802-P: Beneficial Effects of a Functionally Selective Insulin on Vascular Function and Liver Triglycerides

802-P: Beneficial Effects of a Functionally Selective Insulin on Vascular Function and Liver Triglycerides

Selective insulin resistance, where insulin's ability to lower blood glucose via the Akt signaling pathway gradually decreases while retaining its effectiveness in activating other signaling pathways (e.g. MAPK), is a key pathophysiological mechanism underlying the hyperglycemia, dyslipidemia a...

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Published in:Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
Main Authors: OLSEN, GRITH S., PEDERSEN, THOMAS A., SLAABY, RITA, HANSEN, BO F., GLENDORF, TINE, DEMOZAY, DAMIEN, HVID, HENNING, NISHIMURA, ERICA, BRANDT, JAKOB, POVLEN, GRO
Format: Journal Article
Language:English
Published: New York American Diabetes Association 20-06-2023
Subjects:
Adipocytes
AKT protein
Amino acids
Arterioles
Cardiovascular diseases
Diabetes mellitus (non-insulin dependent)
Dyslipidemia
Glucose
Glycogen
Hepatocytes
Hyperglycemia
Insulin resistance
Lipogenesis
Lipolysis
Liver
MAP kinase
mRNA
Signal transduction
Triglycerides
Vasodilation
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Summary:Selective insulin resistance, where insulin's ability to lower blood glucose via the Akt signaling pathway gradually decreases while retaining its effectiveness in activating other signaling pathways (e.g. MAPK), is a key pathophysiological mechanism underlying the hyperglycemia, dyslipidemia and vascular dysfunction in type 2 diabetes (T2D). Here we hypothesize that a selective signaling insulin analog that activates Akt signaling but has a considerably reduced effect on MAPK should counteract selective insulin resistance and provide effective glucose lowering with improved vascular function, reduced hepatic lipid accumulation and generally alleviate insulin resistance over time compared to human insulin (HI). NNC-965, a basal insulin analog with 4 amino acid modifications and a C18 fatty diacid, was designed as a functionally selective insulin, with greater Akt than MAPK activation in several cellular systems and in vivo. NNC-965 fully activates glucose regulating pathways, including inhibition of glucose output, glycogen accumulation and inhibition of gluconeogenic mRNAs in rat hepatocytes as well as stimulation of glucose uptake and inhibition of lipolysis in rat adipocytes. In contrast, NNC-965 displayed reduced induction of lipogenic mRNA and de novo lipogenesis in rat liver cells compared to HI. In a mouse model of T2D, treatment with NNC-965 for 6 weeks to the same glucose level as insulin 700 (an insulin degludec-like analog) resulted in 35% less liver triglycerides and improved acetylcholine mediated vasodilation in ex vivo studies using mesenteric arterioles. In conclusion, NNC-965 is a novel functionally selective insulin analog that can potentially improve insulin resistance and eventually reduce cardiovascular risk by restoring balanced insulin signaling. Disclosure G.S.Olsen: Employee; Novo Nordisk A/S. G.Povlen: Employee; Novo Nordisk. T.A.Pedersen: Employee; Novo Nordisk A/S. R.Slaaby: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. B.F.Hansen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. T.Glendorf: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. D.Demozay: None. H.Hvid: Employee; Novo Nordisk A/S. E.Nishimura: Employee; Novo Nordisk A/S. J.Brandt: Employee; Novo Nordisk A/S.
ISSN:0012-1797
1939-327X
DOI:10.2337/db23-802-P