Research Interests:
The principal goal of our research program is to elucidate the underlying molecular mechanisms that link fetal growth retardation to the later development of type 2 diabetes in adulthood. We currently have 3 major projects and several smaller projects. The first project focuses on the relationship between oxidative stress and ß-cell dysfunction and insulin resistance. We have developed a model of fetal growth retardation in the rodent (mice and rats) which leads to the later development of diabetes in adult animals. We have established that fetal growth retardation induces progressive mitochondrial dysfunction, oxidative stress, mtDNA mutations, and electron transport defects. These defects cause abnormal ß-cell function and development, hepatic and muscle insulin resistance. Oxidative stress decreases transcription of key genes related to ß-cell development, induces modifications of proteins of the Krebs cycle in the liver, and muscle. The goals of the second project are to determine the molecular mechanisms underlying the protective effect of Exendin-4, a glucagon-like peptide-1 homolog. In collaboration with Dr. Doris Stoffers in the Department of Medicine, we have shown that exendin-4 treatment of newborn growth-retarded rats prevents the development of diabetes. Furthermore, Exendin-4 prevents the decline in ß-cell mass normally observed in growth retarded rats, by inducing Pdx-1 (a homebox gene critical for pancreas development) transcription which in turn enhances ß-cell neogenesis and proliferation. The third project is defining the epigenetic mechanisms underlying the permanent changes in Pdx-1 transcription observed in our animal model and are studying the effects of redox state on DNA methylation and histone modifications.

Recent Representative Publications:
Stoffers DA, Desai BM, Ng DD, and Simmons RA: Neonatal Exendin-4 Prevents the Development of Diabetes Mellitus in the Intrauterine Growth Retarded Rat: Diabetes 52: 734-740, 2003.

Selak MA, Storey BT, Peterside IE, Simmons RA: Impaired Oxidative Phosphorylation in Skeletal Muscle Contributes to Insulin Resistance and Hyperglycemia: American Journal of Physiology. 285:E130-E137, 2003.

Chennathukuzhi V, Stein JM, Abel T, Donlon S, Allman DM, Seykora J, Simmons RA, and Hecht NB: Mice deficient for TB-RBP exhibit a coordinate loss of Trax, a loose skin phenotype, reduced fertility, altered gene expression in the brain and behavioral defects: Molecular and Cellular Biology 23:6419-6434, 2003.

Peterside IE, Selak MA, and Simmons RA: Impaired oxidative phosphorylation in hepatic mitochondria of growth retarded rats alters glucose metabolism: American Journal of Physiology 285:E1258-1264, 2003.

Vuguin P, Raab E, Liu B, Barzilai N, Simmons RA: Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation: Diabetes 53: 2617-2622, 2004.

Selak MA, Suponitsky-Kroyter I, Simmons RA: Progressive accumulation of MtDNA mutations and decline of mitochondrial function lead to ß-cell failure. J Biol Chem 280 28785-28791, 2005.

Stefan M, Ji H, Simmons RA, Cummings DE, Ahima RS, Friedman MI, Nicholls RD. Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. Endocrinology, 146:4377-4385, 2005.

Simmons R: The perinatal programming of obesity. Experimental Gerontology, 40: 863-866, 2005.

Simmons RA: Fetal Origins of Adult Disease: Role of oxidative stress, Free Radical Biology and Medicine, 40:917-922, 2006.

Hoe FM, Thornton P, Wanner LA, Steinkrauss L, Bhatia P, Simmons RA, Stanley CA: Clinical Features and Insulin Regulation in Infants with a Syndrome of Prolonged Neonatal Hyperinsulinism. J Pediatr, 148:207-212, 2006.