Developmental origins of adult metabolic disease: concepts and controversies.

The 'thrifty phenotype' hypothesis proposes that the fetus adapts to an adverse intrauterine milieu by optimizing the use of a reduced nutrient supply to ensure survival. However, favoring the development of some organs over that of others leads to persistent alterations in the growth and function of developing tissues. Although this concept has been somewhat controversial, recent epidemiological, clinical and animal studies provide support for the developmental origins of disease hypothesis.

Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure.

A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function, which can have deleterious effects. Critical questions are whether mitochondrial dysfunction progressively declines after birth, and if so, what mechanism might underlie this process. To address this, we developed a model of intrauterine growth retardation (IUGR) in the rat that leads to diabetes in adulthood.