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Dr. Katsilambros: It was very interesting to note that in your initial slides it was clearly shown that Chinese women presented much higher gestational diabetes as compared to Caucasians. This is very curious since the diabetes rate per se in the general Chinese population is lower than that in Caucasians. Could it be that this reflects the fact that Chinese women are thinner? You have shown during pregnancy thin women tend to gain a lot of weight as compared to women who are heavier before pregnancy. Could it also be that Chinese women produce relatively more estrogens during pregnancy or even that their tissues are relatively more sensitive to estrogens than the tissues of Caucasian women? Please also take into account the fact that in China only one child per woman is the common policy. I say that because we know that the greater the number of pregnancies the greater the diabetic tendency.
Dr. Metzger: I failed to make it clear that these Chinese and other Asian women were people who were born in China or Vietnam, and then migrated and lived in Australia. So the Westernization effect of the first generation is what we are seeing. We have seen the same thing in Korean women moving to Chicago. So the high expression of diabetes is seen in the new environment. However, in other countries I do believe that gestational diabetes is also increased. There have been reports of an increase in India, although I have to say that these population-base studies are not adjusted for confounding factors as those from California. In studies that have looked at this, greater weight is associated with gestational diabetes even within populations with relatively little obesity. So it looks as if the same factors worsen their insulin resistance as occur in the areas where there is more obesity.
Ms. Franz: Traditionally the focus of nutrition therapy for gestational diabetes has been on blood glucose control and glucose outcomes. Are you suggesting that weight control and/or caloric intake should receive more attention?
Dr. Metzger: I would like to see them raised. Yes, in terms of other outcomes I believe in judging if glyburide therapy is equivalent to insulin, or is one form of insulin equivalent to another, we probably should be looking at some of the other metabolic changes that are part of diabetes and gestational diabetes as well as perinatal outcomes to help us determine what really does normalize the environment most effectively.
Dr. Slama: Have you any experience with increased physical activity as promoted by Jovanovic in the past? More and more of our patients are treated with glargine and ultra-rapid analogs. What do you do when such perfectly controlled diabetic girls become pregnant while using glargine and analogs?
Dr. Metzger: There have been two approaches to physical activity in published studies. One is the upper arm approach that Jovanovic has used, and other groups simply used walking and more traditional forms of increasing physical activity with similar effects on improving glucose levels in patients with gestational diabetes. So I believe the full component of lifestyle intervention should be encouraged more than we have done in the past. Your question with regard to analogs deals more with people with existing diabetes, and my approach has been as follows. The short-acting insulin analogs have now been used for a decade although some initial concerns were raised. There have been no systematic clinical trials, but there also has been no evidence that they have any adverse effects. So women who are using short-acting analogs can continue that with very little concern and very little additional discussion. With the long-acting analogs such glargine insulin, I would encourage my colleagues to discuss the pros and cons of their use during pregnancy with the women before they become pregnant. There have been no clinical trials, although there are some animal data that have raised concern that high doses of glargine might increase the levels or might interact with IgF receptors in addition to insulin receptors that could potentially be harmful. There are no published data in large numbers. so the safety issues are not fully resolved. I encourage people to have a discussion with their female patients before glargine insulin is started as to whether they would want to use it during pregnancy. Women that have been brought in good control and are comfortable with a given regimen, find it very disconcerting to be asked to make a change. So if it can possibly be done before pregnancy, it is much easier. Having said that, I have never had anybody who wanted to discontinue glargine insulin once the pregnancy has started.
Dr. Chiasson: I was surprised by your conclusion suggesting that the glucagon-like peptide-1 inhibitor of dipeptidyl peptidase-4 (DPP4) could be one of the tools we could use in the future because the enzyme DPP4 is involved in a number of metabolic pathways, and the safety has yet to be proven. In the future we may find that it is safe. In fact gestational diabetes, at least at the beginning, is a postprandial disease. I was wondering why you would not suggest an approach that specifically addresses the postprandial plasma glucose rise, such as a-glucosidase inhibitors, which could be tested? These seem, at least certainly a-glucosidase inhibitors, to be safe, non-toxic and most likely without any detrimental effects, and could be a safe drug for gesta-tional diabetes.
Dr. Metzger: I am not really optimistic that we will be using DPP4 inhibitors in the near future unless they are very specifically known not to cross the placenta. However, glucagon-like peptide-1 agonists might be approachable in the near future and would help restore insulin secretion. Other agents have the burden of transpla-cental delivery, and a-glucosidase inhibitors are absorbed to a limited extent. They carry warnings for pregnancy because the 2 or 3% that is absorbable is hepatically active and potentially hepatotoxic in large doses. So they also face the burden of concern for introduction in pregnancy.
Dr Velarde: You mentioned that some of the patients who were diagnosed with gestational diabetes already had substantial weight gain at the time of diagnosis. This implies that perhaps they had some insulin resistance going on for weeks, maybe at the time of conception. While the interventions that you mentioned may prevent the respiratory complications, macrosomia, large for gestational age infants, do you think we should be more aggressive with the early diagnosis and treatment of these patients to prevent the congenital malformations?
