Insulin Signalling Pathways in Aorta and Muscle from Two Animal Models of Insulin Resistance--the Obese Middle-aged and the Spontaneously Hypertensive Rats

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2003 Apr 8

PMID 12679867

Citations 14

Authors

H G Zecchin

R M N Bezerra

J B C Carvalheira

M A Carvalho-Filho

K Metze

K G Franchini

M J A Saad

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: The aim of this study was to investigate insulin signalling pathways directly in vivo in skeletal muscle and thoracic aorta from obese middle-aged (12-month-old) rats, which have insulin resistance but not cardiovascular disease, and from spontaneously hypertensive rats (SHR), an experimental model of insulin resistance and cardiovascular disease.

Methods: We have used in vivo insulin infusion, followed by tissue extraction, immunoprecipitation and immunoblotting.

Results: Obese middle-aged rats and the SHR showed marked insulin resistance, which parallels the reduced effects of this hormone in the insulin signalling cascade in muscle. In aortae from obese middle-aged rats, the PI 3-kinase/Akt pathway is preserved, leading to a normal activation of endothelial nitric oxide synthase. In SHR this pathway is severely blunted, with reductions in eNOS protein concentration and activation. Both animals, however, showed higher concentrations and higher tyrosine phosphorylation of mitogen-activated protein (MAP) kinase isoforms in aortae.

Conclusions/interpretation: Alterations in the IRS/PI 3-K/Akt pathway in muscle of 12-month-old rats and SHR could be involved in the insulin resistance of these animals. The preservation of this pathway in aorta of 12-month-old rats, apart from increases in MAP kinase protein concentration and activation, could be a factor that contributes to explaining the absence of cardiovascular disease in this animal model. However, in aortae of SHR, the reduced insulin signalling through IRS/PI 3-kinase/Akt/eNOS pathway could contribute to the endothelial dysfunction of this animal.

Citing Articles

Combined antihypertensive effect of unripe Rubus coreanus Miq. and Dendropanax morbiferus H. Lév. Extracts in 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats.

Park S, Lee K, Choi H, Jang G, Kang W, Kim E BMC Complement Med Ther. 2021; 21(1):271.

PMID: 34711215 PMC: 8555169. DOI: 10.1186/s12906-021-03438-4.

Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes.

Harasim-Symbor E, Polak-Iwaniuk A, Konstantynowicz-Nowicka K, Bielawiec P, Malinowska B, Kasacka I Molecules. 2020; 25(8).

PMID: 32326330 PMC: 7221735. DOI: 10.3390/molecules25081932.

How Hypertension Affects Heart Metabolism.

Polak-Iwaniuk A, Harasim-Symbor E, Golaszewska K, Chabowski A Front Physiol. 2019; 10:435.

PMID: 31040794 PMC: 6476990. DOI: 10.3389/fphys.2019.00435.

Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations.

Low Wang C, Hess C, Hiatt W, Goldfine A Circulation. 2016; 133(24):2459-502.

PMID: 27297342 PMC: 4910510. DOI: 10.1161/CIRCULATIONAHA.116.022194.

Age-Associated Changes in the Vascular Renin-Angiotensin System in Mice.

Yoon H, Kim E, Kim M, Lim J, Jang I, Ban T Oxid Med Cell Longev. 2016; 2016:6731093.

PMID: 27200147 PMC: 4855022. DOI: 10.1155/2016/6731093.

References

Laemmli U . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259):680-5. DOI: 10.1038/227680a0. View

Mendez R, Myers Jr M, White M, Rhoads R . Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mol Cell Biol. 1996; 16(6):2857-64. PMC: 231278. DOI: 10.1128/MCB.16.6.2857. View

Reaven G . Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models. Diabetes Care. 1991; 14(3):195-202. DOI: 10.2337/diacare.14.3.195. View

Fulton D, Gratton J, McCabe T, Fontana J, Fujio Y, Walsh K . Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999; 399(6736):597-601. PMC: 3637917. DOI: 10.1038/21218. View

Trinder P . Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol. 1969; 22(2):158-61. PMC: 474026. DOI: 10.1136/jcp.22.2.158. View

HARUTA T, Morris A, Rose D, Nelson J, Mueckler M, Olefsky J . Insulin-stimulated GLUT4 translocation is mediated by a divergent intracellular signaling pathway. J Biol Chem. 1995; 270(47):27991-4. DOI: 10.1074/jbc.270.47.27991. View

Steinberg H, Brechtel G, Johnson A, Fineberg N, Baron A . Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994; 94(3):1172-9. PMC: 295191. DOI: 10.1172/JCI117433. View

Scherrer U, Randin D, Vollenweider P, VOLLENWEIDER L, NICOD P . Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994; 94(6):2511-5. PMC: 330085. DOI: 10.1172/JCI117621. View

King G, Goodman A, Buzney S, Moses A, Kahn C . Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985; 75(3):1028-36. PMC: 423655. DOI: 10.1172/JCI111764. View

10.

Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher A . Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999; 399(6736):601-5. DOI: 10.1038/21224. View

11.

Towbin H, Staehelin T, Gordon J . Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979; 76(9):4350-4. PMC: 411572. DOI: 10.1073/pnas.76.9.4350. View

12.

Cheatham B, Vlahos C, Cheatham L, Wang L, Blenis J, Kahn C . Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994; 14(7):4902-11. PMC: 358862. DOI: 10.1128/mcb.14.7.4902-4911.1994. View

13.

Papapetropoulos A, Rudic R, Sessa W . Molecular control of nitric oxide synthases in the cardiovascular system. Cardiovasc Res. 2000; 43(3):509-20. DOI: 10.1016/s0008-6363(99)00161-3. View

14.

Zeng G, Quon M . Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996; 98(4):894-8. PMC: 507502. DOI: 10.1172/JCI118871. View

15.

Myers Jr M, Backer J, Sun X, Shoelson S, Hu P, Schlessinger J . IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci U S A. 1992; 89(21):10350-4. PMC: 50336. DOI: 10.1073/pnas.89.21.10350. View

16.

Obata T, Kashiwagi A, Maegawa H, Nishio Y, Ugi S, Hidaka H . Insulin signaling and its regulation of system A amino acid uptake in cultured rat vascular smooth muscle cells. Circ Res. 1996; 79(6):1167-76. DOI: 10.1161/01.res.79.6.1167. View

17.

Eizirik D, Welsh N, Niemann A, Velloso L, Malaisse W . Succinic acid monomethyl ester protects rat pancreatic islet secretory potential against interleukin-1 beta (IL-1 beta) without affecting glutamate decarboxylase expression or nitric oxide production. FEBS Lett. 1994; 337(3):298-302. DOI: 10.1016/0014-5793(94)80213-0. View

18.

Sun X, Rothenberg P, Kahn C, Backer J, Araki E, Wilden P . Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991; 352(6330):73-7. DOI: 10.1038/352073a0. View

19.

Shepherd P, Nave B, Siddle K . Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem J. 1995; 305 ( Pt 1):25-8. PMC: 1136424. DOI: 10.1042/bj3050025. View

20.

Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V . Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab. 1989; 68(2):374-8. DOI: 10.1210/jcem-68-2-374. View