A thorough review of the pathophysiology of GDM is found in other sources (20-26) and is beyond the scope of this chapter. A brief review of the normal adaptations in glucose homeostasis and the maladaptations seen in GDM follows.

In normal pregnancy, glucose homeostasis changes in order to meet and maintain the demands of the growing fetus. Maternal adaptations ensure that there is an adequate nutrient supply of glucose and amino acids to the fetus, even at the expense of maternal glucose homeostasis. Pregnancy is characterized by hyperplasia of the pancreatic beta cells, increased insulin secretion, and an early increase in insulin sensitivity followed by progressive insulin resistance (23). Yet fasting glucose concentrations are 20% lower during pregnancy due to increased storage of tissue glycogen, increased peripheral glucose utilization, decreased hepatic glucose production, and glucose consumption by the fetus in late pregnancy (23). Increased levels of estrogen, human placental lactogen, growth hormone, corticotropin-releasing hormone and progesterone characterize the hormonal milieu during pregnancy(27) and these hormones play a major role in mobilizing maternal fuels either directly or indirectly increasing maternal insulin resistance. Subsequently, insulin requirements increase 1.5 to 2.5fold in normal pregnancy over the nonpregnant state (28).

Overcoming the normal insulin resistance of pregnancy requires a compensatory increase in insulin secretion to maintain maternal glucose concentrations within the normal range. When pancreatic beta cells are unable to compensate for the normal insulin resistance of pregnancy, GDM ensues. Individuals with GDM have both decreased insulin sensitivity and decreased insulin secretion. Although patients with GDM have insulin responses similar to those seen in normal pregnancy, their baseline glucose levels are higher indicating a diminished beta-cell response to glucose. In GDM, the insulin response to a glycemic stimulus is about half that of normal pregnancy (29). Euglycemic clamp studies demonstrate diminished insulin secretion in women with GDM, despite the same or greater insulin resistance than that seen in pregnant women without GDM. Thus, failure of appropriate beta-cell compensation characterizes the onset of GDM (20). The mechanism of insulin resistance is unclear. Studies suggest that the GLUT4 transporter may play a role in insulin resistance (30,31). GLUT4 content is normal in skeletal muscle in women with GDM; however, in adipocytes, there is a decrease in number and sub-cellular distribution (30). Fifty percent of women with GDM have significant decreases in GLUT4 concentration, with glucose transporter function depressed by 60% (31).

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