Fig. 7.

Overall hypothetical scheme summarizing the integrative proposal that placental insufficiency and intrauterine growth restriction (IUGR) increases the risk for the development of metabolic dysfunction and exaggerated cardiovascular-renal disease (CVRD). Briefly, this is promoted by programming of immune cell activation (78, 197, 201) eliciting increased insulin resistance, hyperglycemia and hyperlipidemia, and nonalcoholic fatty liver disease (NAFLD). The events allow propagation of further hyperglycemia and hyperlipidemia to allow the progression of NAFLD, liver injury, which involves endoplasmic reticulum stress and reduced autophagy, and worsened type 2 diabetes mellitus (T2DM). The latter metabolic dysfunction combined with the hypertension found in IUGR may promote greater vascular dysfunction and drive exaggerated incidence of CVRD in these offspring. The dashed line indicates that it is important to tease out the contribution of inflammation to both the development of T2DM and NAFLD and the hypothesis that metabolic disease accelerates CVRD in IUGR. This overall response may be even further exaggerated by combined maternal obesity (*) or in the face of adverse diets (**) in these offspring. Dashed lines represent the role for additional integrative mechanisms that mediate IUGR-induced pancreatic and renal dysfunction.