TY - JOUR
T1 - Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond
AU - Ong, Shee Chee
AU - Belgi, Alessia
AU - Merriman, Allanah L.
AU - Delaine, Carlie A.
AU - van Lierop, Bianca
AU - Andrikopoulos, Sofianos
AU - Robinson, Andrea J.
AU - Forbes, Briony E.
PY - 2022/6/27
Y1 - 2022/6/27
N2 - The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6–A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
AB - The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6–A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
KW - biased signalling agonists
KW - cell signalling
KW - dicarba insulin
KW - extracellular-signal-regulated kinase (ERK)
KW - glucose metabolism
KW - insulin
KW - insulin receptor
KW - mitogenic
UR - http://www.scopus.com/inward/record.url?scp=85133932985&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/ARC/LP120200792
UR - http://purl.org/au-research/grants/NHMRC/1069328
U2 - 10.3389/fendo.2022.907864
DO - 10.3389/fendo.2022.907864
M3 - Article
AN - SCOPUS:85133932985
SN - 1664-2392
VL - 13
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 907864
ER -