Increased susceptibility to metabolic diseases including diabetes and hypertension during adult life has been recognized for offspring born to mothers with nutritional stress during pregnancy. We recently developed a unique gestational low-protein (LP) rat model in which the offspring are not obese but have glucose intolerance (GI) and insulin resistance (IR), and are unable to regulate glucose production, similar to that seen in humans who are metabolically aberrant with normal weight. Based on our recent exciting resultant observations with metabolic syndrome, we are focusing on the role of sex steroid hormones (testosterone (T) and estradiol (E2)) in regulating the onset and progression of GI and IR in the offspring exposed in utero to LP diet, and mechanisms involved. The central hypothesis is that the offspring from maternal LP- programming are GI and IR and their onset and progression are sex- and sex steroid (T in males and E2 in females)-dependent, and involve regulatory mechanisms of glucose homeostasis, insulin signaling, and mitochondrial function.
Three specific aims are proposed:
Specific Aim 1 : Establish the onset and progression of GI and IR, in maternal LP programmed offspring and determine if these are sex-and sex steroid hormone-dependent.
Sub aim 1 a: We hypothesize that onset and progression of GI and IR in maternal LP-programmed offspring are catch-up growth associated, sex dependent and sex steroid hormone-related.
Sub aim 1 b: We hypothesize that steroid supplementation (T for males and E2 for females) prior to the onset will prevent and after the onset will reverse GI and IR.
Specific Aim 2 : Assess changes in insulin sensitivity in skeletal muscles and liver, and hepatic glucose production in LP offspring, and their regulation by sex and sex steroids.
Sub aim 2 a: We hypothesize that insulin signaling for glucose transport and glycogen synthesis are defective in LP rats and these changes are sex-dependent and steroid hormone related.
Sub Aim 2 b: We hypothesize that the regulation of hepatic glucose production by gluconeogenesis (GNG) and glycogenolysis (GYG) is impaired in LP offspring and this impairment is sex dependent and regulated by sex steroids.
Specific Aim 3 : Identify the mechanistic relationship between in utero nutrition, sex steroids and insulin resistance.
Sub aim 3 a: We hypothesize that gestational LP diet affects the epigenetic profiles of key genes involved in steroidogenesis and decreases synthesis of T in males and E2 in females.
Specific Aim 3 b: We hypothesize that mitochondrial structure and function is compromised in LP offspring contributing to the development of IR.
Sub aim 3 c: We hypothesize that alterations in mitochondrial structure and function in LP offspring are sex steroid mediated. The outcomes of this project are expected to provide new information about the onset, progression and the development of metabolic disturbances in a lean animal model, and the involvement of sex and sex steroid hormone related mechanisms. Understanding of these mechanisms involved in this maternal LP-induced programming model could aid in developing sex-specific strategies for the prevention and treatment of metabolic disorders.

Public Health Relevance

Programming of adult health and disease appeared to be dependent upon the fetal exposure to various in utero environmental factors. Many models of fetal programming and epidemiological data in the human suggest gender-dependent variation in the susceptibility to hypertension and Type II diabetes. This proposal investigates the mechanisms by which sex-steroid hormones may regulate the Type II diabetes in the offspring from protein restricted mothers which has reached an epidemic proportion with 1 in 10 suffering from the disease in America and an is estimated that 1 in 3 Americans will have diabetes by 2050.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Silva, Corinne M
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Baylor College of Medicine
Obstetrics & Gynecology
Schools of Medicine
United States
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