Dr. Metzger: Congenital malformations that occur in women who we label as having gestational diabetes are probably related to one of two things. One, they had diabetes before pregnancy and had overt hyperglycemia at the time they became pregnant which wasn't detected. Second, there is increasing evidence that obesity, independent of hyperglycemia, is associated with a higher risk of malformations. The true mediators of those malformations are not known. The background against which we need to compare malformations in gestational diabetes are women of the same weight and other characteristics who don't have abnormal glucose levels. I do think that many women in whom we diagnose or who even develop gestational diabetes over the course of pregnancy have abnormalities earlier than we can detect. Decisions concerning the time, or multiple times during pregnancy to screen for gestational diabetes are made pragmatically. We have many places in the world where it is not feasible to test once for gestational diabetes. So it is hard to make a set of recommendations to do earlier screening when in many instances it is not feasible to even screen once. The focus on screening at around 28 weeks of gestation is based on a pragmatic yield versus cost basis with still enough time to intervene for potential benefit.
Dr. T. Wilkin: At the NIH earlier this year in Bethesda there was a presentation suggesting that there may be gene methylation of the germline of the offspring that may have long-term transgenerational effects. I just wonder if you could comment on whether you look beyond the next generation, to the one after that, and after that, because the impact of hyperglycemia and insulin resistance in the gestationally diabetic female doesn't just stop with the early effects on the offspring.
Dr. Metzger: This is a topic about gestational diabetes that I am very interested in. There is certainly strong evidence that the exposure to the intrauterine environment of diabetes has lasting consequences. The animal model data have supported this for a couple of decades; there have been very good epidemiological studies from the Pima population that Dabelea et al.  conducted, and we have done a long-term study of children from diabetic mothers, a cohort we followed for 20 years . The findings are complementary. So there is strong evidence that exposure in the intrauterine environment to diabetes accelerates or promotes both obesity and glucose intolerance in the next generation. I believe that preventing the long-term consequences of diabetes is as important as the perinatal issues. We are pretty successful with the perinatal issues, we don't know that we can successfully intervene to prevent the long-term effects.
Dr. Hill: Are high levels of physical activity or high physical fitness protective against gestational diabetes?
Dr. Metzger: I think they are. Of course the data come from long-term observational studies, not from prospective trials of any kind. I believe the Nurses Health Study has shown a reduced prevalence in gestational diabetes associated with higher levels of physical activity . Many years ago I was in communication with an investigator in an African country where physical activity remained extremely high and women remained in the field until they delivered and came back to the field a few hours later. They performed a series of studies during pregnancy in which there was very little weight gain, no increase in body fat, and glucose tolerance tests which showed no change in glucose tolerance at all during pregnancy. So I suspect that we can probably intervene under certain circumstances to reduce the amount of insulin resistance that occurs during normal pregnancy, and that would in a similar way probably reduce the incidence in gestational diabetes.
Dr. Jianqin Sun: Do you have any data on the prevalence of the macrosomia among diabetic mothers and normally pregnant women?
Dr. Metzger: The incidence of macrosomia in normal pregnancy varies a lot in different populations around the world, and one of the major factors is the amount of obesity and insulin resistance in the normal population. In patients with gestational diabetes, the observed frequency of macrosomia is a very complex thing to interpret because once we make a diagnosis we intervene with treatment that is intended to prevent the macrosomia that we measure as an outcome. So there are very few data that would say how much macrosomia would occur in untreated gestational diabetes. Where untreated gestational diabetes with more severe hyperglycemia exists, the incidence is very high. In the hyperglycemia and adverse outcome study that we are currently doing, we will have data on how much macrosomia occurs with lesser levels of hyperglycemia because that is a purely observational study. Dr. Knowler can you add something with regard to outcomes in untreated Pima?
Dr. Knowler: We have been studying pregnancy and pregnancy outcome in the Pima Indians for a period of about 40 years during which time there have been tremendous improvements in the treatment of diabetic pregnancy. Unfortunately some of the adverse outcomes such as the risk of diabetes in the offspring, do not show any sign of declining overtime. So I agree with the conclusion you made, treatment of diabetes in pregnancy certainly can be effective in reducing a lot of the perinatal outcomes but it is not clear whether it would be effective in the long-term adverse outcomes in the children.
1 Dabelea D, Knowler WC, Pettitt DJ: Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med 2000;9:83-88.
2 Silverman BL, Rizzo TA, Cho NH, Metzger BE: Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care 1998;21(suppl 2):B142-B149.
3 Solomon CG, Willett WC, Carey VJ, et al: A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 1997;278:1078-1083.
Bantle JP, Slama G (eds): Nutritional Management of Diabetes Mellitus and Dysmetabolic Syndrome. Nestlé Nutr Workshop Ser Clin Perform Program, vol 11, pp 171-181, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2006.
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