Perturbed skeletal muscle insulin signaling in the adult female intrauterine growth-restricted rat
| Autor: | Gerald Pan, Shilpa A. Oak, Mannikkavasagar Thamotharan, Sherin U. Devaskar, Cang Tran |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Physiology Endocrinology Diabetes and Metabolism Intrauterine growth restriction Biology Rats Sprague-Dawley Phosphatidylinositol 3-Kinases Insulin resistance Downregulation and upregulation Physiology (medical) Internal medicine medicine Animals Insulin Phosphorylation Muscle Skeletal Caloric Restriction Fetus Fetal Growth Retardation Type 2 Diabetes Mellitus Skeletal muscle medicine.disease Receptor Insulin Rats Up-Regulation Insulin receptor Endocrinology medicine.anatomical_structure biology.protein Female Signal transduction Signal Transduction |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 290:E1321-E1330 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00437.2005 |
| Popis: | To determine the molecular mechanism(s) linking fetal adaptations in intrauterine growth restriction (IUGR) to adult maladaptations of type 2 diabetes mellitus, we investigated the effect of prenatal seminutrient restriction, modified by early postnatal ad libitum access to nutrients (CM/SP) or seminutrient restriction (SM/SP), vs. early postnatal seminutrient restriction alone (SM/CP) or control nutrition (CM/CP) on the skeletal muscle postreceptor insulin-signaling pathway in the adult offspring. The altered in utero hormonal/metabolic milieu was associated with no change in basal total IRS-1, p85, and p110β subunits of PI 3-kinase, PKCθ, and PKCζ concentrations but an increase in basal IRS-2 ( P < 0.05) only in the CM/SP group and an increase in basal phospho (p)-PDK-1 ( P < 0.05), p-Akt ( P < 0.05), and p-PKCζ ( P < 0.05) concentrations in the CM/SP and SM/SP groups. Insulin-stimulated increases in p-PDK-1 ( P < 0.05) and p-Akt ( P < 0.0007), with no increase in p-PKCζ, were seen in both CM/SP and SM/SP groups. SHP2 ( P < 0.03) and PTP1B ( P < 0.03) increased only in SM/SP with no change in PTEN in CM/SP and SM/SP groups. Aberrations in kinase and phosphatase moieties in the adult IUGR offspring were initiated in utero but further sculpted by the early postnatal nutritional state. Although the CM/SP group demonstrated enhanced kinase activation, the SM/SP group revealed an added increase in phosphatase concentrations with the net result of heightened basal insulin sensitivity in both groups. The inability to further respond to exogenous insulin was due to the key molecular distal roadblock consisting of resistance to phosphorylate and activate PKCζ necessary for GLUT4 translocation. This protective adaptation may become maladaptive and serve as a forerunner for gestational and type 2 diabetes mellitus. |
| Databáze: | OpenAIRE |
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