Gestational diabetes is becoming more common at the same time as the obesity epidemic, both in Finland and worldwide [1]. Pregnancy, and especially in its latter half, is associated with severe insulin resistance. High levels of body fat increase insulin resistance, which disrupts glucose metabolism, especially in obese women. In Finland, one in five pregnant women is diagnosed with gestational diabetes [2]. As a result of obesity and insulin resistance, fat often accumulates outside the actual adipose tissue as ectopic fat. One target organ for such fat is the liver, often resulting in non-alcoholic fatty liver disease (NAFLD).

In Finland, fatty liver disease is diagnosed in about one in four people, and the global incidence is even higher [3]. Although gestational diabetes is most often a reversible disorder of glucose metabolism that resolves after pregnancy, the risk of developing type 2 diabetes in follow-up studies has been up to 7-10-fold over ten years compared to women with normal glucose tolerance during pregnancy [1,4,5]. Type 2 diabetes and its common precursor, the metabolic syndrome, are major risk factors for myocardial infarction and stroke in women [6]. Every effort should be made to prevent the later development of type 2 diabetes in a woman with gestational diabetes [7].

In addition to type 2 diabetes, gestational diabetes also predicts the development of fatty liver disease [8]. It is also known that up to 60-70% of diabetics have fatty liver. Fatty liver disease and metabolic syndrome share a common pathophysiology: insulin resistance, chronic mild inflammation, and enhanced sympathetic system activity , so these two metabolic disorders often occur simultaneously in the same individual [9]. The same pathophysiological mechanisms are highlighted in hypertensive pregnancy and gestational diabetes [10,11].

The clinical spectrum of fatty liver disease during pregnancy is quite wide. Its manifestations range from asymptomatic fatty liver during pregnancy to acute fatty liver, a dangerous complication of late pregnancy [12].

Fatty liver disease has also been shown to predict the development of gestational diabetes. Fatty liver disease diagnosed in the first trimester of pregnancy predicts the development of gestational diabetes at 24–28 weeks of 3 gestation [13,14]. A recent study by Loo et al in Singapore supports this finding (15). It examined 382 women before the onset of pregnancy by magnetic spectroscopy (MRS). The subjects were 20-44 years old and had a mean body mass index of 23.5 kg / m2. Liver fat percentage - even before the onset of pregnancy - predicted the development of gestational diabetes significantly better than body mass index, smoking, diabetic burden, or socioeconomic background [14,15]. In addition to gestational diabetes, fatty liver disease, especially more serious levels (degree of steatosis 2-3) in the first trimester of pregnancy increases the risk of large foetal size [16]. Fatty liver disease also increases the risk of other pregnancy complications, such as hypertensive pregnancy, preterm labor, and postpartum hemorrhage [17].

Figure 1: Non-alcoholic fatty liver disease (NAFLD) increases the risk of gestational diabetes and type 2 diabetes. Placental hormones cause physiological insulin resistance in late pregnancy. Leptin secreted by a fat cell in an obese woman stimulates the sympathetic nervous system in the hypothalamus, further increasing insulin resistance both directly and indirectly by increasing lipolysis and free fatty acids through hormone-sensitive lipase. Strong insulin resistance stresses the function of beta cells in the pancreas and poses a risk of developing gestational diabetes and later type 2 diabetes.

Offspring of women with gestational diabetes are at increased risk of being overweight, obese and diabetic. Obese neonates in women with gestational diabetes also have significantly higher intracellular fat levels than neonates in healthy mothers of normal weight [18]. The amount of intracellular fat in newborns correlates with the body mass index measured before pregnancy. The results of experimental animal studies suggest that intestinal microbes in the offspring of obese mothers increase the risk of inflammation and fatty liver disease [19]. The amount of fat in the liver after developing gestational diabetes is indicative of insulin resistance and associated pathological conditions [20]. Women with the highest liver fat levels also had the highest blood levels of triglycerides and insulin, the highest blood pressure, and the lowest levels of whole-body insulin sensitivity.

