Introduction
Gestational diabetes mellitus (GDM) is recognised to be an early manifestation of type 2 diabetes mellitus, with shared pathogenic features [
1]. Recently, it has been demonstrated that individuals with type 2 diabetes can durably be returned to non-diabetic glucose control by substantial weight loss depending on initial reduction in liver triacylglycerol content [
2,
3]. However, information on liver triacylglycerol content in GDM is limited even in animal models [
4].
In type 2 diabetes, both liver triacylglycerol and fasting plasma glucose are normalised within 7 days of a substantial reduction in energy intake [
5]. Over a period of weeks, a more moderate reduction of energy intake to 5 MJ (1200 kcal)/day decreases liver triacylglycerol content and plasma glucose [
6]. High levels of liver triacylglycerol are known to be present years before the diagnosis of type 2 diabetes [
7] and women with previous GDM have markedly elevated liver triacylglycerol levels [
8,
9]. As normal pregnancy is associated with a greater than twofold increase in plasma triacylglycerol levels [
10], a physiological rise in liver triacylglycerol would be expected during pregnancy as these variables are usually closely associated [
11]. This may be exaggerated in pregnancies complicated by GDM.
Food restriction in pregnancy, as a way to improve adverse metabolic factors, understandably raises concerns. Many of these concerns are unfounded [
12] and, conversely, both obesity and gestational diabetes are known to confer substantial risks [
13,
14]. Meta-analysis has shown that weight loss in pregnancy in healthy women reduces the incidence of GDM and also pre-eclampsia, gestational hypertension and preterm birth, with no effect on fetal growth [
15]. However, current guidelines do not recommend weight loss during pregnancy [
16]. Further, there is little information on how accepting women with GDM would be towards receiving specific advice to decrease energy intake.
The primary aims of this study were to define the extent of liver triacylglycerol accumulation during pregnancy in women diagnosed with GDM and the effect upon this of modest energy restriction. The metabolic effects and acceptability of energy restriction in GDM were also examined.
Discussion
The present study suggests that GDM is not typically characterised by high levels of liver triacylglycerol. The hypo-energetic diet brought about a weight loss of 0.4 kg/week and halved liver triacylglycerol content. Over the 4 week treatment period there was no change in insulin secretion in response to a test meal. The diet was well tolerated, resulting in glycaemic control equivalent to that achieved using conventional management (insulin and metformin as required).
The observation of normal liver triacylglycerol levels did not match the expectation arising from analysis of the literature. Previous studies have demonstrated that non-pregnant women with a history of GDM have elevated liver triacylglycerol levels [
8,
9] and have a greater risk of non-alcoholic fatty liver disease in later life [
28]. Given that excess intrahepatic triacylglycerol is an important underlying factor in the development of type 2 diabetes, with average levels of 12.8 ± 2.4% [
3,
7], it was anticipated that increased fat would be observed in women with newly diagnosed GDM. Further, raised liver triacylglycerol levels in type 2 diabetes are associated with raised plasma triacylglycerol [
29], and plasma triacylglycerol levels are increased to a greater extent in GDM than in non-diabetic pregnancy [
29]. Abnormal lipid metabolism appears to have a central role in GDM [
10]. The present data are the first in vivo magnetic resonance liver triacylglycerol measurements to be reported during human pregnancy. The observation of apparently normal liver triacylglycerol content in most participants raises the possibility that liver triacylglycerol content may decrease during pregnancy despite increases in plasma triacylglycerol, and that levels which are normal in the non-pregnant state may be associated with GDM. It is interesting to note that liver triacylglycerol, but not plasma triacylglycerol, decreased following hypo-energetic dieting. This is likely to reflect the physiological adaptation of pregnancy, with requirement for a sharp increase in plasma triacylglycerol after the first trimester, and change in nutritional state is unlikely to change this.
The present data raise the possibility that liver fat levels fall reciprocally with elevation of plasma triacylglycerol. This hypothesis can be tested in a future study. It is consistent with ultrasound findings of an association between the presence of liver steatosis in early pregnancy and the subsequent risk of GDM [
30] and also the association of raised ALT with risk of GDM [
31]. However, in the aforementioned study, liver ultrasound was performed between 11 and 14 weeks, before the onset of either raised plasma triacylglycerol or significant insulin resistance. In the present study we did not observe any marked change in liver triacylglycerol after pregnancy, although it is not known how long any pregnancy-associated change in liver triacylglycerol may take to return to non-pregnancy levels. Now that the safety of MRS in pregnancy is accepted, further work is required to establish the physiology of liver triacylglycerol in non-diabetic pregnancy and to compare differences in GDM. To our knowledge, there are no quantitative studies of human or animal liver fat during normal pregnancy. It is established that a very-high-fructose diet during pregnancy is associated with histologically assessed steatosis in animal models [
4].
