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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 20-November-2009, Vol 122 No 1306

Obesity and gestational diabetes mellitus: breaking the cycle
Sarah Bristow, Janet Rowan, Elaine Rush
In New Zealand and around the world, the prevalence of obesity is increasing.1 A growing body of evidence suggests that the environment an individual is exposed to early in life can alter their long-term health and risk of disease. Throughout the lifecycle, glucose homeostasis affects development and future health, and is of key importance during pregnancy, as the long-term health of the baby may be influenced by maternal glucose concentrations. Of particular concern for future generations is the increase in rates of gestational diabetes mellitus (GDM), where maternal glucose intolerance develops or is first recognised during pregnancy.
The prevalence of known GDM has increased by 10% to 100% in certain ethnic groups over the past 20 years, reflecting the increasing prevalence of obesity and type 2 diabetes mellitus (T2DM) in young women.2 It is, however, unclear as to whether this represents a true rise in GDM prevalence or merely reflects an increase in GDM screening. The definition of GDM as a glucose intolerance that develops during pregnancy makes it difficult to distinguish between pre-existing undiagnosed T2DM and true GDM, particularly in women of childbearing age, who are not usually screened for diabetes.2
In New Zealand, several factors will contribute to increases in the prevalence of diagnosed GDM over the next few years. Firstly, with the adoption of universal screening recommendations, more women with GDM will be recognised.2 Secondly, international criteria for diagnosing GDM are being developed and, as data show that glucose levels below those currently used to diagnose GDM are associated with perinatal complications, the recommended glucose thresholds for diagnosis are likely to be lowered.3,4 Thirdly, with our changing population, rates will rise as ethnicity is an important factor determining the risk of GDM.
Data from women delivering at National Women’s Hospital, Auckland, during 2008 show GDM was diagnosed in over 16% of Indian, almost 10% of other Asian, and over 6% of Pacific Island and Māori women (groups known to have high rates of T2DM)5 compared with 3% of NZ European women.6
The association of GDM with pregnancy complications and later risks of T2DM in the mother is well-recognised,7 however, the long-term implications for the offspring deserves better recognition. There are accumulating data demonstrating increased risk of obesity and early T2DM in the offspring.8–11 Society needs to consider how we should address this issue to improve the health of the next generation.

