High Blood Glucose Levels in Early Pregnancy May Deprive Embryo of Oxygen and Lead to Birth Defects, Joslin Diabetes Center Study Shows

04 Oct, 2005, 01:00 ET from Joslin Diabetes Center

    BOSTON, Oct. 4 /PRNewswire/ -- The babies of women with diabetes are two
 to five times more likely to develop birth defects than offspring of women
 without the disease.  A recent study in animals by scientists at Joslin
 Diabetes Center in Boston helps explain why.  The research, appearing in the
 October issue of the American Journal of Physiology: Endocrinology and
 Metabolism, suggests that high blood glucose levels early in pregnancy deprive
 the embryo of oxygen, interfering with its development.
     "Until recently, it was not understood how diabetic pregnancy could cause
 birth defects.  My laboratory wanted to explore this research because the more
 we know about the effects of the mother's diabetes on the embryo, the more
 tools we have to identify therapies that may prevent birth defects in diabetic
 pregnancy," says the study's lead investigator, Mary R. Loeken, Ph.D., an
 investigator in Joslin's Section on Developmental and Stem Cell Biology and
 Assistant Professor of Medicine at Harvard Medical School.
     Women with both type 1 and type 2 diabetes run a high risk of having
 babies with birth defects, especially of the heart and spinal cord.  Because
 these organs form during the first few weeks of pregnancy, coinciding with the
 time that a woman may first learn she is pregnant, aggressive control of blood
 glucose levels just before and after conception is critical.  "Women with
 diabetes should be consulting with their healthcare team to be sure they have
 good glycemic control before becoming pregnant," says Dr. Loeken.  Maintaining
 blood glucose control continues to be important throughout the pregnancy, but
 it is particularly important during the first eight weeks, when an embryo's
 organs are forming.
     In addition to recommending that women with diabetes have good control of
 their glucose levels before becoming pregnant, Dr. Loeken recommends that
 obese women who don't know if they have diabetes but who are planning to
 become pregnant be tested for diabetes.  There have been several recent
 reports of increased birth defects in the pregnancies of obese women.  "Many
 obese individuals have type 2 diabetes and do not know it, so it is a good
 idea to bring glucose levels to within the normal range before becoming
 pregnant, and to monitor women with pre-diabetes closely during pregnancy to
 make sure that they don't develop diabetes," Dr. Loeken says.
     In the new study, Dr. Loeken and her colleagues examined embryos of
 pregnant mice injected with glucose (the sugar that is elevated in the blood
 during diabetes) to mimic diabetic pregnancy.  The researchers knew that
 oxygen is needed by cells to break down glucose and produce energy, and that
 normally, when oxygen is consumed, more oxygen is delivered to tissues by
 increasing blood flow to those tissues.  However, at the stage of embryonic
 development in which birth defects in women with diabetes frequently are
 believed to occur, the embryo does not yet have a heart or blood supply, and
 so the scientists theorized it might not be possible to replace oxygen as
 rapidly as it is consumed.  This has the potential to cause hypoxic stress, or
 damage to cells caused by low oxygen (hypoxia).
     Working in collaboration with Peter Smith, Ph.D., Director of the
 BioCurrents Research Center at the Marine Biological Laboratory at Woods Hole,
 Mass., Dr. Loeken found that the oxygen concentrations in embryos of mice
 injected with glucose were significantly lower than in control embryos.  This
 demonstrated that breaking down higher amounts of glucose caused oxygen to be
 used up faster than it could be delivered.
     The researchers then injected pregnant mice with glucose, or exposed them
 to varying levels of oxygen to see if raising and lowering oxygen delivery to
 the embryos had the same effect as raising and lowering glucose.  The
 scientists' goal was to see whether oxygen deprivation is what mediates the
 effects of high glucose on the embryo in pregnant diabetic mice.  Dr. Loeken's
 lab had previously found that inducing high blood glucose levels in pregnant
 mice suppressed Pax3 expression in embryos.  Pax3 is a gene required for
 healthy formation of the brain and spinal cord.
     In the new study, the researchers found that restricting oxygen delivery
 (by housing pregnant mice for one day in cages containing 12 percent oxygen --
 a concentration that did not cause any stress to the mothers, but which might
 significantly reduce the amount of oxygen delivered to the uterus -- instead
 of 20 percent oxygen contained in room air at sea level) had the same effect
 as high glucose.  In fact, embryos from pregnant mice with high blood glucose
 levels, or oxygen-restricted mice, had five-fold decreases in Pax3 expression
 and eight-fold increases in a severe type of birth defect called neural tube
 defects.  Conversely, increasing the oxygen delivery to pregnant diabetic mice
 (by housing them in cages containing 30 percent oxygen) blocked the decrease
 in Pax3 expression and neural tube defects in their embryos.
     Neural tube defects occur when parts of the brain, spinal cord, or their
 protective coverings fail to develop properly.  For example, spina bifida --
 the most common neural tube defect in humans -- results from the incomplete
 closure of the spinal cord.  Neural tube defects and heart abnormalities are
 the most common birth defects affecting babies born to women with diabetes.
     Previous research by Dr. Loeken and others has shown that in pregnant
 mice, high blood glucose levels boost an embryo's production of free radicals
 -- products of metabolism that cause oxidative stress, and that oxidative
 stress leads to birth defects.  These new experiments showed that glucose also
 caused hypoxic stress in embryos.  However, what Dr. Loeken and her colleagues
 did not know was whether glucose caused two different disturbances, hypoxic
 stress and oxidative stress, each having separate effects on Pax3 expression,
 or whether the two disturbances were linked.  To their surprise, when they
 investigated the production of free radicals, they found that embryos of
 oxygen-restricted mice showed the same three- to five-fold changes in markers
 of oxidative stress as did embryos of glucose-injected mice.  Conversely, the
 markers of oxidative stress were suppressed in embryos of oxygen-supplemented
 diabetic mice.  These results suggest that the lack of oxygen caused by
 increased glucose consumption triggers the production of free radicals, which
 then causes birth defects, Dr. Loeken explains.
     The researchers also found that administration of high levels of
 antioxidants -- which keep free radicals from wreaking cellular havoc --
 prevented the decrease in Pax3 expression and birth defects in embryos of
 diabetic mice.  This lends weight to the theory that lack of oxygen and the
 accompanying increase in free radical production that occurs in mice with high
 blood glucose levels are what ultimately increase risk of birth defects.
 "We're trying to pinpoint all the steps that occur between oxygen deprivation
 and gene expression, and to identify the signals and molecules that regulate
 Pax3," Dr. Loeken says.
     Funding for this study was provided in part by the National Institutes of
 Health.  The citation for the article is Am J Physiol Endocrinol Metab 289:
 E591-E599, 2005 (October).
 
