Metabolic programming in the pathogenesis of insulin resistance.
This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic beta-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries.
Devaskar
Sherin U
SU
Division of Neonatology & Developmental Biology and the Neonatal Research Center, Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA. sdevaskar@mednet.ucla.edu
Thamotharan
Manikkavasagar
M
D000107:Acetylation; D000818:Animals; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D011247:Pregnancy
D006657:Histones