Developmental programming of obesity

Obesity is a disease of altered energy balance, where energy intake exceeds expenditure over a period of time. The pathogenesis of obesity, while complex and poorly understood, is thought to result from interactions between an individual’s genes and environment.12 In a recent review, Bouchard proposes common forms of childhood obesity result from a genetic predisposition towards obesogenic behaviours in an obesogenic environment.13 Thus, within any population, individuals will exhibit variable risk towards becoming obese as their genetic background determines how they respond to environmental factors such as the food supply and opportunities for physical activity. This relationship between genes and environment is further complicated by the fact that at critical times, environmental influences, such as fetal nutrition, can lead to a heritable change in gene expression without changing gene structure. This is termed an epigenetic phenomenon, and may be of key importance when considering how the intrauterine environment influences later health.
Later consequences of environmental influences, the ‘fetal origins of disease’ was first proposed by Barker and colleagues, who demonstrated a relationship between low birth weight (a marker of poor fetal nutrition in utero) and adult hypertension, dyslipidaemia and insulin resistance.14 They suggested the fetus was not “programmed” to cope with a postnatal environment of plentiful nutrition, thus it has a reduced ability to develop an increased muscle mass, a reduced subcutaneous fat storage capacity and has to store excess nutrients as ectopic/visceral fat, which leads to later health consequences. This hypothesis formed the basis of a broader concept of ‘developmental programming’, which refers to any situation where an insult at an important period in development has a lasting effect on health or function.15 A comparable situation may arise for offspring of women with diabetes whose placental function is impaired in association with hypertensive complications of pregnancy.
At the other end of the spectrum, exposure to an unbalanced excess nutrient supply secondary to maternal diabetes is also associated with a greater risk of obesity and T2DM in offspring. A long-term prospective evaluation of offspring exposed to maternal diabetes was carried out by the Northwestern University Diabetes in Pregnancy Center.10 Children were compared with controls whose mothers did not have diabetes. At birth, 50% of the offspring of mothers with diabetes were above the 90th percentile of weight for gestational age. Although weight normalised by 12 months of age, after 5 years weight increased dramatically in the offspring of mothers with diabetes and by 8 years 50% had weights above the 90th percentile.
During adolescence, mean body mass index (BMI) in the affected offspring was 24.6 ± 5.8 kg/m² compared with 20.9 ± 3.4 kg/m² in control subjects (p=0.001).8 In addition to obesity, 36% of the offspring of mothers with diabetes had evidence of impaired glucose tolerance by the age of 17 years compared with only 3% of the control population.
Nuclear family studies, where children have similar genetic risks for obesity and T2DM, have further examined the effect of the intrauterine environment.11 Children born before their mother developed diabetes were compared with a sibling born after their mother developed diabetes, thus differing in only in their intrauterine environment. The offspring exposed to maternal diabetes had a mean BMI 2.6kg/m² higher and were more likely to develop T2DM (odds ratio 3.7, p = 0.02) than their sibling born before their mother developed diabetes. These results suggest exposure to GDM transmits greater risk to offspring for T2DM than that from inherited genetic predisposition alone.
The intergenerational transmission of increased risk is supported by a report from McLean et al,16 who screened 5850 pregnancies for hyperglycaemia and asked women to report their family history of T2DM (a mother, father, both parents or no parents with T2DM). As GDM during pregnancy is often the first sign of a genetic predisposition to T2DM, the authors postulated that subjects who had a mother with diabetes may have been exposed to GDM. As expected, among the pregnant study population, GDM/T2DM was more common in those women who had a mother with diabetes than a father with diabetes, while having two parents with diabetes conferred no additional risk than for mother with diabetes alone. The authors interpreted their results as not supporting a predominantly genetic transmission of T2DM, where risk would have been transmitted equally by both parents.
The relative contribution of genetic versus intrauterine transmission of risk for T2DM was examined more recently in an elegant study in an European popluation.17 Four groups of participants were compared in this study: offspring with a genetic predisposition to T2DM (family history of diabetes) whose mothers had GDM (O-GDM), offspring with a similar genetic predisposition whose mothers did not have GDM (O-NoGDM), offspring with a low genetic predisposition to T2DM whose mothers had type 1 diabetes (O-Type1) and offspring with a low genetic predisposition whose mother did not have diabetes during pregnancy—the background population (O-BP).
At a mean age of 22 years, the prevalence of T2DM was 21% in O-GDM, 12% in O-NoGDM, 11% in O-Type1 and 4% in BP. This study demonstrates the increased risk of T2DM in offspring with higher genetic risk and in offspring exposed to maternal diabetes in utero, with the highest risk in offspring exposed to both factors.
Developmental programming may occur in the absence of full-blown maternal diabetes, with exposure to milder levels of maternal hyperglycaemia linked with an increased risk of obesity in offspring. This was demonstrated in a recent prospective study, where a positive trend for increasing childhood overweight and obesity between the ages of 5 to 7 was found across a range of increasing maternal glucose screen values—even after adjustment for maternal weight, age, parity and birth weight.18
Importantly, it was shown that the risk of obesity was attenuated in the offspring of mothers with diagnosed, treated GDM, compared with the risk in offspring whose mothers had untreated milder hyperglycaemia. It is possible these mechanisms are also relevant for offspring of obese women during pregnancy, who have higher postprandial glucose levels than lean women.19

Dysregulation of the adipoinsular axis

What could be the mechanism behind maternal hyperglycaemia leading to obesity and T2DM in the offspring? In a pregnancy complicated by GDM, maternal hyperglycaemia causes increased amounts of glucose to cross the placenta, leading to increased fetal insulin release. Insulin is an anabolic hormone which is very important in fetal growth. In the presence of excess glucose, raised insulin in the fetus during the third trimester is thought to lead to increased fat synthesis and deposition.20 Indeed it has been shown that even in a sample of average-for-gestational-age newborns, those exposed to GDM in utero have greater fat mass, body fat percentage and skin fold thickness when compared with those born to glucose tolerant mothers.21
For an individual in energy balance who can choose when to eat, an increase in fat stores results in increased plasma leptin concentrations, which signals satiety, reduces food intake and inhibits insulin production and adipogenesis. This endocrine feedback system, termed the adipoinsular axis, is associated with maintaining adipose homeostasis.
In the intrauterine environment, a fetus exposed to excess nutrition will develop an increased fat mass, but despite increased leptin levels, there is continued excess nutrient supply from the mother. Over time this may lead to dysregulation of the adipoinsular axis and development of leptin resistance. A New Zealand study demonstrated hyperinsulinaemia and hyperleptinaemia in newborns of women with GDM in Māori, Pacific Island, Indian, and European populations, suggesting leptin resistance may be present at birth.22 Additionally, there is evidence from an animal study hyperinsulinaemia and hyperleptinaemia play a role in the development of postnatal hyperphagia in offspring, which could make postnatal interventions to improve long-term health more difficult to achieve.23
Though the molecular mechanisms that underlie the programming of obesity and T2DM are beyond the scope of this article, it important to understand that fetal programming is thought occur via epigenetics rather than changes to actual DNA base sequence.24 Epigenetics refers to the mechanisms that lead to long-term changes in the expression of a gene, such as gene silencing by methylation in the promoter region—a process involved in the differentiation of cells for different tissues.
Vitamin B12 and folate are important methyl donors, and are essential for normal cell growth and division. Research now suggests these micronutrients may play a role in fetal programming. Genetically obese Agouti mice fed a methylating cocktail of vitamin B12, folic acid, betaine and choline during pregnancy had offspring who were less obese and had a different coat colour—despite inheriting the Agouti mutation.25
A recent study in India demonstrated women with low B12 status had increased adiposity and a higher prevalence of insulin resistance and GDM compared to those with adequate B12,26 while the longitudinal Pune Maternal Nutritional Study has shown that 6-year-old offspring of women with high folate and low B12 concentrations during pregnancy had greater adiposity and insulin resistance than offspring whose mothers had normal B12 status.27 B12 deficiency is common among Indian women due to vegetarian dietary practices,28 and could potentially contribute to the high prevalence of GDM and T2DM seen in Indian women in New Zealand and overseas.

