Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart

Luigi Laviola, Gaetana Belsanti, Alberto M. Davalli, Raffaele Napoli, Sebastio Perrini, Gordon C. Weir, Riccardo Giorgino, Francesco Giorgino

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Abstract

The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52Shc are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.

Original languageEnglish
Pages (from-to)2709-2720
Number of pages12
JournalDiabetes
Volume50
Issue number12
Publication statusPublished - Dec 2001

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Insulin Receptor Substrate Proteins
Islets of Langerhans Transplantation
Experimental Diabetes Mellitus
Phosphatidylinositol 3-Kinase
Phosphorylation
Insulin
Glycogen Synthase Kinase 3
Therapeutics
Capsules
Tyrosine
Myocardium
Kidney
Insulin Receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Cite this

Laviola, L., Belsanti, G., Davalli, A. M., Napoli, R., Perrini, S., Weir, G. C., ... Giorgino, F. (2001). Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. Diabetes, 50(12), 2709-2720.

Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. / Laviola, Luigi; Belsanti, Gaetana; Davalli, Alberto M.; Napoli, Raffaele; Perrini, Sebastio; Weir, Gordon C.; Giorgino, Riccardo; Giorgino, Francesco.

In: Diabetes, Vol. 50, No. 12, 12.2001, p. 2709-2720.

Research output: Contribution to journalArticle

Laviola, L, Belsanti, G, Davalli, AM, Napoli, R, Perrini, S, Weir, GC, Giorgino, R & Giorgino, F 2001, 'Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart', Diabetes, vol. 50, no. 12, pp. 2709-2720.
Laviola L, Belsanti G, Davalli AM, Napoli R, Perrini S, Weir GC et al. Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. Diabetes. 2001 Dec;50(12):2709-2720.
Laviola, Luigi ; Belsanti, Gaetana ; Davalli, Alberto M. ; Napoli, Raffaele ; Perrini, Sebastio ; Weir, Gordon C. ; Giorgino, Riccardo ; Giorgino, Francesco. / Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. In: Diabetes. 2001 ; Vol. 50, No. 12. pp. 2709-2720.
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