• Gestational diabetes
• The beta cell adaptation to pregnancy
• Regulation of the functional beta-cell mass

Gestational diabetes and the islet adaptation to pregnancy

Pregnancy presents the maternal metabolism with the problem of providing for the energy requirements of the growing fetus while maintaining fuel homeostasis in the mother. The reversible adaptive changes include a progressive increase in maternal insulin resistance during the last 20 weeks of gestation. In a healthy mother the insulin resistance is countered by increased insulin secretion to maintain normoglycaemia. The increased insulin secretory capacity is met through functional and structural changes in the islets, including an increased β-cell mass.

Failure to compensate for the increased metabolic demand in pregnancy leads to the development of glucose intolerance, hyperglycaemia and gestational diabetes mellitus (GDM). Undiagnosed and untreated hyperglycaemia in pregnancy is associated with a range of problems, including preeclampsia, large for gestational age (birth weight>90th centile), birth injury, and neonatal hyperinsulinism and hypoglycaemia. The rapid worldwide increase in the prevalence of type 2 diabetes mellitus (T2DM) is well-documented, but it is less appreciated that the incidence of GDM is also rapidly rising in parallel with the T2DM pandemic. 

Under normal conditions, β-cells have little proliferative capacity. Pregnancy is one of the few physiological states in which β-cells exhibit a reversible increase in proliferation, along with increases in β-cell size and reduced apoptosis, providing an interesting model for studying the cellular mechanisms that regulate β-cell mass. At present the signals regulating β-cell proliferation and hypertrophy during pregnancy are unclear. Prolactin and placental lactogen have been implicated, however lactogenic hormones are unlikely to explain all of the β-cell adaptive responses. A more complete understanding of the mechanisms involved in β-cell mass during pregnancy would be of obvious benefit for GDM, but may also be important for the development of novel treatments for T2DM, which is now recognised as being associated with a progressive reduction in the functional β-cell mass.

Kisspeptin is a recently-discovered molecule that is found, along with its receptor, in a few areas of the human body – the hypothalamic area of the brain, the placenta and the endocrine pancreas. One important function of kisspeptin in the brain is to control when the process of puberty starts and to regulate subsequent reproductive function, but the function(s) of kisspeptin in the placenta and the pancreas are mostly unknown. Under normal conditions levels of kisspeptin found in the blood are very low, but these levels increase during pregnancy due to massive release from the placenta.

We have previously shown that kisspeptin, a peptide that is essential for normal reproductive function, plays a physiological role in regulating the adaptation of islets to pregnancy and are continuing to further investigate the mechanisms underlying this adaptation and the signals involved.