Key points are not available for this paper at this time.
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. Reactive oxygen species (ROS) production and oxidative stress gradually increased in IUGR islets. ATP production was impaired and continued to deteriorate with age. The activities of complex I and III of the electron transport chain progressively declined in IUGR islets. Mitochondrial DNA point mutations accumulated with age and were associated with decreased mitochondrial DNA content and reduced expression of mitochondria-encoded genes in IUGR islets. Mitochondrial dysfunction resulted in impaired insulin secretion. These results demonstrate that IUGR induces mitochondrial dysfunction in the fetal β-cell, leading to increased production of ROS, which in turn damage mitochondrial DNA. A self-reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in β-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues. 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. Reactive oxygen species (ROS) production and oxidative stress gradually increased in IUGR islets. ATP production was impaired and continued to deteriorate with age. The activities of complex I and III of the electron transport chain progressively declined in IUGR islets. Mitochondrial DNA point mutations accumulated with age and were associated with decreased mitochondrial DNA content and reduced expression of mitochondria-encoded genes in IUGR islets. Mitochondrial dysfunction resulted in impaired insulin secretion. These results demonstrate that IUGR induces mitochondrial dysfunction in the fetal β-cell, leading to increased production of ROS, which in turn damage mitochondrial DNA. A self-reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in β-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues. Epidemiological studies have revealed strong statistical links between poor fetal growth and the subsequent development of type 2 diabetes in adulthood (1.Barker D.J.P. 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This abnormal metabolic intrauterine milieu affects development of the fetus by modifying gene expression and function of susceptible cells, such as the β-cell (16.Simmons R.A. Templeton L.J. Gertz S.A. Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google Scholar, 17.Peterside I.E. Selak M.A. Simmons R.A. Am. J. Physiol. 2003; 285: E1258-E1264Crossref PubMed Scopus (132) Google Scholar, 18.Selak M.A. Storey B.T. Peterside I.E. Simmons R.A. Am. J. Physiol. 2003; 285: E130-E137Crossref PubMed Scopus (139) Google Scholar, 19.Stoffers D.A. Desai B.M. Ng D.D. Simmons R.A. Diabetes. 2003; 52: 734-740Crossref PubMed Scopus (238) Google Scholar). The molecular mechanisms responsible for permanent changes in gene expression are not known, but they are a critical element in our understanding of how factors in early development can lead to long term consequences in aging and disease. A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function (17.Peterside I.E. Selak M.A. Simmons R.A. Am. J. Physiol. 2003; 285: E1258-E1264Crossref PubMed Scopus (132) Google Scholar, 18.Selak M.A. Storey B.T. Peterside I.E. Simmons R.A. Am. J. Physiol. 2003; 285: E130-E137Crossref PubMed Scopus (139) Google Scholar). However, these alterations in mitochondrial function can have deleterious effects, especially in cells that have a high energy requirement, such as the β-cell. The β-cell depends upon the normal production of ATP for nutrient-induced insulin secretion (20.Panten U. Zielman S. Langer J. Zunkler B.J. Lenzen S. Biochem. J. 1984; 219: 189-196Crossref PubMed Scopus (51) Google Scholar, 21.Newgard C.B. McGarry J.D. Annu. Rev. Biochem. 1995; 64: 689-719Crossref PubMed Scopus (494) Google Scholar, 22.Schuit F. J. Biol. 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Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google with the of most of type 2 diabetes in the progressive in insulin secretion and insulin action to the of (16.Simmons R.A. Templeton L.J. Gertz S.A. Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google Scholar). leads to a progressive decline in β-cell D.A. Desai B.M. Ng D.D. Simmons R.A. Diabetes. 2003; 52: 734-740Crossref PubMed Scopus (238) Google Scholar). A critical is whether mitochondrial dysfunction that is by abnormal intrauterine milieu in fetal cells is and if so, what might underlie this process. this we have the that the function of the electron transport chain in the fetal β-cell and leads to a of increased production of oxygen which in turn damage mitochondrial DNA and cause production of The result is progressive of β-cell function and development of type 2 diabetes in the have our (13.Ogata E.S. Bussey M. Finley S. Metabolism. 1986; 35: 950-977Abstract Full Text PDF PubMed Scopus (160) Google Scholar, 14.Simmons R.A. Gounis A.S. Bangalore S.A. Ogata E.S. Pediatr. Res. 1991; 31: 59-63Crossref Scopus (105) Google Scholar, 15.Unterman T. Lascon R. Gotway M. Oehler D. Gounis A. Simmons R.A. Ogata E.S. Endocrinology. 1990; 127: 2035-2037Crossref PubMed Scopus (97) Google Scholar, R.A. Templeton L.J. Gertz S.A. Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google Scholar). were and to rat and of is the were with and and were This results in in a and to and The were to and the was reduced to at birth to of between IUGR and The were to normal and with they were studies were in and at and of age to the of the disease to the of were to the associated with were in the insulin were in by rat insulin as the The and of for the insulin were and secretion was by at the of and by T. Ishihara H. P. Wollheim C.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were and by as C.B. 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A. A. 1997; PubMed Scopus Google Scholar). this the was for is in this J.E. J. Med. Biol. Res. 1999; PubMed Scopus Google Scholar, A.S. Simmons R.A. Biochem. Med. 1996; PubMed Scopus Google Scholar). DNA of and at of age was to were of DNA. were as cycle at at the for the 2 at at at the 2 at were by at for was were with of and for and and the The was a in was with for whether IUGR mutations was DNA was of IUGR and and and was to the of the of were To for was DNA and the at that were for of of and of the were for and of for for and for were to by and DNA were with the of corresponding were with in the mitochondrial DNA the of DNA to we The was to for and the were with and were in of and of and of and The were in DNA were by the for by the and the as a of at was as a was to of were of and for was of IUGR and of for were of IUGR and of were to the of to β-cell. These studies were by the of the of and the of (16.Simmons R.A. Templeton L.J. Gertz S.A. Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google birth of IUGR were of IUGR and of and insulin were in the normal at in IUGR insulin were with of were and insulin in with in IUGR was decreased with at of age IUGR of β-cell was reduced in IUGR of IUGR The of in the increased with age in IUGR and was of cells at with for glucose, and insulin in IUGR and in a in studies (16.Simmons R.A. Templeton L.J. Gertz S.A. Diabetes. 2001; 50: 2279-2286Crossref PubMed Scopus (526) Google we that insulin secretion in to was impaired in IUGR in the and progressively with age. To whether insulin secretion impaired after a metabolic insulin secretion was in insulin at was in of IUGR and at and of age. However, insulin secretion in to was in IUGR and progressively with age insulin secretion was impaired in IUGR and was of at of of at of and at and insulin at at and at at and at at and at at and at at and at at and at at and in a Mitochondrial production in to was in fetal IUGR ATP production was impaired in IUGR at ATP production in the of was that with in fetal of However, to ATP production in IUGR fetal to ATP production in IUGR The mitochondrial electron transport chain of the mitochondrial III, and and the complex The activities of complex I and III to were in IUGR with and declined with age This was in the of I III not was in the of the complex in the mitochondrial complex not between and in and However, by of in IUGR was of ROS of ROS was and after the of to islets. of ROS were in IUGR fetal in the of not ROS production birth, of ROS in IUGR but they were the of glucose, ROS production was at of ROS production was in IUGR with studies have that intrauterine growth retardation is associated with increased oxidative stress in the fetus L. 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