The contribution of intra-organ fat deposition to insulin resistance in normal pregnancy and gestational diabetes

Abstract

Gestational diabetes (GDM) affects 3-5% of pregnancies and is associated with stillbirth, accelerated fetal growth and fetal growth restriction, birth trauma, increased risk of caesarean section and third degree tear. Many mothers with GDM go on to develop type 2 diabetes (T2DM) in later life. T2DM is associated with increased fat deposition in the muscle, liver and pancreas leading to insulin resistance, impaired insulin secretion and hyperglycaemia. Muscle insulin resistance and its association with raised intramyocellular lipid is one of the first detectable changes in T2DM. Low calorie dieting causes reversal of T2DM and removal of intra-organ fat. The pathophysiology of GDM is poorly understood, but fat deposition may play a similarly important role. Low calorie dieting is poorly studied and viewed with caution in pregnancy. This work explores the nature of physiological insulin resistance in pregnancy and the clinical and metabolic outcomes of reducing calorie intake to 1,200kcal/day in pregnancy affected by GDM (WELLBABE – WEight Loss Looking for Babe and mother BEtter outcomes study). The LIPIDPREG study used magnetic resonance spectroscopy (MRS), a non-invasive technique that has not been previously used in pregnancy, to quantify intramyocellular lipid within the soleus muscle in women with normal glucose tolerance. A standardised meal test was used to calculate insulin sensitivity and secretion. Studies were done at 34 weeks gestation and 12 weeks postpartum. Eleven primiparous healthy pregnant women (age: 27-39 years, body mass index 24.0±3.1 kg/m2) and no personal or family history of diabetes underwent magnetic resonance studies to quantify intramyocellular lipid, plasma lipid fractions, and insulin sensitivity. The meal-related insulin sensitivity index was considerably lower in pregnancy (45.6±9.9 vs. 193.0±26.1; 10-4 dl/kg/min per pmol/l, p=0.0002). Fasting plasma triglyceride levels were elevated 3-fold during pregnancy (2.3±0.2 vs. 0.8±0.1 mmol/l, p<0.01) and the low-density density lipoprotein fraction, responsible for fatty acid delivery to muscle and other tissues, was 6-fold elevated (0.75±0.43 vs. 0.12±0.09 mmol/l; p=0.001). However, mean intramyocellular lipid concentrations of the soleus muscle were not different during pregnancy (20.0±2.3 vs. 19.1±3.2 mmol/l, p=0.64). In conclusion, the pregnancy effect on muscle insulin resistance is distinct from that underlying type 2 diabetes. The WELLBABE study recruited women with an abnormal oral glucose tolerance test from 21 to 34 weeks (mean 27 weeks) gestation. MRS quantification of liver fat, a standardised meal test and plasma lipid profiles were performed before and after a 1,200kcal/day diet. Participants food diary and glycaemic control were reviewed on a daily basis for 4 weeks, iv through the use of smartphone technology. Fourteen women, who completed the study, achieved a weight loss of 1.6±1.7 kg over the 4 week dietary period. Mean weight change was -0.4 kg/week in the study group vs +0.3 kg/week in the comparator group (p=0.002). Liver triacylglycerol level was normal but decreased following diet (3.7% [interquartile range, IQR 1.2-6.1%] vs 1.8% [IQR 0.7-3.1%], p=0.004). There was no change in insulin sensitivity or production. Insulin was required in six comparator women vs none in the study group (eight vs two required metformin). Blood glucose control was similar for both groups. The hypo-energetic diet was well accepted. Liver triacylglycerol in women with GDM was not elevated, unlike observations in non-pregnant women with a history of GDM. A 4 week hypo-energetic diet resulted in weight loss, reduced liver triacylglycerol and minimised pharmacotherapy. The underlying pathophysiology of glucose metabolism appeared unchanged. The results of these two studies are presented in this thesis and from this work a hypothetical model of insulin resistance in pregnancy and GDM is presented. It is demonstrated that reduced calorie dietary intervention is both acceptable and feasible in pregnancy and reduced the need for medication in women with GDM. Further studies are needed in this area to unravel the true pathophysiology of GDM and to develop a reduced calorie dietary intervention that could be used in routine clinical practice.