Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02479113 |
| Other study ID # |
201401-0691 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
February 4, 2015 |
| Last updated |
October 31, 2016 |
| Start date |
March 2014 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
October 2016 |
| Source |
University of Malaya |
| Contact |
Shireene Vethakkan, MD |
| Email |
shireene.vethakkan[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
Malaysia: National Medical Research Register |
| Study type |
Observational
|
Clinical Trial Summary
Besides maternal hyperglycemia, a strong link between maternal pregravid weight/maternal
triglyceride(Tg) levels and fetal growth/childhood obesity/metabolic syndrome in offspring
has been demonstrated in largely Caucasian populations. This study aims to explore the link
between maternal hypertriglyceridemia and offspring health in Asians.
Description:
The prevalence of gestational diabetes mellitus (GDM) worldwide is increasing, with
accelerated rates of obesity in women of child-bearing age, increasing maternal age and
improved survival of very low and high birth weight (BW) female offspring in modern times.
GDM prevalence rates are known to be higher in some Asian populations compared with Western
populations. The incidence rate amongst South Indians in India, and Malaysians in an urban
tertiary centre in Kuala Lumpur are 14 and 11.4% respectively while in Western populations
GDM only accounts for 2-9% of all pregnancies.
It is now well-established that exposure to an intrauterine diabetic milieu, in both
pregnant women with type 2 diabetes (T2DM) and those with GDM, imparts increased future risk
of diabetes, obesity, metabolic syndrome and cardiovascular disease in offspring. Besides
maternal hyperglycemia, a strong link between maternal pregravid weight/maternal
triglyceride (Tg) levels and fetal growth/childhood obesity/metabolic syndrome in offspring
has been demonstrated in largely Caucasian populations.
The mechanisms of the developmental origins of adult disease however are poorly understood.
The in utero environment via changes to the epigenome that do not involve alterations in DNA
sequence can exert stimulatory or inhibitory effects on fetal growth and adiposity6. It has
been proposed that a pathological metabolic milieu in utero results in fetal epigenetic
changes such as DNA methylation and histone modification, thus modulating biological
processes related to intrauterine development, such as gene expression, chromatin
accessibility, DNA replication, imprinting and human disease patterns.
Lipotoxicity in adults is well-established to result in the development of insulin
resistance and pancreatic beta-cell dysfunction. Much emphasis has already been given to
management of maternal hyperglycemia during pregnancy. It is possible however that maternal
hypertriglyceridemia on the other hand will soon become a therapeutic target in the fight
against childhood diabetes and obesity. Normal pregnancy is associated with a physiological
increase in Tg from 10 weeks gestation onwards; with a 2-3 fold increase in serum Tg levels
by the 3rd trimester. These elevations can be attributed to enhanced hepatic production of
VLDL, increased intestinal absorption of dietary lipids, reduced clearance of Tg due to
decreased extra-hepatic lipoprotein lipase activity and reduced insulin sensitivity during
pregnancy. Even so, Tg levels during pregnancy are known to be higher in women with T2DM and
GDM when compared with healthy pregnant controls. Maternal hypertriglyceridemia independent
of maternal glucose has been linked with increased BW and fetal adiposity in offspring of
Caucasian women. This association has been shown to hold true in women with GDM as well as
those with Normal Glucose Tolerance (NGT) but risk factors for GDM. Maternal
hypertriglyceridemia has even been linked with pre-eclampsia. Indeed, the fact that Langer
et al, has demonstrated that insulin therapy results in lower macrosomia rates in obese GDM
women than diet therapy despite equivalent glycemic control seems to indicate that some
other metabolic target besides glucose which is modulated by insulin therapy is in play. It
is highly likely that this 'invisible' metabolic variable is maternal triglyceride.