Fatty liver has been shown to predispose to type 2 diabetes. Fatty liver disease is a major risk factor for gestational diabetes, especially when associated with insulin resistance. Efforts to prevent gestational diabetes have been initiated too late: little emphasis has been placed on inhibiting the development of gestational diabetes during pregnancy [21]. It is clear that the early diagnosis and prevention of fatty liver disease through lifestyle changes can prevent the development of gestational diabetes and later type 2 diabetes [8]. When a lifestyle intervention — physical activity and diet — was initiated before or at the beginning of pregnancy, the intervention reduced the 4 development of gestational diabetes was reduced by 20–45% [22]. However, additional research evidence on the subject is needed.

References

1. Damm P, Houshmand-Oeregaard A, Kelstrup L, (2016) Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia.
2. FinnisNational Birth Registry. 2016.
3. Hyysalo J, Männistö VT, Zhou Y, (2014) A population-based study on the prevalence of NASH using scores validated against liver histology. J Hepatol 60: 839–46.
4. Bellamy L, Casas JP, Hingorani AD (2009) Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 373:1773–9
5. Vounzoulaki E, Khunti K, Abner SC, (2020) Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and metaanalysis. BMJ 369: m1361.
6. Juutilainen A, Kortelainen S, Lehto S, (2004) Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 27: 2898–904.
7. Kaaja R, Harjutsalo V, Groop PH (2016) Diabetes in woman should be prevented (Editorial, in finnish) Duodecim 132: 1405–6
8. Ajmera VH, Gunderson EP, vanWanger LB (2016) Gestational diabetes mellitus is strongly associated with non-alcoholic fatty liver disease. Am J Gastroenterol 111: 658–64.
9. Ei-alkoholiperäinen rasvamaksatauti (NAFLD). Current guidelines (Duodecim 2020) .
10. Hurr C, Simonyan H, Morgan DA, (2019) Liver sympathetic denervation reverses obesity-induced hepatic steatosis. J Physio 597: 4565–80.
11. Kaaja RJ, Pöyhönen-Alho MK (2006) Insulin resistance and sympathetic overactivity in women. J Hypertens 24: 131–41.
12. Liu J, Ghaziani TT, Wolf JL (2017) Acute fatty liver disease of pregnancy: updates in pathogenesis, diagnosis, and management. Am J Gastroenterol 112: 838–46.
13. Lee SM, Kwak SH, Ja Koo JN, (2019) Nonalcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus. Diabetologia 62: 238–48.
14. Michael N, Sadananthan SA, Tint MT, (2020) Should the threshold for assessing fatty liver be lowered in Asian women? Obesity reviews 21: AD04.
15. Loo EXL, Soh SE, Loy SL, (2021) Cohort profile: Singapore preconception study of long-term maternal and child outcomes (S-PRESTO). Eur J Epidemiol 36: 129– 42.
16. Seung Mi Lee, Byoung Jae Kim, Ja Nam Koo, (2019) Nonalcoholic fatty liver disease is a risk factor for large-for-gestational-age birthweight. PLoS One 14: e0221400.
17. Sarkar M, Grab J, Dodge JL, (2020) Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes. Hepatol 73: 516–52217.
18. Brumbaugh DE, Tearse P, Cree-Green M, (2013) Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr 162: 930–6.
19. Soderborg TK, Clark SE, Mulligan CE, (2018) The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat Commun 9: 4462.
20. Tiikkainen M, Tamminen M, Häkkinen AM, (2002) Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes Obes Res 10: 859–67.
21. Chatzakis C, Goulis DG, Mareti E, (2019) Prevention of gestational diabetes mellitus in overweight or obese pregnant women: a network meta-analysis. Diabetes Res Clin Pract 158: 107924.

Mijatovic-Vukas J, Capling L, Sonia Cheng S, (2018) Associations of diet and physical activity with risk for gestational diabetes mellitus: a systematic review and metaanalysis. Nutrients: 1.