The study group were representative of the wider population of women with GDM. Age and BMI were similar to those of participants in larger studies of GDM [
14,
32]. HbA
1c in the study group (5.3 ± 0.4% [34 ± 4 mmol/mol]) was similar to that at the time of diagnosis in all women recorded in the Newcastle GDM database (5.5 ± 0.8% [36 ± 9 mmol/mol]). The group was predominantly white British, reflecting the population of the North East of England.
The time course of return of normal first-phase insulin secretion for people with type 2 diabetes during a very-low-energy diet has been defined [
5]. Even at 2.5–3.3 MJ (600–800 kcal)/day, 8 weeks was required for normal insulin secretion to be restored and at 4 weeks improvement was modest. The present study necessarily used a less severely restricted diet of 5 MJ (1200 kcal)/day and, as a first step, this was advised for 4 weeks only. The lack of change in insulin secretion following the test meal is therefore not unexpected. Further work is required to establish whether the insulin secretory abnormality in GDM [
33], being of short duration, is more readily reversed than that of type 2 diabetes.
Dietary weight loss during pregnancy is viewed with caution by many obstetricians, even though obesity is a major risk factor for macrosomia and associated adverse outcomes. The benefits of minimising weight gain during pregnancy, in the present era of steady weight gain during adult life, were first reported several years ago [
34]. This is especially relevant in GDM [
14,
32,
35]. A clear decrease in energy intake has been achieved on a whole-clinic basis by Asbjornsdottir and colleagues who achieved a decrease in median weight gain during pregnancy from 12.1 to 3.7 kg [
36]. This was associated with decreases in large-for-gestational-age infants (39% to 12%) and perinatal morbidity (71% to 35%). At the time when GDM is diagnosed there is likely to be increased motivation to decrease energy intake. All 14 women who completed the study reported that they were comfortable with the explanation of likely benefit for their baby. The present study is unique in demonstrating the effectiveness and acceptability of modest weight loss at the time of diagnosis of GDM. A randomised study of dietary weight loss is now required.
Several practical features of the dietary intervention merit discussion. The reasons why weight loss in pregnancy was believed to be important for fetal health were carefully explained to each woman. Diets were individualised according to preferred eating habits and women were asked to discuss this with family and friends. The use of current smartphone technology encouraged engagement with the diet and regular communication with the study team. Women reported that this immediacy of communication facilitated dietary compliance and allowed access to medical advice for management of their blood glucose levels. The dietary intervention was more intensive than conventional intermittent clinic review, although halving of gestational weight gain has previously been reported using monthly dietetic consultations [
37].
The number of women studied was small, but the participants were representative of the wider population with GDM. The study was large enough to demonstrate a highly statistically significant difference in weight loss between intervention and comparator groups. However, due to the small sample size it was not possible to adjust for other factors that may differ between the groups, nor was it possible to subanalyse the group (for example, to study the outcome of those who lost more weight than others). As women were advised of the diagnosis of GDM and of the aims of the study at a clinic visit several days before the baseline measurements, the baseline necessarily reflects an initial dietary intervention (mean fasting glucose falling from 5.0 mmol/l to 4.3 mmol/l). Avoidance of insulin therapy is associated with major benefit in simplifying peripartum obstetric management as well as minimising weight gain, personal inconvenience and use of healthcare resources. Even so, most women were in the lower range of plasma glucose concentration for diagnosis of GDM and it will be important to study women with higher presenting blood glucose levels. Size restrictions within the magnetic resonance scanner preclude women with an abdominal circumference greater than 102 cm from taking part in such studies. However, no woman in this study was excluded on this criterion. Women with the highest BMI might be expected to have the strongest association between GDM and hepatic steatosis and to experience a more dramatic effect of energy restriction on the liver. However, recent data on the lack of association between raised ALT and risk of GDM in more obese women suggest that this is unlikely [
31].
The present study highlights the important question of liver triacylglycerol physiology in normal and GDM pregnancy and provides data for informing the design of further studies. Additionally, there is a need for a prospective randomised therapeutic study of dietary weight loss from the time of diagnosis of GDM.
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