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Effects of Intranasally Administered Insulin and Gangliosides on Metabolic Parameters and Activity of the Hepatic Insulin System in Rats with Type 2 Diabetes Mellitus

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Abstract

Insulin regulates glucose metabolism via both direct hormone interactions with its signaling system and glucose transporters in cells of peripheral tissues and indirectly through the central nervous system. In type 2 diabetes mellitus (T2DM), impaired receptor-mediated transport across the blood–brain barrier leads to insulin deficiency in the brain and causes dysfunctions of eating behavior, thermogenesis, carbohydrate and lipid metabolism. Intranasal insulin (I-I) administration is used as an alternative way of its delivery to increase the hormone level in the brain. A combination of I-I administration with various insulin sensitizers facilitates the restoration of glucose tolerance in a shorter period of time at lower doses of insulin. Such a therapy, combining I-I administration (0.5 IU/rat/day) and intranasally administered total calf brain gangliosides (6 mg/kg/day), was applied here for the first time to treat T2DM rats. Intranasal co-administration of insulin and gangliosides led to the normalization of glucose tolerance in T2DM animals after 4 weeks of treatment, while taken separately, the drugs were less effective. As shown by Western blotting, the increase in hepatic insulin sensitivity may be due to a significant decrease in the expression of a negative insulin signaling regulator protein tyrosine phosphatase 1B (PTP1B) and an increase in the phosphorylation level of the key effector protein kinases Akt at Ser473, GSK3β at Ser9 and p38-MAPK at Thr180/Tyr182. Inhibitory phosphorylation of GSK3β at Ser9 may occur due to the activation of both Akt kinase and p38-MAPK, with the contribution of the latter being, in our opinion, more significant. Since intranasally administered insulin and gangliosides may directly affect brain regions responsible for the regulation of peripheral insulin sensitivity and hepatic carbohydrate metabolism, we concluded that the central mechanism of their action was predominant under conditions used in this study.

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Funding

This work was supported by funding from the Ministry of Science and Higher Education of the Russian Federation to the IEPhB RAS (AAAA-A18-118012290427-7).

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  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    I. O. Zakharova, L. V. Bayunova, K. V. Derkach, I. O. Ilyasov, A. O. Shpakov & N. F. Avrova

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  1. I. O. Zakharova
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  2. L. V. Bayunova
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Contributions

Conceptualization and experimental design (N.F.A., I.O.Z., K.V.D., L.V.B.), data collection (I.O.Z., L.V.B., K.V.D., I.O.I.), data processing (I.O.Z., L.V.B., K.V.D.), writing and editing the manuscript (I.O.Z., A.O.S., L.V.B., N.F.A.).

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Correspondence to I. O. Zakharova.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2022, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2022, Vol. 58, No. 2, pp. 141–154https://doi.org/10.31857/S0044452922020085.

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Zakharova, I.O., Bayunova, L.V., Derkach, K.V. et al. Effects of Intranasally Administered Insulin and Gangliosides on Metabolic Parameters and Activity of the Hepatic Insulin System in Rats with Type 2 Diabetes Mellitus. J Evol Biochem Phys 58, 380–394 (2022). https://doi.org/10.1134/S0022093022020077

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