TY - JOUR

T1 - Mass Spectrometry Supports That the Structure of Circulating Human Insulin-Like Factor 3 Is a Heterodimer

AU - Albrethsen, Jakob

AU - Juul, Anders

AU - Andersson, Anna Maria

PY - 2020

Y1 - 2020

N2 - The structure of the testicular peptide hormone insulin-like factor 3 (INSL3) has been the subject of discussion for more than a decade. Some studies support that the central C-domain of INSL3 is proteolytically removed and that INSL3 is secreted by the testicular Leydig cells into circulation as a small heterodimer consisting of an A- and a B-chain linked by two disulfide bridges. Other studies support that the INSL3 peptide remains uncleaved and that the predominant structure of circulating INSL3 is the larger pro-form. Furthermore, the structure of INSL3 could differ between species, and both structural forms of INSL3 could, in principle, be present in circulation. Recently, we have developed a mass spectrometry (MS)-based method for INSL3 in human serum that provides new information about the structure of circulating INSL3. Based on recent and newly presented data, we argue that in healthy men, the common, and probably the only, form of circulating INSL3 is the smaller AB heterodimer. For the first time, we demonstrate that the same analytical principle, with slight modifications, can also be applied to sera from other species, and we show that the INSL3 AB heterodimer is also present in serum from rodents. Improved understanding of the structure and biochemistry of circulating INSL3 could be valuable for the interpretation of INSL3 as a marker for reproductive and developmental disorders in humans and domesticated animals.

AB - The structure of the testicular peptide hormone insulin-like factor 3 (INSL3) has been the subject of discussion for more than a decade. Some studies support that the central C-domain of INSL3 is proteolytically removed and that INSL3 is secreted by the testicular Leydig cells into circulation as a small heterodimer consisting of an A- and a B-chain linked by two disulfide bridges. Other studies support that the INSL3 peptide remains uncleaved and that the predominant structure of circulating INSL3 is the larger pro-form. Furthermore, the structure of INSL3 could differ between species, and both structural forms of INSL3 could, in principle, be present in circulation. Recently, we have developed a mass spectrometry (MS)-based method for INSL3 in human serum that provides new information about the structure of circulating INSL3. Based on recent and newly presented data, we argue that in healthy men, the common, and probably the only, form of circulating INSL3 is the smaller AB heterodimer. For the first time, we demonstrate that the same analytical principle, with slight modifications, can also be applied to sera from other species, and we show that the INSL3 AB heterodimer is also present in serum from rodents. Improved understanding of the structure and biochemistry of circulating INSL3 could be valuable for the interpretation of INSL3 as a marker for reproductive and developmental disorders in humans and domesticated animals.

KW - INSL3

KW - insulin family

KW - LC-MS/MS

KW - peptide hormone

KW - structure

U2 - 10.3389/fendo.2020.00552

DO - 10.3389/fendo.2020.00552

M3 - Journal article

C2 - 32982964

AN - SCOPUS:85090866108

VL - 11

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

SN - 1664-2392

M1 - 552

ER -