ng/ml (proinsulin).2. For insulin the MCR fell progressively from 34 ml kg-' min-' at a mean fasting insulin concentration of 3.8 punitslml to 11.4 ml kg-' min-' at the highest concentration achieved (280 punits/ml); for proinsulin MCR averaged 3.7 ml kg -' min-' at a mean plasma concentration of 4.2 ng/ml and fell to 2.71 ml kg-' min-' at 10.7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml.3. The half-disappearance time (T+) from the plasma, after the end of the infusion, averaged 4.3 min for insulin and 25.6 min for proinsulin.4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98.9 ml/kg of proinsulin).5. There was a direct correlation between T+ and DS for both hormones. 6. Although the higher MCR of insulin was reflected in its shorter T+, there was, for each hormone, no relationship between MCR and T+.7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin.8. The responses of serum growth hormone and cortisol were shown to be directly related to the degree of hypoglycaemia induced.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

A Comparative Study on the Metabolism of Human Insulin and Porcine Proinsulin in Man

et al. 1973

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“…These studies have been recently reviewed (3,4). In the circulation, there appears to be negligible conversion of proinsulin to insulin (5)(6)(7)(8)(9), and proinsulin degradation in the liver appears to be independent of any conversion to insulin (10,11). However, such processes operating at the plasma membrane of target cells were specifically not excluded by these studies.…”

Section: Introductionmentioning

confidence: 99%

The Interactions of Proinsulin with Insulin Receptors on the Plasma Membrane of the Liver

Freychet¹

1974

J. Clin. Invest.

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“…Also, human insulin levels measured using ELISA assay in mice injected with AdSsCbdInsF3 were threefold higher compared with those injected with AdSsCbdProins (data not shown). Proinsulin is known to be roughly 5-10% as potent as mature insulin (Shaw & Chance 1968, Lazarus et al 1970.…”

Section: Diabetic Mice Infected With a Construct Designed To Express mentioning

confidence: 99%

Glucose regulates secretion of exogenously expressed insulin from HepG2 cells in vitro and in a mouse model of diabetes mellitus in vivo

Liu¹,

Jia²,

Wanke³

et al. 2013

Journal of Molecular Endocrinology

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Glucose-controlled insulin secretion is a key component of its regulation. Here, we examined whether liver cell secretion of insulin derived from an engineered construct can be regulated by glucose. Adenovirus constructs were designed to express proinsulin or mature insulin containing the conditional binding domain (CBD). This motif binds GRP78 (HSPA5), an endoplasmic reticulum (ER) protein that enables the chimeric hormone to enter into and stay within the ER until glucose regulates its release from the organelle. Infected HepG2 cells expressed proinsulin mRNA and the protein containing the CBD. Immunocytochemistry studies suggested that GRP78 and proinsulin appeared together in the ER of the cell. The amount of hormone released from infected cells varied directly with the ambient concentration of glucose in the media. Glucose-regulated release of the hormone from infected cells was rapid and sustained. Removal of glucose from the cells decreased release of the hormone. In streptozotocin-induced diabetic mice, when infected with adenovirus expressing mature insulin, glucose levels declined. Our data show that glucose regulates release of exogenously expressed insulin from the ER of liver cells. This approach may be useful in devising new ways to treat diabetes mellitus.

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Studies on the biological activity of porcine proinsulin

Cited by 41 publications

References 18 publications

A Comparative Study on the Metabolism of Human Insulin and Porcine Proinsulin in Man

A Comparative Study on the Metabolism of Human Insulin and Porcine Proinsulin in Man

The Interactions of Proinsulin with Insulin Receptors on the Plasma Membrane of the Liver

Glucose regulates secretion of exogenously expressed insulin from HepG2 cells in vitro and in a mouse model of diabetes mellitus in vivo

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