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C-Peptide and Insulin during Combined Intranasal Administration Improve the Metabolic Parameters and Activity of the Adenylate Cyclase System in the Hypothalamus, Myocardium, and Epididymal Fat of Rats with Type 2 Diabetes

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Abstract—

C-peptide, a product of proinsulin proteolysis, regulates physiological and biochemical processes by increasing the bioavailability of insulin due to the formation of complexes and also by binding to C-peptide receptors. Under insulin deficiency in severe forms of type 2 diabetes mellitus (DM), the levels of C-peptide and insulin in the brain, the target of their action, are decreased. This deficit can be compensated by intranasally administered C-peptide (IACP) and insulin (IAI). It is assumed that the administration of IACP and IAI in type 2 diabetes will lead to the normalization of the activity of the adenylate cyclase signal system (ACSS) in the hypothalamus and on the periphery and will provide, thereby, a therapeutic effect of IACP and IAI. The aim of the work was to study the effect of a 9-day treatment of 4-month-old male rats with the neonatal model of type 2 diabetes with IACP (at a daily dose of 10 μg per animal) and IAI (at a daily dose of 20 μg per animal) under their combined and separate administration on metabolic and hormonal indicators and the activity of ACSS in the hypothalamus, myocardium and epididymal fat (EF). The treatment of diabetic rats with IAI and IACP + IAI weakened hyperglycemia and insulin resistance, improved lipid metabolism and decreased atherogenic index. In the hypothalamus, the regulation of adenylate cyclase (AC) activity by MC4-melanocortin and D2-dopamine receptor agonists weakened in type 2 diabetes was restored. In the myocardium and EF, the restoration of stimulating effects of β1/β2- and β3-adrenoreceptor agonists on the AC activity were noted, which indicates an improvement in hormonal regulation of the cardiovascular system and lipolytic processes in the adipose tissue. The combined use of IACP + IAI was more effective than the IAI monotherapy, which evidences an increase in the regulatory effects of insulin in the presence of C-peptide. The treatment of diabetic rats with IACP was not very effective. The obtained results suggest the prospects for the combined use of equimolar amounts of IACP and IAI for the correction of metabolic and functional disorders in severe forms of type 2 diabetes.

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REFERENCES

  1. Altan, V.M., Arioglu, E., Guner, S., and Ozcelikay, A.T., The influence of diabetes on cardiac B-adrenoceptor subtypes, Heart Fail. Rev., 2007, vol. 12, pp. 58–65.

    Article  CAS  PubMed  Google Scholar 

  2. Chistyakova, O.V., Bondareva, V.M., Shipilov, V.N., Sukhov, I.B., and Shpakov, A.O., Intranasal administration of insulin eliminates the deficit of long-term spatial memory in rats with neonatal diabetes mellitus, Dokl. Biochem. Biophys., 2011, vol. 440, pp. 216–218.

    Article  CAS  PubMed  Google Scholar 

  3. Derkach, K.V., Chistyakova, O.V., and Shpakov, A.O., A change of hormonal regulation of adenylyl cyclase in epididymal adipose tissue of rats with experimental models of diabetes mellitus, J. Evol. Biochem. Physiol., 2014, vol. 50, no. 2, pp. 95–102.

    Article  CAS  Google Scholar 

  4. Derkach, K.V., Bogush, I.V., Berstein, L.M., and Shpakov, A.O., The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats, Horm. Metab. Res., 2015a, vol. 47, pp. 916–924.

    Article  CAS  PubMed  Google Scholar 

  5. Derkach, K.V., Bondareva, V.M., Chistyakova, O.V., Berstein, L.M., and Shpakov, A.O., The effect of long-term intranasal serotonin treatment on metabolic parameters and hormonal signaling in rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes, Int. J. Endocrinol., 2015b, vol. 2015, p. 245459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Derkach, K.V., Bondareva, V.M., Moiseyuk, I.V., and Shpakov, A.O., The effect of 2-month bromocriptine treatment on the activity of the adenylate cyclase signaling system in the myocardium and testes of rats with type 2 diabetes, Cell Tissue Biol., 2015c, vol. 9, no. 5, pp. 395–405.

