Kisspeptin as an Insulin Secretagogue

Gestational diabetes mellitus (GDM), characterized by new onset glucose intolerance during pregnancy, affects ~8% of all pregnancies and increases the risk for diabetes with the associated health consequences in both mother and offspring. In GDM, the pancreatic β-cell is unable to produce more insulin to compensate for pregnancy-induced insulin resistance leading to post-prandial hyperglycemia. Even post-prandial hyperglycemia in mothers without the full diagnosis of GDM results in adverse outcomes for mother and fetus. Understanding how GDM develops and discovering new ways to control post-prandial hyperglycemia are both critical to improving pregnancy outcomes.

This grant presents a new factor, kisspeptin, which may increase glucose-stimulated insulin secretion. