Insulinomas and expression of an insulin splice variant

Alexandra H. Minn, Mark Kayton, Dominique Lorang, Steven C. Hoffmann, David M. Harlan, Steven K. Libutti, Anath Shalev

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: Insulinomas are β-cell tumours characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. However, the mechanisms allowing such excessive insulin secretion are not known. Insulin secretion can occur only when the β-cell insulin stores have been replenished by insulin biosynthesis, which is mainly controlled by translation. Such specific translational regulation often involves the 5′ untranslated region. We have identified an insulin splice variant in isolated human pancreatic islets of non-diabetic donors that retains 26 bp of intron 1 and thereby changes the 5′ untranslated region, but leaves the coding region unchanged. This splice variant has increased translation efficiency in vitro and in vivo compared with native insulin mRNA. However, splice variant expression is less than 1% of native insulin mRNA in normal islets. Methods: To test whether this splice variant is involved in insulin production by human insulinomas, we extracted RNA from nine laser-captured surgical insulinoma samples and from isolated islets of nine donors who did not have diabetes. We then determined the ratio of splice variant to native insulin mRNA by quantitative real-time RT-PCR. Findings: The mean ratio of the splice variant to native insulin mRNA was increased more than 50-fold in insulinomas compared with normal islets, and this difference was present in all nine human insulinomas. Overexpression of the splice variant therefore seems to be a general characteristic of insulinomas and is estimated to contribute about 90% to insulin synthesis by these tumours. Interpretation: Overexpression of the insulin splice variant with increased translation efficiency in insulinomas might explain how these tumours maintain high levels of insulin synthesis and secretion leading to hyperinsulinaemia - the hallmark of this disease.

Original languageEnglish (US)
Pages (from-to)363-367
Number of pages5
JournalLancet
Volume363
Issue number9406
DOIs
StatePublished - Jan 31 2004
Externally publishedYes

Fingerprint

Insulinoma
Insulin
Messenger RNA
5' Untranslated Regions
Neoplasms
Hyperinsulinism
Islets of Langerhans
Hypoglycemia
Introns
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Minn, A. H., Kayton, M., Lorang, D., Hoffmann, S. C., Harlan, D. M., Libutti, S. K., & Shalev, A. (2004). Insulinomas and expression of an insulin splice variant. Lancet, 363(9406), 363-367. https://doi.org/10.1016/S0140-6736(04)15438-X

Insulinomas and expression of an insulin splice variant. / Minn, Alexandra H.; Kayton, Mark; Lorang, Dominique; Hoffmann, Steven C.; Harlan, David M.; Libutti, Steven K.; Shalev, Anath.

In: Lancet, Vol. 363, No. 9406, 31.01.2004, p. 363-367.

Research output: Contribution to journalArticle

Minn, AH, Kayton, M, Lorang, D, Hoffmann, SC, Harlan, DM, Libutti, SK & Shalev, A 2004, 'Insulinomas and expression of an insulin splice variant', Lancet, vol. 363, no. 9406, pp. 363-367. https://doi.org/10.1016/S0140-6736(04)15438-X
Minn AH, Kayton M, Lorang D, Hoffmann SC, Harlan DM, Libutti SK et al. Insulinomas and expression of an insulin splice variant. Lancet. 2004 Jan 31;363(9406):363-367. https://doi.org/10.1016/S0140-6736(04)15438-X
Minn, Alexandra H. ; Kayton, Mark ; Lorang, Dominique ; Hoffmann, Steven C. ; Harlan, David M. ; Libutti, Steven K. ; Shalev, Anath. / Insulinomas and expression of an insulin splice variant. In: Lancet. 2004 ; Vol. 363, No. 9406. pp. 363-367.
@article{51c252a879a64e7fbda7d27c7b5d4abe,
title = "Insulinomas and expression of an insulin splice variant",
abstract = "Background: Insulinomas are β-cell tumours characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. However, the mechanisms allowing such excessive insulin secretion are not known. Insulin secretion can occur only when the β-cell insulin stores have been replenished by insulin biosynthesis, which is mainly controlled by translation. Such specific translational regulation often involves the 5′ untranslated region. We have identified an insulin splice variant in isolated human pancreatic islets of non-diabetic donors that retains 26 bp of intron 1 and thereby changes the 5′ untranslated region, but leaves the coding region unchanged. This splice variant has increased translation efficiency in vitro and in vivo compared with native insulin mRNA. However, splice variant expression is less than 1{\%} of native insulin mRNA in normal islets. Methods: To test whether this splice variant is involved in insulin production by human insulinomas, we extracted RNA from nine laser-captured surgical insulinoma samples and from isolated islets of nine donors who did not have diabetes. We then determined the ratio of splice variant to native insulin mRNA by quantitative real-time RT-PCR. Findings: The mean ratio of the splice variant to native insulin mRNA was increased more than 50-fold in insulinomas compared with normal islets, and this difference was present in all nine human insulinomas. Overexpression of the splice variant therefore seems to be a general characteristic of insulinomas and is estimated to contribute about 90{\%} to insulin synthesis by these tumours. Interpretation: Overexpression of the insulin splice variant with increased translation efficiency in insulinomas might explain how these tumours maintain high levels of insulin synthesis and secretion leading to hyperinsulinaemia - the hallmark of this disease.",
author = "Minn, {Alexandra H.} and Mark Kayton and Dominique Lorang and Hoffmann, {Steven C.} and Harlan, {David M.} and Libutti, {Steven K.} and Anath Shalev",
year = "2004",
month = "1",
day = "31",
doi = "10.1016/S0140-6736(04)15438-X",
language = "English (US)",
volume = "363",
pages = "363--367",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9406",

}

TY - JOUR

T1 - Insulinomas and expression of an insulin splice variant

AU - Minn, Alexandra H.

AU - Kayton, Mark

AU - Lorang, Dominique

AU - Hoffmann, Steven C.

AU - Harlan, David M.

AU - Libutti, Steven K.

AU - Shalev, Anath

PY - 2004/1/31

Y1 - 2004/1/31

N2 - Background: Insulinomas are β-cell tumours characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. However, the mechanisms allowing such excessive insulin secretion are not known. Insulin secretion can occur only when the β-cell insulin stores have been replenished by insulin biosynthesis, which is mainly controlled by translation. Such specific translational regulation often involves the 5′ untranslated region. We have identified an insulin splice variant in isolated human pancreatic islets of non-diabetic donors that retains 26 bp of intron 1 and thereby changes the 5′ untranslated region, but leaves the coding region unchanged. This splice variant has increased translation efficiency in vitro and in vivo compared with native insulin mRNA. However, splice variant expression is less than 1% of native insulin mRNA in normal islets. Methods: To test whether this splice variant is involved in insulin production by human insulinomas, we extracted RNA from nine laser-captured surgical insulinoma samples and from isolated islets of nine donors who did not have diabetes. We then determined the ratio of splice variant to native insulin mRNA by quantitative real-time RT-PCR. Findings: The mean ratio of the splice variant to native insulin mRNA was increased more than 50-fold in insulinomas compared with normal islets, and this difference was present in all nine human insulinomas. Overexpression of the splice variant therefore seems to be a general characteristic of insulinomas and is estimated to contribute about 90% to insulin synthesis by these tumours. Interpretation: Overexpression of the insulin splice variant with increased translation efficiency in insulinomas might explain how these tumours maintain high levels of insulin synthesis and secretion leading to hyperinsulinaemia - the hallmark of this disease.

AB - Background: Insulinomas are β-cell tumours characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. However, the mechanisms allowing such excessive insulin secretion are not known. Insulin secretion can occur only when the β-cell insulin stores have been replenished by insulin biosynthesis, which is mainly controlled by translation. Such specific translational regulation often involves the 5′ untranslated region. We have identified an insulin splice variant in isolated human pancreatic islets of non-diabetic donors that retains 26 bp of intron 1 and thereby changes the 5′ untranslated region, but leaves the coding region unchanged. This splice variant has increased translation efficiency in vitro and in vivo compared with native insulin mRNA. However, splice variant expression is less than 1% of native insulin mRNA in normal islets. Methods: To test whether this splice variant is involved in insulin production by human insulinomas, we extracted RNA from nine laser-captured surgical insulinoma samples and from isolated islets of nine donors who did not have diabetes. We then determined the ratio of splice variant to native insulin mRNA by quantitative real-time RT-PCR. Findings: The mean ratio of the splice variant to native insulin mRNA was increased more than 50-fold in insulinomas compared with normal islets, and this difference was present in all nine human insulinomas. Overexpression of the splice variant therefore seems to be a general characteristic of insulinomas and is estimated to contribute about 90% to insulin synthesis by these tumours. Interpretation: Overexpression of the insulin splice variant with increased translation efficiency in insulinomas might explain how these tumours maintain high levels of insulin synthesis and secretion leading to hyperinsulinaemia - the hallmark of this disease.

UR - http://www.scopus.com/inward/record.url?scp=0842283233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0842283233&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(04)15438-X

DO - 10.1016/S0140-6736(04)15438-X

M3 - Article

C2 - 15070567

AN - SCOPUS:0842283233

VL - 363

SP - 363

EP - 367

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9406

ER -