    Article  Google Scholar 

  7. Derkach, K.V., Sukhov, I.B., Kuznetsova, L.A., Buzanakov, D.M., and Shpakov, A.O., The functional activity of hypothalamic signaling systems in rats with neonatal diabetes mellitus treated with metformin, Dokl. Biochem. Biophys., 2016, vol. 467, pp. 95–98.

    Article  CAS  PubMed  Google Scholar 

  8. Derkach, K.V., Bondareva, V.M., and Shpakov, A.O., Coadministration of intranasally delivered insulin and proinsulin C-peptide to rats with the types 1 and 2 diabetes mellitus restores their metabolic parameters, Adv. Gerontol., 2018, vol. 8, pp. 139–146.

    Google Scholar 

  9. Heni, M., Kullmann, S., Ketterer, C., Guthoff, M., Linder, K., Wagner, R., Stingl, K.T., Veit, R., Staiger, H., Häring, H.U., Preissl, H., and Fritsche, A., Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions, Diabetologia, 2012, vol. 55, pp. 1773–1782.

    Article  CAS  PubMed  Google Scholar 

  10. Kleinridders, A., Ferris, H.A., Cai, W., and Kahn, C.R., Insulin action in brain regulates systemic metabolism and brain function, Diabetes, 2014, vol. 63, pp. 2232–2243.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kolar, G.R, Grote, S.M, and Yosten, G.L., Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146, J. Int. Med., 2017, vol. 281, pp. 25–40.

    Article  CAS  Google Scholar 

  12. Landreh, M., Johansson, J., and Jörnvall, H., C-peptide: a molecule balancing insulin states in secretion and diabetes-associated depository conditions, Horm. Metab. Res., 2013, vol. 45, pp. 769–773.

    Article  CAS  PubMed  Google Scholar 

  13. Novak, V., Milberg, W., Hao, Y., Munshi, M., Novak, P., Galica, A., Manor, B., Roberson, P., Craft, S., and Abduljalil, A., Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes, Diabetes Care, 2014, vol. 37, pp. 751–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pinger, C.W., Entwistle, K.E., Bell, T.M., Liu, Y., and Spence, D.M., C-peptide replacement therapy in type 1 diabetes: are we in the trough of disillusionment?, Mol. Biosyst., 2017, vol. 13, pp. 1432–1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shafqat, J., Melles, E., Sigmundsson, K., Johansson, B.L., Ekberg, K., Alvelius, G., Henriksson, M., Johansson, J., Wahren, J., and Jörnvall, H., Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects, Cell Mol. Life Sci., 2006, vol. 63, pp. 1805–1811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shpakov, A.O., The role of alterations in the brain signaling systems regulated by insulin, IGF-1 and leptin in the transition of impaired glucose tolerance to overt type 2 diabetes mellitus, Tsitologiia, 2014, vol. 56, no. 11, pp. 789–799.

    CAS  PubMed  Google Scholar 

  17. Shpakov, A.O., New achievements in the study of the mechanisms and targets of action of proinsulin C-peptide, Tsitologiia, 2015, vol. 57, no. 6, pp. 405–414.

    CAS  PubMed  Google Scholar 

  18. Shpakov, A.O., Mechanisms of action and therapeutic potential of proinsulin C-peptide, J. Evol. Biochem. Physiol., 2017, vol. 53, no. 3, pp. 180–190.

    Article  CAS  Google Scholar 

  19. Shpakov, A.O. and Derkach, K.V., The functional state of hormone-sensitive adenylyl cyclase signaling system in diabetes mellitus, J. Signal Transduction, 2013, vol. 2013, p. 594213.

    Article  CAS  Google Scholar 

  20. Shpakov, A.O. and Derkach, K.V., Gormonal’nye sistemy mozga i sakharnyi diabet 2 tipa (The Brain Hormonal Systems and Type 2 Diabetes Mellitus), St. Petersburg: Polytekh. Univ., 2015.

  21. Shpakov, A.O. and Granstrem, A.O., C-peptide structure, functions and molecular mechanisms of action, Tsitologiia, 2013, vol. 55, no. 1, pp. 16–27.

