Intrauterine Growth Retardation Leads to the Development of Type 2 Diabetes in the Rat

  1. Rebecca A. Simmons,
  2. Lori J. Templeton and
  3. Shira J. Gertz
  1. Division of Neonatology, Department of Pediatrics, University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania


    Intrauterine growth retardation has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Bilateral uterine artery ligation was performed on day 19 of gestation (term is 22 days) in the pregnant rat; sham-operated pregnant rats served as controls. Birth weights of intrauterine growth–retarded (IUGR) animals were significantly lower than those of controls until ∼7 weeks of age, when IUGR rats caught up to controls. Between 7 and 10 weeks of age, the growth of IUGR rats accelerated and surpassed that of controls, and by 26 weeks of age, IUGR rats were obese (P < 0.05 vs. controls). No significant differences were observed in blood glucose and plasma insulin levels at 1 week of age. However, between 7 and 10 weeks of age, IUGR rats developed mild fasting hyperglycemia and hyperinsulinemia (P < 0.05 vs. controls). At age 26 weeks, IUGR animals had markedly elevated levels of glucose (P < 0.05 vs. controls). IUGR animals were glucose-intolerant and insulin-resistant at an early age. First-phase insulin secretion in response to glucose was also impaired early in life in IUGR rats, before the onset of hyperglycemia. There were no significant differences in β-cell mass, islet size, or pancreatic weight between IUGR and control animals at 1 and 7 weeks of age. However, in 15-week-old IUGR rats, the relative β-cell mass was 50% that of controls, and by 26 weeks of age, β-cell mass was less than one-third that of controls (P < 0.05). The data presented here support the hypothesis that an abnormal intrauterine milieu can induce permanent changes in glucose homeostasis after birth and lead to type 2 diabetes in adulthood.


    • Address correspondence and reprint requests to Rebecca Simmons, MD, University of Pennsylvania, BRB II/III 13th floor, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: rsimmons{at}

      Received for publication 24 May 2000 and accepted in revised form 20 June 2001.

      IUGR, intrauterine growth–retarded.

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