Determining early predictors of development of metabolic syndrome (MS) in offspring will
enable targeted childhood intervention programs. In Western populations it has been
established that pregravid maternal BMI is a strong independent predictor of childhood
obesity/MS whereas birth weight and GDM alone are poor correlates of offspring obesity and
risk of metabolic syndrome. In Boney et al's cohort of Caucasian offspring who were
evaluated from age 6, for example, combination of large for gestational age (LGA) status and
maternal GDM was associated with OR of 10.4 of insulin resistance in offspring at age 11yrs
and increased prevalence of MS at any age. However the prevalence of MS in offspring was not
significantly different between offspring of mothers with NGT whether LGA/average for
gestational age (AGA), and AGA offspring of GDM mothers. Neither were maternal GDM alone and
LGA at birth independently associated with insulin resistance. Maternal obesity alone
however independently conferred an approximate increase in hazard of MS of 2-fold by 11
years of age whereas GDM status alone did not. The risk of developing MS in GDM offspring
diverged between those with LGA and AGA status at age 7, so that by the time these children
were 11 years old the risk was 3.6 fold greater in LGA compared with AGA offspring of GDM
mothers. Alarmingly 50% of GDM offspring who had LGA status at birth had at least 2 out of 4
criteria of MS at any age-point between the ages of 6-11 years. These associations and
relationships however are less well-delineated in Asian populations. In addition, much of
these data, including those of Boney et al's are based on diagnostic definitions of GDM that
have altered since the evidence obtained from the HAPO study. It is possible that Malaysian
GDM offspring may develop a higher risk of metabolic syndrome at an age younger than 7 years
and therefore require intervention programs before the age of school attendance. Hence the
need for studies evaluating metabolic health in GDM offspring in the local Malaysian setting
based on current diagnostic criteria of GDM that will enable more effective intervention
programs tailored to the local setting and based on local data. There is also evidence in
Caucasian and Hong Kong Chinese offspring that in utero hyperinsulinemia is an independent
predictor of abnormal glucose tolerance in childhood. In Hong Kong Chinese offspring, cord
blood insulin was very predictive of abnormal glucose tolerance in children aged 8 years (OR
6.12) whereas BW > 4kg was not, indicating perhaps that in Asians as well, BW is a poor
early predictor of risk of metabolic dysfunction. Evidence indicates that dyslipidemia
precedes development of dysglycemia in offspring of GDM mothers but that there are subtle
differences between Caucasians and Asians with regards to which component of the lipid
profile is impaired. Studies have shown that hypertriglyceridemia is more prevalent than
dysglycemia in Caucasian GDM offspring aged 7-11 years , whereas low HDL is more common in
Hong Kong Chinese GDM offspring aged 8.
Leptin is an established candidate gene for the pathogenesis of obesity and diabetes. It is
secreted by adipocytes and placental tissue and is involved in energy metabolism and insulin
sensitivity control. Leptin levels are increased in obesity, diabetes and pregnancy. 2hr
post-OGTT glucose levels have been shown to correlate with placental leptin gene methylation
levels in pregnant women with impaired glucose tolerance and increased placental leptin gene
methylation is associated with decreased fetal leptin gene expression. 2 hour plasma glucose
however only explains between 19-28% of DNA methylation variability at the leptin gene
locus. The relationship between maternal hypertriglyceridemia and placental leptin gene
methylation/leptin gene expression however has not been as well studied. It is possible that
maternal triglyceride levels are also associated with alterations in placental leptin gene
methylation thus leading to increased fetal adiposity. These changes in leptin gene DNA
methylation adaptations are potentially important as they may be part of the mechanism
whereby the in utero diabetic milieu results in fetal programming i.e. the induction of
permanent changes in cellular structure or function in offspring that result in adult
metabolic dysfunction/obesity. Plasma leptin is known to play an important neurotrophic role
in hypothalamic development. It has been hypothesized that alterations to leptin homeostasis
in utero may disrupt neuronal connections between nuclei that control energy balance and
appetite in the hypothalamus perhaps leading to obesity.