    CAS  PubMed  Google Scholar 

  22. Shpakov, A., Chistyakova, O., Derkach, K., and Bondareva, V., Hormonal signaling systems of the brain in diabetes mellitus, in Neurodegenerative Diseases, Chang, R. C.-C., Ed., Rijeka, Croatia: Intech Open Access Publ., 2011, pp. 349–386.

  23. Shpakov, A.O., Chistyakova, O.V., Derkach, K.V., Moiseyuk, I.V., and Bondareva, V.M., Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes, Central Eur. J. Biol., 2012, vol. 7, pp. 33–47.

    CAS  Google Scholar 

  24. Shpakov, A.O., Derkach, K.V., Chistyakova, O.V., Moiseyuk, I.V., Sukhov, I.B., and Bondareva, V.M., Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus, J. Evol. Biochem. Physiol., 2013, vol. 49, no. 2, pp. 153–164.

    Article  CAS  Google Scholar 

  25. Shpakov, A.O., Derkach, K.V., and Berstein, L.M., Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases, Future Science OA (FSO), 2015, vol. 1, no. 3, p. FSO25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sukhov, I.B., Derkach, K.V., Chistyakova, O.V., Bondareva, V.M. and Shpakov, A.O., Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin, J. Evol. Biochem. Physiol., 2016, vol. 52, no. 3, pp. 204–216.

    Article  CAS  Google Scholar 

  27. Vasic, D. and Walcher, D., Proinflammatory effects of C-peptide in different tissues, Int. J. Inflam., 2012, vol. 2012, p. 932 725.

    Article  CAS  Google Scholar 

  28. Wahren, J., Kallas, A., and Sima, A.A., The clinical potential of C-peptide replacement in type 1 diabetes, Diabetes, 2012, vol. 61, pp. 761–772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Walcher, D. and Marx, N., C-peptide in the vessel wall, Rev. Diabet. Stud., 2009, vol. 6, pp. 180–186.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yosten, G.L., Kolar, G.R., Redlinger, L.J., and Samson, W.K., Evidence for an interaction between proinsulin C-peptide and GPR146, J. Endocrinol., 2013, vol. 218, pp. B1–B8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

    K. V. Derkach, V. M. Bondareva, A. A. Perminova & A. O. Shpakov

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  1. K. V. Derkach
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  2. V. M. Bondareva
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  3. A. A. Perminova
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  4. A. O. Shpakov
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Correspondence to A. O. Shpakov.

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Translated by D. Novikova

   Abbreviations: AC—adenylate cyclase, Aden1R and Aden2R—adenosine type 1 and type 2 receptors, ACSS—adenylate cyclase signaling system, β-AR—β-adrenergic receptors, GppNHp—5'-guanylylimidodiphosphate, GTT—glucose tolerance test, IGTT—insulin-glucose tolerance test, IAI—intranasally administered insulin, D1R and D2R—dopamine type 1 and type 2 receptors, IACP—intranasally administered C-peptide, IR—insulin resistance, MC4R—melanocortin type 4 receptor, α-MSH—α-melanocyte-stimulating hormone, DM—diabetes mellitus, S1BR and S6R—serotonin type 1B and type 6 receptors, Chol-LDL and Chol-HDL—cholesterol complexes with low- and high-density lipoproteins, ED—epididymal fat, AUC0-120—integrated area under the curve “glucose concentration (mmol/L)–time (min)”, BRL-37344—[4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]acetic acid sodium salt, EMD-386088—5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, SKF 82958—3-allyl-6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, THIQ—N-[(1R)-1-[(4-chlorophenyl)methyl]-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)-1-piperidinyl]-2-oxoethyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide.

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Derkach, K.V., Bondareva, V.M., Perminova, A.A. et al. C-Peptide and Insulin during Combined Intranasal Administration Improve the Metabolic Parameters and Activity of the Adenylate Cyclase System in the Hypothalamus, Myocardium, and Epididymal Fat of Rats with Type 2 Diabetes. Cell Tiss. Biol. 13, 228–236 (2019). https://doi.org/10.1134/S1990519X19030039

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