The fetal glucose steal: an underappreciated phenomenon in diabetic pregnancy

Abstract

Adverse neonatal outcomes continue to be high for mothers with type 1 and type 2 diabetes, and are far from eliminated in mothers with gestational diabetes mellitus. This is often despite seemingly satisfactory glycaemic control in the latter half of pregnancy. Here we argue that this could be a consequence of the early establishment of fetal hyperinsulinaemia, a driver that exaggerates the fetal glucose steal. Essentially, fetal hyperinsulinaemia, through its effect on lowering fetal glycaemia, will increase the glucose concentration gradient across the placenta and consequently the glucose flux to the fetus. While the steepness of this gradient and glucose flux will be greatest at times when maternal hyperglycaemia and fetal hyperinsulinaemia coexist, fetal hyperinsulinaemia will favour a persistently high glucose flux even at times when maternal blood glucose is normal. The obvious implication is that glycaemic control needs to be optimised very early in pregnancy to prevent the establishment of fetal hyperinsulinaemia, further supporting the need for pre-pregnancy planning and early establishment of maternal glycaemic control. An exaggerated glucose steal by a hyperinsulinaemic fetus could also attenuate maternal glucose levels during an OGTT, providing an explanation for why some mothers with fetuses with all the characteristics of diabetic fetopathy have 'normal' glucose tolerance.

Keywords: Diabetic fetopathy; Fetal glucose steal; Fetal hyperinsulinaemia; Gestational diabetes mellitus; Placenta; Pregnancy; Review; Transplacental glucose transfer; Type 1 diabetes; Type 2 diabetes.

Fig. 1

Maternal (M) glucose is transferred to the fetus (F) across the placenta down a concentration gradient. The glucose gradient is determined by both maternal and fetal glucose levels. Maternal high glucose (MHG) and/or lower fetal glucose will steepen the gradient, leading to augmented glucose flux into the fetus. MHG is a consequence of inadequate control of maternal diabetes, which promotes increased glucose transfer to the fetus, increased fetal blood glucose, increased stimulation of insulin release from fetal islets and, consequently, fetal hyperinsulinaemia (FHI), as described by Pedersen and Osler [12]. Importantly, FHI, by increasing the rate of glucose utilisation by the fetus, will lower fetal glucose, thereby increasing the steepness of the transplacental glucose gradient and the rate of glucose transfer. In effect, MHG pushes glucose and FHI pulls glucose (the fetal glucose steal) across the placenta to the fetus. The ensuing increased glucose delivery from diabetic mothers, together with the FHI, stimulates fetal triacylglycerol formation and the deposition of excess fetal adipose tissue

Fig. 2

OGTTs were performed in 34 mothers with GDM at 25 and 31 weeks prior to any commencing insulin therapy. Amniocentesis was also performed at week 31 and AFI levels were measured [9]. In the mothers of the 13 normoinsulinaemic fetuses (AFI <48.6 pmol/l; solid blue line), maternal glucose tolerance deteriorated from the first to the second time point as manifested by a higher 1 h post-load glucose value (9.3 vs 10.0 mmol/l; p = 0.0006). In the mothers of the 21 hyperinsulinaemic fetuses (AFI >48.6 pmol/l; dotted red line), the glucose levels at 1 and 2 h of the repeated OGTT were lower (significant for the 1 h reading only) than at 25 weeks (1 h, 11.2 vs 9.9 mmol/l, p = 0.002; 2 h, 8.8 vs 7.7 mmol/l, p = 0.158) [9]. Figure created from data from Weiss et al [9]