Insulin resistance is a key feature of T2DM and has been implicated in the early
pathogenesis of the disease. Micro-RNA 29 has been implicated in the development of insulin
resistance in type 2 diabetes in vitro. Micro-RNAs are small untranslated/non-coding RNAs
that negatively regulate mRNA translation. MiRNAs are involved in biological functions such
as cell growth and proliferation, development, differentiation, organogenesis and metabolism
and therefore have been linked to the pathogenesis of diabetes. In vitro studies with
adipocyte cell lines have shown that genetic upregulation and overexpression of the miRNA 29
(a,b,c) family occurs in in the presence of hyperglycemia and that this blocks
insulin-stimulated glucose uptake by the adipocyte by inhibiting insulin signalling via the
Akt pathway (and hence expression of GLUT4 on the surface of the cell membrane). MiRNA 29 is
also upregulated in skeletal muscle in a rat model of insulin resistance. There is also
evidence that miRNA 29 is elevated in the presence of high NEFA levels and that this leads
to skeletal muscle insulin resistance (unpublished data, personal communication, Zierath IDF
2013). Skeletal muscle is the primary site of glucose uptake postprandially, accounting for
75% of insulin-mediated glucose removal from plasma. Elevated miR29 is also associated with
reduced insulin secretion. Human in vivo evidence linking miRNA 29 to insulin resistance and
elevated NEFA is however lacking. Pregnancy is a meta-inflammatory state that is associated
with markedly elevated levels of triglyceride, cytokines and NEFA in obese and dysglycemic
women. It is possible that fetal exposure to high NEFA levels in women with gestational
diabetes will result in elevated fetal miRNA 29 at birth which would be positively
correlated with measures of insulin resistance such as HOMA2-%S. Removal from this
glucolipotoxic milieu with parturition could result in a reduction in miRNA 29 with time and
reduced insulin resistance.
There is however a dearth of prospective large studies examining the relationship between
pregravid BMI/maternal hypertriglyceridemia in Asian mothers with GDM, and the metabolic
health of offspring at birth and during childhood. Limited data on Korean women with GDM and
Japanese pregnant women with NGT but positive diabetic screens is available but little
research has been carried out in Southeast Asia. In addition these Asian studies only
examined the link between maternal triglyceride and BW but not offspring body composition.
Maternal hypertriglyceridemia has been associated with increased BW and adiposity at birth,
but very few studies have looked at the association between maternal hypertriglyceridemia
and body weight/ adiposity during childhood in either Asian or Caucasian populations. There
is no consensus, even in western populations, on normal ranges of maternal triglyceride
levels at different stages of pregnancy. Given the well-established fact that adult
adiposity is greater in Asians compared with Caucasians of the same BMI, one could
hypothesize that the association between maternal hyperlipidemia and offspring adiposity and
metabolic health will be stronger in Asians. Asian mothers are known to be twice as likely
to have GDM at a lower BMI. Indeed there is already some evidence that the correlation
between maternal triglyceride levels and birth weight is stronger in Asian-born GDM women
compared with Australian and European-born mothers. It is also possible Malaysian mothers
with BMI considered to be in the non-obese range for Caucasian mothers i.e. 23-30 kg/m2
might have offspring with metabolic dysfunction. These associations have not been studied in
Malaysian GDM offspring of Malay, Chinese and Indian descent. In recent times the
trans-generational impact of maternal nutrition, via fetal epigenetic changes, on the
metabolic health of offspring has been recognized. Given the differences, both current and
historical, in socioeconomic development that impact on population health/wealth between
Western Europe/North America and countries such as India, China and Malaysia it would be
reasonable to postulate that maternal hypertriglyceridemia may have a larger impact on the
health of offspring in developing nations with the sudden transition from poverty to
relative wealth. It is worth evaluating the relationship between maternal metabolic
characteristics during pregnancy, and offspring metabolic health, growth and development in
Chinese and Indian Malaysians as these relationships may differ from those derived from
studies done in Korea, Japan, Hong Kong, China and India given the markedly different
historical trajectories of socio-economic development amongst even Asian countries. Very
little work has also been done amongst mothers with GDM of Malay descent as this ethnic
group is mainly only found in South-east Asia i.e. Malaysia and Indonesia.
With this in mind, we designed a prospective observational longitudinal cohort study to
examine the associations of pregravid BMI and maternal hypertriglyceridemia in Asian GDM
mothers with placental epigenetic changes to the placental leptin gene and offspring
adiposity/metabolic function at birth/during childhood. We also aimed to evaluate cord blood
miRNA29 at birth and 6 months of age. This study will also evaluate 2nd and 3 rd trimester
serum triglyceride ranges in lean and obese Asian pregnant women with Normal Glucose
Tolerance. The study will require participation of researchers from 5 disciplines:
obstetrics, genetics, neonatology, paediatric endocrinology and adult endocrinology.
