The role of adipose tissue in the insulin resistance of pregnancy in humans : a clinical and laboratory assessment

Russell, Anthony William (2004). The role of adipose tissue in the insulin resistance of pregnancy in humans : a clinical and laboratory assessment PhD Thesis, School of Medicine, The University of Queensland.

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Author Russell, Anthony William
Thesis Title The role of adipose tissue in the insulin resistance of pregnancy in humans : a clinical and laboratory assessment
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2004
Thesis type PhD Thesis
Supervisor John Prins
David McIntyre
Total pages 302
Collection year 2004
Language eng
Subjects L
321004 Endocrinology
730105 Endocrine organs and diseases (incl. diabetes)
Formatted abstract

The metabolic changes that occur during pregnancy help maintain an adequate supply of nutrients to the fetus. One of these metabolic changes is the development of insulin resistance with compensatory hyperinsulinaemia. In some pregnancies, defects in these metabolic changes result in the development of gestational diabetes mellitus (GDM). Pregnancy and GDM are therefore models of insulin resistance and a further understanding of the mechanisms underlying this insulin resistance could greatly benefit not only the treatment of GDM but also Type 2 Diabetes Mellitus (T2DM).

It has been considered that the aetiology of these metabolic changes in pregnancy is due to the secretion of hormones produced form the placenta. It is not known which hormone(s) is/are causative or exactly how it/they induce insulin resistance. Pregnancy is associated with on average 3-4 kg accumulation of fat mass and the contribution of this to the development of insulin resistance is not clear. Adipose tissue is increasingly being considered central to the development of insulin resistance; not only as a site of insulin resistance but in its ability to secrete factors which affect whole body insulin sensitivity. Examples of these factors include leptin and adiponectin.

In pregnancy, the molecular mechanisms associated with insulin resistance are not completely understood. Recent studies in cell cultures have identified a PI-3-kinase (PI3K) independent pathway (APS, Cb1, CAP, Ckll, C3G, TCIO, GLUT4) that is necessary for insulin-stimulated glucose uptake in conjunction with the well described PI3K dependent pathway (IRS-1, PI3K, Akt, atypical PKC's, GLUT4). Hyperosmolarity induced by sorbitol also stimulates glucose uptake by a pathway that converges with the PI3K independent pathway. To date there has been no assessment of this non-insulin mediated form of glucose uptake in human adipose tissue or of the PI3K independent pathway. An assessment of both insulin and sorbitol-stimulated glucose uptake could clarify in which of these two pathways a defect in insulin-stimulated glucose uptake may occur.

The hypotheses, upon which the studies of this thesis were designed to address, were that:

1. Adipose tissue is a site of insulin resistance in pregnancy.

2. The mechanisms underlying the insulin resistance in adipose tissue are depot-specific and due to the abnormal subcellular distribution of key molecules involved in insulin-stimulated glucose uptake.

3. The aetiology of the insulin resistance in pregnancy is due to factors secreted from adipose tissue itself or from the conceptus.

The major aims were to recruit pregnant women with normal glucose tolerance (NGT), GDM and nonpregnant controls and:

1. Measure basal, insulin- and sorbitol-stimulated glucose uptake in subcutaneous and omental adipose tissue.

2. Assess the subcellular distribution of the insulin receptor, p85 (the regulatory subunit of PI3K), cbl-associated protein (CAP) and the glucose transporters GLUT4/GLUT1.

3. Derive an in vivo measure of insulin sensitivity from fasting serum glucose and insulin.

4. Measure PGH, ghrelin, leptin and adiponectin in maternal and cord blood where applicable and correlate these with variables assessed in aims 1, 2 and 3.

The major findings of this thesis are:

1. Adipose tissue is not a site of insulin resistance in normal pregnancy or GDM and there are no depot-specific differences in insulin-stimulated glucose uptake. Similarly there were no differences in the subcellular distribution of the insulin receptor, p85, GLUT4, or GLUT1 in pregnancy or GDM.

2. Sorbitol stimulates glucose uptake into subcutaneous adipose tissue. This effect is impaired in pregnancy and GDM and this may correlate with reduced protein expression of CAP in subcutaneous adipose tissue in normal pregnancy and GDM.

3. Maternal leptin, adiponectin, PGH and ghrelin are not responsible for the insulin resistance of pregnancy or the development of GDM.

4. Correlations exist between cord blood levels of leptin, adiponectin and ghrelin with PGH in NGT pregnancies. These correlations are disrupted in GDM.

These findings negate the hypotheses that adipose tissue is a site of insulin resistance or induces insulin resistance through the production of adiponectin and leptin in pregnancy and GDM. They highlight that the PI3K independent pathway may have physiological significance. Serum adiponectin and ghrelin need to be further investigated as to whether they directly modify insulin-stimulated glucose uptake. To ensure adequate nutrition the conceptus may regulate the secretion of PGH via the production of adiponectin, leptin and ghrelin and in so doing alter maternal metabolism.

Keyword Insulin resistance
Pregnancy -- Complications

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 18:23:05 EST