Gestational Protein Restriction Impairs Glucose Disposal in the Gastrocnemius Muscles of Female Rats.
Gestational low-protein (LP) diet causes hyperglycemia and insulin resistance in adult offspring, but the mechanism is not clearly understood. In this study, we explored the role of insulin signaling in gastrocnemius muscles of gestational LP-exposed female offspring. Pregnant rats were fed a control (20% protein) or an isocaloric LP (6%) diet from gestational day 4 until delivery. Normal diet was given to mothers after delivery and to pups after weaning until necropsy. Offspring were euthanized at 4 months, and gastrocnemius muscles were treated with insulin ex vivo for 30 minutes. Messenger RNA and protein levels of molecules involved in insulin signaling were assessed at 4 months. LP females were smaller at birth but showed rapid catchup growth by 4 weeks. Glucose tolerance test in LP offspring at 3 months showed elevated serum glucose levels (P < 0.01; glycemia Δ area under the curve 342 ± 28 in LP vs 155 ± 23 in controls, mmol/L * 120 minutes) without any change in insulin levels. In gastrocnemius muscles, LP rats showed reduced tyrosine phosphorylation of insulin receptor substrate 1 upon insulin stimulation due to the overexpression of tyrosine phosphatase SHP-2, but serine phosphorylation was unaffected. Furthermore, insulin-induced phosphorylation of Akt, glycogen synthase kinase (GSK)-3α, and GSK-3β was diminished in LP rats, and they displayed an increased basal phosphorylation (inactive form) of glycogen synthase. Our study shows that gestational protein restriction causes peripheral insulin resistance by a series of phosphorylation defects in skeletal muscle in a mechanism involving insulin receptor substrate 1, SHP-2, Akt, GSK-3, and glycogen synthase causing dysfunctional GSK-3 signaling and increased stored glycogen, leading to distorted glucose homeostasis.
Division for Reproductive Endocrinology and Infertility, University of Texas Medical Branch, Galveston, Texas.
Chellakkan S
CS
Blesson
Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
Vijayakumar
V
Chinnathambi
Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
Sathish
S
Kumar
Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas .
Chandrasekhar
C
Yallampalli
D000818:Animals; D018753:Diet, Protein-Restricted; D005260:Female; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D039382:Maternal Nutritional Physiological Phenomena / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D005947:Glucose