Abstract
C-peptide is the product of proinsulin proteolysis, which is not only a signal molecule but is also able to modulate insulin signaling functions by forming a complex with it. The insulin-sensitive signaling systems in the hypothalamus and other brain areas are among the insulin targets. We hypothesized that, in the systemic deficiency of insulin and C-peptide in type-1 diabetes mellitus (DM) and in severe forms of type-2 DM, an increase in the C-peptide level in the central nervous system (CNS) will improve the central effects of insulin, including its influence on the peripheral metabolism. To verify this, the influence of separate and coadministration of intranasal insulin (II) and C-peptide (IP) on their metabolic parameters and insulin sensitivity in rats with acute and mild type-1 DM induced by streptozotocin at doses of 60 and 35 mg/kg and in rats with neonatal type-2 DM corresponding to severe long-term form of type-2 DM in humans was studied. The treatment of animals with II and IP was carried out for 7 days in daily doses of 20 and 10 µg/rat, respectively. The coadministration of II and IP leading to increased insulin and C-peptide levels in the brain showed the highest effect. In rats with type-1 DM treated with a combination of II and IP, hyperglycemia was decreased and weight loss was prevented. In rats with type-2 DM, coadministration of II and IP led to normalization of glucose homeostasis and increased insulin sensitivity, as shown by the glucose-tolerance and insulin-glucose tolerance tests, as well as to improved lipid metabolism, as demonstrated by a decrease in the atherogenic index. The effectiveness of monotherapy with II was lower than in case of a combination of II and IP, while monotherapy with C-peptide had little effect on the studied indicators. Thus, a simultaneous increase in the insulin and C-peptide levels in the brain upon their deficiency due to diabetic pathology can be considered a promising approach to the restoration of central insulin–dependent regulation of peripheral metabolism and improved glucose utilization in different DM forms.
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Kuznetsova, L.A., Sharova, T.S., Pertseva, M.N., and Shpakov, A.O., Beta-adrenergic regulation of adenylyl cyclase signaling system in the myocardium and brain of rats with obesity and type 2 diabetes mellitus as affected by long-term intranasal insulin administration, J. Evol. Biochem. Physiol., 2015, vol. 51, no. 3, pp. 198–209.
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
Sukhov, I.B., Shipilov, V.N., Chistyakova, O.V., Trost, A.M., and Shpakov, A.O., Long-term intranasal insulin administration improves spatial memory in male rats with prolonged type 1 diabetes mellitus and in healthy rats, Dokl. Biol. Sci., 2013, vol. 453, no. 1, pp. 349–352
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, no. 1, pp. 216–218.
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
Shpakov, A.O. and Granstrem, O.K., C-peptide structure, functions and molecular mechanisms of action, Tsitologiya, 2013, vol. 55, no. 1, pp. 16–27
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
Shpakov, A.O., Chistyakova, O.V., Derkach, K.V., Moyseyuk, I.V., and Bondareva, V.M., Activity of receptor guanylyl cyclases in rats with neonatal streptozotocin diabetes and effect of intranasal administration of insulin and serotonin, Cell Tissue Biol., 2011, vol. 5, no. 5, pp. 453–462
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., 2015, vol. 47, no. 12, pp. 916–924
Heni, M., Kullmann, S., Ketterer, C., et al., Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and rewardrelated human brain regions, Diabetologia, 2012, vol. 55, no. 6, pp. 1773–1782
Inoue, H., Central insulin-mediated regulation of hepatic glucose production, Endocrinol. J., 2016, vol. 63, no. 1, pp. 1–7
Kullmann, S., Fritsche, A., Wagner, R., et al., Hypothalamic insulin responsiveness is associated with pancreatic insulin secretion in humans, Physiol. Behav., 2017, vol. 176, pp. 134–138
Landreh, M., Alvelius, G., Willander, H., et al., Insulin solubility transitions by pH-dependent interactions with proinsulin C-peptide, FEBS J., 2012, vol. 279, no. 24, pp. 4589–4597
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, no. 11, pp. 769–773
Nerelius, C., Alvelius, G., and Jörnvall, H., N-terminal segment of proinsulin C-peptide active in insulin interaction/ desaggregation, Biochem. Biophys. Res. Commun., 2010, vol. 403, no. 3–4, pp. 462–467.
Novak, V., Milberg, W., Hao, Y., et al., Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes, Diabetes Care, 2014, vol. 37, no. 3, pp. 751–759
Ott, V., Benedict, C., Schultes, B., et al., Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism, Diabetes Obes. Metab., 2012, vol. 14, no. 3, pp. 214–221
Shafqat, J., Melles, E., Sigmundsson, K., et al., Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects, Cell. Mol. Life Sci., 2006, vol. 63, no. 15, pp. 1805–1811
Shpakov, A.O., Chistyakova, O.V., Derkach, K.V., et al., Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes, Central Eur. J. Biol., 2012, vol. 7, no. 1, pp. 33–47
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 Sci. OA, 2015, vol. 1, no. 3. doi doi 10.4155/fso.15.23
Shpakov, A., Derkach, K., Moyseyuk, I., and Chistyakova, O., Alterations of hormone-sensitive adenylyl cyclase system in the tissues of rats with long-term streptozotocin diabetes and the influence of intranasal insulin, Dataset Pap. Sci., 2013, vol. 2013, p. 698435. https://doi.org/10.7167/2013/698435
Sima, A.A., Zhang, W., Muzik, O., et al., Sequential abnormalities in type 1 diabetic encephalopathy and the effects of C-peptide, Rev. Diabetic Stud., 2009, vol. 6, no. 3, pp. 211–222
Sima, A.A. and Li, Z.G., The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats, Diabetes, 2005, vol. 54, no. 5, pp. 1497–1505
Thon, M., Hosoi, T., and Ozawa, K., Possible integrative actions of leptin and insulin signaling in the hypothalamus targeting energy homeostasis, Front. Endocrinol. (Lausanne), 2016, vol. 7, p. 138.
Vasic, D. and Walcher, D., Proinflammatory effects of C-peptide in different tissues, Int. J. Inflam., 2012, vol. 2012, p. 932725.
Wahren, J., Kallas, A., and Sima, A.A., The clinical potential of C-peptide replacement in type 1 diabetes, Diabetes, 2012, vol. 61, no. 4, pp. 761–772
Walcher, D. and Marx, N., C-peptide in the vessel wall, Rev. Diabetic Stud., 2009, vol. 6, no. 3, pp. 180–186
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, no. 2, pp. B1–B8.
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Original Russian Text © K.V. Derkach, V.M. Bondareva, A.O. Shpakov, 2017, published in Uspekhi Gerontologii, 2017, Vol. 30, No. 6, pp. 851–858.
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Derkach, K.V., Bondareva, V.M. & Shpakov, A.O. Coadministration of Intranasally Delivered Insulin and Proinsulin C-Peptide to Rats with Types 1 and 2 Diabetes Mellitus Restores Their Metabolic Parameters. Adv Gerontol 8, 140–146 (2018). https://doi.org/10.1134/S2079057018020030
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DOI: https://doi.org/10.1134/S2079057018020030