     For more information, contact:
      Marjorie Dwyer or Jenny Eriksen, Joslin Communications, (617) 732-2415
      Marjorie.dwyer@joslin.harvard.edu
      Jenny.eriksen@joslin.harvard.edu
 
 

SOURCE Joslin Diabetes Center
    BOSTON, Oct. 4 /PRNewswire/ -- The babies of women with diabetes are two
 to five times more likely to develop birth defects than offspring of women
 without the disease.  A recent study in animals by scientists at Joslin
 Diabetes Center in Boston helps explain why.  The research, appearing in the
 October issue of the American Journal of Physiology: Endocrinology and
 Metabolism, suggests that high blood glucose levels early in pregnancy deprive
 the embryo of oxygen, interfering with its development.
     "Until recently, it was not understood how diabetic pregnancy could cause
 birth defects.  My laboratory wanted to explore this research because the more
 we know about the effects of the mother's diabetes on the embryo, the more
 tools we have to identify therapies that may prevent birth defects in diabetic
 pregnancy," says the study's lead investigator, Mary R. Loeken, Ph.D., an
 investigator in Joslin's Section on Developmental and Stem Cell Biology and
 Assistant Professor of Medicine at Harvard Medical School.
     Women with both type 1 and type 2 diabetes run a high risk of having
 babies with birth defects, especially of the heart and spinal cord.  Because
 these organs form during the first few weeks of pregnancy, coinciding with the
 time that a woman may first learn she is pregnant, aggressive control of blood
 glucose levels just before and after conception is critical.  "Women with
 diabetes should be consulting with their healthcare team to be sure they have
 good glycemic control before becoming pregnant," says Dr. Loeken.  Maintaining
 blood glucose control continues to be important throughout the pregnancy, but
 it is particularly important during the first eight weeks, when an embryo's
 organs are forming.
     In addition to recommending that women with diabetes have good control of
 their glucose levels before becoming pregnant, Dr. Loeken recommends that
 obese women who don't know if they have diabetes but who are planning to
 become pregnant be tested for diabetes.  There have been several recent
 reports of increased birth defects in the pregnancies of obese women.  "Many
 obese individuals have type 2 diabetes and do not know it, so it is a good
 idea to bring glucose levels to within the normal range before becoming
 pregnant, and to monitor women with pre-diabetes closely during pregnancy to
 make sure that they don't develop diabetes," Dr. Loeken says.
     In the new study, Dr. Loeken and her colleagues examined embryos of
 pregnant mice injected with glucose (the sugar that is elevated in the blood
 during diabetes) to mimic diabetic pregnancy.  The researchers knew that
 oxygen is needed by cells to break down glucose and produce energy, and that
 normally, when oxygen is consumed, more oxygen is delivered to tissues by
 increasing blood flow to those tissues.  However, at the stage of embryonic
 development in which birth defects in women with diabetes frequently are
 believed to occur, the embryo does not yet have a heart or blood supply, and
 so the scientists theorized it might not be possible to replace oxygen as
 rapidly as it is consumed.  This has the potential to cause hypoxic stress, or
 damage to cells caused by low oxygen (hypoxia).
     Working in collaboration with Peter Smith, Ph.D., Director of the
 BioCurrents Research Center at the Marine Biological Laboratory at Woods Hole,
 Mass., Dr. Loeken found that the oxygen concentrations in embryos of mice
 injected with glucose were significantly lower than in control embryos.  This
 demonstrated that breaking down higher amounts of glucose caused oxygen to be
 used up faster than it could be delivered.
     The researchers then injected pregnant mice with glucose, or exposed them
