2.- PLIEGO DE CONDICIONES
2.3.- MODALIDADES DE LA SEÑALIZACIÓN DE OBRA
This study shows that pregnancy does not appear to affect IMCL concentrations even though there is a four-fold increase in insulin resistance during pregnancy compared to postpartum. A three-fold increase in plasma triglycerides was observed as was a small increase in postprandial glucose concentrations, consistent with the insulin resistant state. In addition, the feasibility of MRS at 3 Tesla during pregnancy was demonstrated with the technique well tolerated by all the participants.
These results differ from observations in other insulin resistant states, in particular T2DM where IMCL levels are often elevated and mark the beginning of the pathophysiological process (Perseghin et al., 1999; Virkamaki et al., 2001; Ravikumar et al., 2005). Intracellular fatty acids are metabolised within the cell to intermediaries, especially diacylglycerol and ceramides, which directly cause insulin resistance through preventing translocation of the GLUT4 glucose channel thereby preventing glucose uptake (Roden, 2004). This is the first step in the uptake and metabolism of postprandial glucose, as described in detail in
Chapter 1. The present study indicates that there must be alternative pathways of inducing insulin resistance in pregnancy resulting in equally profound changes. Kirwan et al studied the reversal of insulin resistance in a similar group of normal, non-obese pregnant women, only using muscle biopsy as opposed to MRS (Kirwan et al., 2004). Insulin sensitivity improved by 74% in the postpartum period and this was accompanied by a 42% increase in insulin receptor expression, a 69% increase in IRS-1 protein and a reduction in the p85a alpha regulatory subunit of phosphatidylinositol 3-kinase. These changes allow a greater response to insulin-receptor binding through expression of downstream signalling mechanisms and increased numbers of insulin receptors. Pregnancy regulation of cellular mechanisms and gene expression is thus likely to be hormonal in origin (possibly a combination of corticosteroid and placental e.g. human placental lactogen).
This study investigated the relationship between insulin resistance and IMCL deposition in a group of normoglycaemic, non-obese pregnant women. Although no change in IMCL was noted in this group, evidence from postpartum studies in women with prior GDM would suggest that elevated muscle lipid may contribute to the ‘additional’ insulin resistance seen in these women during pregnancy (Kautzky-Willer et al., 2003). A longitudinal study comparing muscle fat and measuring insulin resistance in women with and without GDM is necessary to test this hypothesis further.
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This study utilised noninvasive techniques (MRS) under normal conditions (meal test) to evaluate everyday metabolic physiology. It is one of the first studies to utilize 3 Tesla magnetic resonance in pregnancy in a research setting. The procedure was well tolerated by all the women and no adverse fetal effects were noted. Scanning protocols were modified to reduce noise and energy deposition. MRS is superior to muscle biopsy as it is noninvasive and less susceptible to contamination and processing artefact (Szczepaniak et al., 1999; Howald et al., 2002).
Meal testing was utilized in this and the subsequent study, and was performed following an overnight fast. This was well accepted by the participants and ketone levels were not unduly high as a result. The breakfast itself was substantial (575kcal) and was not always fully eaten. In order to be able to compare the results from paired samples, the amount of food eaten was noted and repeated on subsequent testing. The standardised meal test is a dynamic test of insulin secretion and glucose uptake in the context of physiological conditions (i.e. it reflects day-to-day parameters of glucose uptake, exposure and disposal). By contrast, HOMA is a non-dynamic estimation of insulin resistance under fasting conditions whilst clamp tests operate under extreme conditions of hyperinsulinaemia or hyperglycaemia. The meal test was advantageous for pregnant women as it is relatively non-invasive (requiring an intravenous cannula, but not drug infusions), avoids hypoglycaemia and allows freedom of movement. However, the study was relatively prolonged (between 2 and 3 hours duration) and this may have an impact on the design of future studies. A quicker assessment of beta cell function (e.g. OGTT or HOMA) and insulin sensitivity may make participation easier. Limitations of the study must be considered. A small sample size was necessary to make detailed magnetic resonance possible and to perform more extensive metabolic testing than would be feasible with a larger sample size. Secondly, the population studied (white British, non-obese, nulliparous) is not representative of the general pregnant population. Strict inclusion criteria were used in order to obtain as homogeneous a sample as possible to avoid confounding factors such as body mass index and ethnicity. Finally, MRS was limited to the soleus muscle. Although some studies have shown relationships between insulin sensitivity and IMCL in tibialis anterior only (Kautzky-Willer et al., 2003), IMCL in the soleus is most widely used as an indicative muscle and has been shown to reflect whole body insulin sensitivity (Krssak et al., 1999). To scan more than one muscle would have prolonged scanning time, which was not felt reasonable given women were in the third trimester of pregnancy.
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In conclusion, this study demonstrates that the insulin resistance of healthy pregnancy does not appear to be associated with IMCL deposition, in contrast to other insulin resistant states. The insulin resistance of muscle that characterises late pregnancy must be caused by a distinct, gestation-mediated mechanism.
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