Trying to understand gestational diabetes

Abstract

Women with normal glucose tolerance pre-gravid and developing gestational diabetes in late gestation have subclinical metabolic dysfunction prior to conception compared with women with normal glucose tolerance. Because of the 60% decrease in insulin sensitivity with normal pregnancy, these women develop clinical hyperglycaemia/gestational diabetes in late gestation. The metabolic dysfunction includes impaired insulin response, decreased hepatic suppression of glucose production during insulin infusion and decreased insulin-stimulated glucose uptake in skeletal muscle, i.e. peripheral insulin resistance. The insulin resistance in normal glucose tolerance pregnancy is related to a decrease in the post-receptor insulin signalling cascade, specifically decreased insulin receptor substrate 1 tyrosine phosphorylation. In women with normal glucose tolerance this is reversed post-partum. In contrast, in gestational diabetes, in addition to the decrease in insulin receptor substrate 1 tyrosine phosphorylation, there is an additional decrease in tyrosine phosphorylation of the intracellular portion of the insulin receptor that is not related to the insulin receptor protein content. Post-partum women with gestational diabetes, who had retention of gestational weight gain, had no significant improvement in insulin sensitivity and increased inflammation expressed as increased plasma and skeletal muscle tumour necrosis factor alpha. The increased inflammation or meta-inflammation is a hallmark of obesity and during pregnancy develops in both white adipose tissue and placenta. Last gene array studies of placenta were associated with alterations in gene expression relating primarily to lipid in contrast to glucose metabolic pathways in gestational diabetes compared with Type 1 diabetes. Future studies are directed at decreasing inflammation prior to and during pregnancy using various lifestyle and nutritional interventions.

FIGURE 1

Glucose infusion rate during hyperinsulinaemic– euglycaemic clamp (mg/kg FFM/min) in non-pregnant women with a previous history of gestational diabetes mellitus and normal glucose tolerance during pregnancy [1].

FIGURE 2

Longitudinal changes in peripheral insulin sensitivity in ( a ) lean women and (b) obese women as indicated by infusion of glucose required to maintain euglycaemia (90 mg/dl) + endogenous glucose production during insulin infusion (mean SD). Reproduced from (a) Catalano et al. (1993) [3], with permission from the American Physiological Society, and (b) Catalano et al. (1999) [4], with permission from Elsevier.

FIGURE 3

Longitudinal changes in (a) first-phase and (b) second-phase insulin response during intravenous glucose tolerance test in lean normal glucose tolerance and gestational diabetes (mean SD). (b) Reproduced from Catalano et al. (1993) [3], with permission from Elsevier.

FIGURE 4

Longitudinal changes in (a) first-phase insulin response during intravenous glucose tolerance test in obese normal glucose tolerance and gestational diabetes and (b) second-phase insulin response during intravenous glucose tolerance test (mean SD). (b) Reproduced from Catalano et al. (1999) [4] with permission from Elsevier.

FIGURE 5

Longitudinal changes in fat mass in (a) lean and (b) obese normal glucose tolerance and gestational diabetes pre-gravid, in early pregnancy and in late pregnancy (mean SD). Reproduced from (a) Catalano et al. (1998) [5] and (b) Okereke et al. (2004) [8] with permission from Elsevier and the American Physiological Society.

FIGURE 6

(a) Longitudinal changes in total basal endogenous glucose production (mean SD) in lean normal glucose tolerance and gestational diabetes. (b) Longitudinal changes in total basal endogenous glucose production expressed in mg/kg fat-free mass¹ min¹ (mean SD). (b) Reproduced from Catalano et al. (1993) [3] with permission from Elsevier.

FIGURE 7

Insulin effect on in vitro glucose uptake in rectus abdominus skeletal muscle. Reproduced from Friedman et al. (1999) [9], with permission from the American Diabetes Association.

FIGURE 8

Insulin effect on tyrosine phosphorylation of insulin receptor is decreased in normal glucose tolerance and gestational diabetes. When adjusted for protein content, the tyrosine phosphorylation was significantly decreased in gestational diabetes. Reproduced from Friedman et al. (1999) [9], with permission from the American Diabetes Association.

FIGURE 9

Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) is decreased in normal glucose tolerance and gestational diabetes but not after normalizing for IRS-1 protein content. Reproduced from Friedman et al. (1999) [9], with permission from the American Diabetes Association.

Figure 10

Correlation between the change in insulin sensitivity and insulin receptor substrate 1 (IRS-1) protein in skeletal muscle from late pregnancy to 1 year post-partum in lean normal glucose tolerance, r = 0.84, P < 0.007. Reproduced from Kirwan et al. [10], with permission from the Endocrine Society.

FIGURE 11

Unsupervised hierarchical clustering shows expression data for the metabolic genes that are modified in pregnancy with gestational diabetes mellitus and Type 1 diabetes mellitus. The prominent clusters that are shown on the right are based on the putative functional characteristics of the genes. The colour tag and intensity represent the expression level from lowest (blue) to highest (red). Data are shown from six representative arrays that were run in duplicate. Reproduced from Radaelli et al. (2009) [19], with permission from Elsevier.

FIGURE 12

(a) A visulization of lipid droplets in primary term placental cells. Freshly isolated trophoblast cells were cultured for 48 h with no addition (control) or the addition of glucose (10 mmol/l), oleate (400 nmol/l) or the combination of both. (b) The quantification of lipid accumulation by scanning densitometry. Results are given as mean SE of 4–6 independent experiments with duplicate culture wells. *Probability value of < 0.0001. Reproduced from Radaelli et al. (2009) [19], with permission from Elsevier.