 to varying levels of oxygen to see if raising and lowering oxygen delivery to
 the embryos had the same effect as raising and lowering glucose.  The
 scientists' goal was to see whether oxygen deprivation is what mediates the
 effects of high glucose on the embryo in pregnant diabetic mice.  Dr. Loeken's
 lab had previously found that inducing high blood glucose levels in pregnant
 mice suppressed Pax3 expression in embryos.  Pax3 is a gene required for
 healthy formation of the brain and spinal cord.
     In the new study, the researchers found that restricting oxygen delivery
 (by housing pregnant mice for one day in cages containing 12 percent oxygen --
 a concentration that did not cause any stress to the mothers, but which might
 significantly reduce the amount of oxygen delivered to the uterus -- instead
 of 20 percent oxygen contained in room air at sea level) had the same effect
 as high glucose.  In fact, embryos from pregnant mice with high blood glucose
 levels, or oxygen-restricted mice, had five-fold decreases in Pax3 expression
 and eight-fold increases in a severe type of birth defect called neural tube
 defects.  Conversely, increasing the oxygen delivery to pregnant diabetic mice
 (by housing them in cages containing 30 percent oxygen) blocked the decrease
 in Pax3 expression and neural tube defects in their embryos.
     Neural tube defects occur when parts of the brain, spinal cord, or their
 protective coverings fail to develop properly.  For example, spina bifida --
 the most common neural tube defect in humans -- results from the incomplete
 closure of the spinal cord.  Neural tube defects and heart abnormalities are
 the most common birth defects affecting babies born to women with diabetes.
     Previous research by Dr. Loeken and others has shown that in pregnant
 mice, high blood glucose levels boost an embryo's production of free radicals
 -- products of metabolism that cause oxidative stress, and that oxidative
 stress leads to birth defects.  These new experiments showed that glucose also
 caused hypoxic stress in embryos.  However, what Dr. Loeken and her colleagues
 did not know was whether glucose caused two different disturbances, hypoxic
 stress and oxidative stress, each having separate effects on Pax3 expression,
 or whether the two disturbances were linked.  To their surprise, when they
 investigated the production of free radicals, they found that embryos of
 oxygen-restricted mice showed the same three- to five-fold changes in markers
 of oxidative stress as did embryos of glucose-injected mice.  Conversely, the
 markers of oxidative stress were suppressed in embryos of oxygen-supplemented
 diabetic mice.  These results suggest that the lack of oxygen caused by
 increased glucose consumption triggers the production of free radicals, which
 then causes birth defects, Dr. Loeken explains.
     The researchers also found that administration of high levels of
 antioxidants -- which keep free radicals from wreaking cellular havoc --
 prevented the decrease in Pax3 expression and birth defects in embryos of
 diabetic mice.  This lends weight to the theory that lack of oxygen and the
 accompanying increase in free radical production that occurs in mice with high
 blood glucose levels are what ultimately increase risk of birth defects.
 "We're trying to pinpoint all the steps that occur between oxygen deprivation
 and gene expression, and to identify the signals and molecules that regulate
 Pax3," Dr. Loeken says.
     Funding for this study was provided in part by the National Institutes of
 Health.  The citation for the article is Am J Physiol Endocrinol Metab 289:
 E591-E599, 2005 (October).
 
     For more information, contact:
      Marjorie Dwyer or Jenny Eriksen, Joslin Communications, (617) 732-2415
      Marjorie.dwyer@joslin.harvard.edu
      Jenny.eriksen@joslin.harvard.edu
 
 SOURCE  Joslin Diabetes Center