Mechanism

β cell feature mimicked

Description

Reference

Glucose-inducible response elements (GIREs)

Glucose-regulatable transcription

Motifs (CACGTG) that are bound by carbohydrate response element binding protein (ChREBP) in

response to elevated glucose levels

[46] - [51]

Glucose-responsive

promoters

Glucose-regulatable transcription

Promoters with enhanced activity under conditions of elevated glucose (i.e. G6Pase, L-PK, GLUT2, S14)

[47] [48] [51] [109] - [112]

Rapamycin-inducible transcription

Glucose-regulatable transcription

Dimerizer-inducible transcription system that is only active upon administration of rapamycin

[52]

Insulin-responsive promoters

Insulin-regulatable transcription

Promoters with altered activity in the presence of insulin (i.e. G6Pase, IGFBP-1, L-PK, PEPCK, GLUT2, S14)

[47] [48] [51] [109] - [111]

ER-aggregating insulin analogue

Regulated secretory pathway

Insulin analogue accumulates as aggregates in ER until exposure to small molecule that induces protein disaggregation and rapid secretion

[42]

Furin-cleavable mutation

Proinsulin processing

Replacement of two basic pairs of amino acids with furin-cleavable site to allow processing of proinsulin in any cell type

[38] [39]

Single-chain insulin analogue

Proinsulin processing

Replacement of C-peptide with short turn-forming heptapeptide to bypass the necessity for processing by PC1/3 and PC2

[40]

B10 mutation

Insulin stability/bioactivity

Naturally-occurring mutation (His B10 to Asp) on the B-chain of insulin that accumulates 10 - 100-fold more than wild-type insulin

[38] [41]

PTB binding sites

Glucose-regulated control of insulin mRNA stability/translation

Pyrimidine-rich stretch found in the 3’ UTR of

insulin mRNA

[23] [24] [53]