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Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue.

Werner U, Korn M, Schmidt R, Wendrich TM, Tennagels N - Arch. Physiol. Biochem. (2014)

Bottom Line: Neither analogue stimulated IGF1R phosphorylation.Suprapharmacological doses of D-GLA did not activate IGF1R in vivo.Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.

View Article: PubMed Central - PubMed

Affiliation: R&D Diabetes Division .

ABSTRACT

Context: Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI).

Objective: To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA).

Methods: Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS.

Results: Blood glucose lowering was prolonged with D-GLA. D-GLA comprised ≥98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation.

Conclusions: Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.

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Related in: MedlinePlus

Insulin receptor (IR) phosphorylation in muscle (A, B), liver (C, D), fat (E, F) and heart (G, H) 1 h after s.c. injection of 1, 12.5 or 200 U/kg of (A21Gly,DiD-Arg) insulin (A, C, E, G) or glargine (B, D, F, H) in 8- to 10-week-old male Wistar rats. Values are mean ± SEM (n = 5); *p < 0.05, **p < 0.01 and ***p < 0.001 versus control.
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f3: Insulin receptor (IR) phosphorylation in muscle (A, B), liver (C, D), fat (E, F) and heart (G, H) 1 h after s.c. injection of 1, 12.5 or 200 U/kg of (A21Gly,DiD-Arg) insulin (A, C, E, G) or glargine (B, D, F, H) in 8- to 10-week-old male Wistar rats. Values are mean ± SEM (n = 5); *p < 0.05, **p < 0.01 and ***p < 0.001 versus control.

Mentions: Phosphorylation of receptor signalling molecules was examined 1 h after s.c. injection of 1, 12.5 or 200 U/kg of either glargine or (A21Gly,DiD-Arg) insulin. (A21Gly,DiD-Arg) insulin increased IR phosphorylation in muscle, heart, liver and fat tissue to a similar extent as insulin glargine at all injected doses (Figure 3). Similar results were observed with Akt phosphorylation (Figure 4). Neither (A21Gly,DiD-Arg) insulin nor glargine had any effect on IGF1R phosphorylation at any dose in muscle or heart (Figure 5; see Supplemental figures for blots).Figure 3.


Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue.

Werner U, Korn M, Schmidt R, Wendrich TM, Tennagels N - Arch. Physiol. Biochem. (2014)

Insulin receptor (IR) phosphorylation in muscle (A, B), liver (C, D), fat (E, F) and heart (G, H) 1 h after s.c. injection of 1, 12.5 or 200 U/kg of (A21Gly,DiD-Arg) insulin (A, C, E, G) or glargine (B, D, F, H) in 8- to 10-week-old male Wistar rats. Values are mean ± SEM (n = 5); *p < 0.05, **p < 0.01 and ***p < 0.001 versus control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219851&req=5

f3: Insulin receptor (IR) phosphorylation in muscle (A, B), liver (C, D), fat (E, F) and heart (G, H) 1 h after s.c. injection of 1, 12.5 or 200 U/kg of (A21Gly,DiD-Arg) insulin (A, C, E, G) or glargine (B, D, F, H) in 8- to 10-week-old male Wistar rats. Values are mean ± SEM (n = 5); *p < 0.05, **p < 0.01 and ***p < 0.001 versus control.
Mentions: Phosphorylation of receptor signalling molecules was examined 1 h after s.c. injection of 1, 12.5 or 200 U/kg of either glargine or (A21Gly,DiD-Arg) insulin. (A21Gly,DiD-Arg) insulin increased IR phosphorylation in muscle, heart, liver and fat tissue to a similar extent as insulin glargine at all injected doses (Figure 3). Similar results were observed with Akt phosphorylation (Figure 4). Neither (A21Gly,DiD-Arg) insulin nor glargine had any effect on IGF1R phosphorylation at any dose in muscle or heart (Figure 5; see Supplemental figures for blots).Figure 3.

Bottom Line: Neither analogue stimulated IGF1R phosphorylation.Suprapharmacological doses of D-GLA did not activate IGF1R in vivo.Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.

View Article: PubMed Central - PubMed

Affiliation: R&D Diabetes Division .

ABSTRACT

Context: Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI).

Objective: To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA).

Methods: Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS.

Results: Blood glucose lowering was prolonged with D-GLA. D-GLA comprised ≥98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation.

Conclusions: Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.

Show MeSH
Related in: MedlinePlus