Prolactin receptors are critical to the adaptation of islets to pregnancy.

During pregnancy there is an enhanced need for insulin to accommodate the growing fetal compartment as well as the substantial increase in insulin resistance. Failure of the islets to adapt to this increased demand for insulin leads to gestational diabetes. The report by Huang et al. (1), using an in vivo model of prolactin (PRL) receptor deficiency, provides an important validation of the hypothesis that -cell PRL receptors are central to mechanisms whereby islets adapt to pregnancy (Fig. 1). This study showed not only that PRL receptor deficiency leads to gestational diabetes, but the genetic phenotype of the mother influences the outcome of islet development in the fetus. That islets undergo changes during pregnancy was observed as early as 1930 (2), when Cramer concluded that islets are a very plastic tissue that undergo considerable changes, especially during pregnancy. The changes he observed included increased secretory activity, islet growth, and neogenesis. Direct evidence for functional changes in islets did not occur until the development of a sensitive insulin assay in the 1960s, when it was reported that there was a progressive increase in both fasting and glucosestimulated insulin secretion throughout the course of human pregnancy (3). This and subsequent research led to the characterization of pregnancy as a condition of elevated serum insulin levels, slightly lower blood glucose levels, and peripheral insulin resistance. The short-term regulation of insulin secretion is achieved by elevating blood glucose. However, if this were the only mechanism available for increasing insulin secretion during pregnancy, there would be a need for persistent hyperglycemia, a condition detrimental both to the mother and the developing fetus. Thus, when there is an increased need for insulin over a prolonged period of time, such as occurs in pregnancy, islets must undergo adaptive changes. The outcome of the up-regulation must be such that there is enhanced insulin secretion at normal glucose levels. There are three basic mechanisms whereby one can increase insulin secretion at normal glucose concentrations: increase the islet -cell mass, increase the sensitivity of insulin secretion in response to glucose, or both. Evidence that there is an increase islet/ -cell mass comes from a number of studies (4–7). These studies indicate that there is an approximate 2-fold increase in islet mass. DNA content per islet also indicates an increase in islet mass, and both morphometric and DNA to protein ratio methods indicate -cell hypertrophy as well as -cell hyperplasia (8– 12). Evidence for increased -cell mitosis comes from tritiated thymidine and bromodeoxyuridine labeling of islets during pregnancy (4, 13, 14). Overall, these reports indicate that islet mass doubles, and the increase is a consequence of new -cell formation as well as an increase in -cell size. There is less information on whether islet neogenesis occurs during pregnancy. One report failed to detect evidence for islet neogenesis during pregnancy but did show that another condition of persistent hyperlactogenemia may result in islet neogenesis (15). There is also evidence for an increase in glucose-sensitive insulin secretion. During rodent pregnancy, fasting serum insulin levels are increased, and glucose levels are decreased (8, 16, 17), similar to that observed in human pregnancy. Green and Taylor (9) showed a leftward shift of the glucose-stimulated insulin secretion response curve in islets isolated from pregnant rats. In a similar study, we used perfused pancreas preparations to examine insulin secretion throughout rat pregnancy. A leftward shift in glucose-responsive insulin secretion as well as above-threshold insulin release was first noted on d 10 and peaked by d 15 (4). The threshold for glucose-stimulated insulin secretion decreased from 5.7–3.3 mM by d 15 pregnancy. The lowering of the threshold for glucose-stimulated insulin secretion is a key feature of islets as they adapt to pregnancy. It is through this maneuver that a large increase in insulin secretion can be achieved at fasting blood glucose levels, as is seen during pregnancy. The most important changes in islet adaptation to pregnancy are enhanced insulin secretion and enhanced -cell mass. Candidate hormones must be shown to induce these changes. Although a variety of hormones increase during pregnancy, only PRL and placental lactogen, which acts through PRL receptors, are capable of inducing the changes that occur in islets during