The postnatal environment

What is not yet known is the relative importance of the prenatal and postnatal environments in determining an individual’s risk of disease during their life course. Evidence from animal models suggests the early postnatal environment may modify the effect of the prenatal environment.29 For example, intrauterine growth restricted rats exposed to a nutritionally limited prenatal environment develop obesity when exposed to a non-restricted postnatal diet. When these rats are exposed to a postnatal high fat diet, obesity is amplified,30 and when they exposed to moderate daily exercise, the development of obesity is prevented.31
Whether postnatal exposures such as breastfeeding, as well as later diet and physical activity can alter the risk of obesity in the offspring of mothers with diabetes are areas that require further research. In the general population there is evidence breastfeeding is protective against obesity,32 suggesting the lactation period could be important in the programming of disease risk. The beneficial effects of breast milk are thought to be due to its macronutrient composition, which may alter the hormonal responses that regulate body fatness and growth. In NZ only 55.8% of infants are estimated to be breastfed exclusively at 3 months of age, this number drops to 7.6% by 6 months.5
There are limited data available on breastfeeding after GDM. Two studies have demonstrated an inverse relationship between breastfeeding and overweight in GDM offspring. The Nurses’ Health Study found risk of overweight at ages 9 to 14 years in the offspring of mothers with diabetes was inversely associated with having been breastfed during the first 6 months of life.33 Similarly a German study reported that offspring of mothers with diabetes who were breastfed for >3 months had a 45% decrease in rates of overweight (BMI ≥90th percentile) at the ages of 2-8 years compared with those who were formula fed.34

Implications for New Zealand

Childhood obesity has reached epidemic proportions in developed countries, with New Zealand no exception. The 2006/2007 New Zealand Health Survey found that one in every five children was now overweight, and one in 12 obese.5 Based on BMI definitions, the prevalence of obesity was higher in Pacific Island and Māori children (23.3% and 11.8% respectively) compared with NZ European and Asian (5.5% and 5.9%, respectively). These data will underestimate rates of obesity in Asian populations, as they have a greater degree of adiposity than Europeans at a specific BMI.35 This has been studied extensively in Indians and is known as the ‘thin-fat’ phenotype, and places this ethnic group at risk for obesity related diseases at relatively low BMI’s. In contrast, Pacific populations have less adipose mass at a given BMI compared with European populations.36
Childhood obesity is associated with a number of co-morbidities including dyslipidaemia, hypertension and abnormal glucose tolerance,37 and increases the risk of children developing chronic diseases such as T2DM and cardiovascular disease later in life.38 Though previously rare, the diagnosis of T2DM in youth is becoming increasingly common and strongly associated with obesity.39 Obesity tends to track from childhood into adulthood,40 and is notoriously difficult to treat. For these reasons, early life interventions that prevent the onset of overweight and obesity are urgently needed.

Conclusion

Infants born to mothers with GDM are at an increased risk of obesity and T2DM in childhood and adolescence. This could impact on the rates of these diseases, particularly in Indian, Pacific Island, and Māori populations, who tend to have higher rates of GDM. In effect a cyclical relationship could develop; where obese and diabetic mothers give birth to infants who become obese and develop diabetes before their childbearing years, only to pass this on to their offspring.
Breaking this cycle requires education and focused efforts to optimise the environment and health of young women before and during pregnancy, recognition and treatment of women with GDM, continued promotion of breastfeeding and follow up of women who have had GDM, plus their children. These are important public health issues that are likely to have far-reaching effects on future generations.
Competing interests: None known.
Author information: Sarah Bristow, MPhil candidate, Centre for Physical Activity and Nutrition Research, AUT University, Auckland; Elaine Rush, Professor of Nutrition, Centre for Physical Activity and Nutrition Research, AUT University, Auckland; Janet Rowan, Obstetric Physician, National Women’s Health, Auckland District Health Board, Auckland
Correspondence: Sarah Bristow, Centre for Physical Activity and Nutrition Research, AUT University, Private Bag 92006, Auckland 1142, New Zealand. Fax +64 (0)9 9219960; email: sarah.bristow@aut.ac.nz
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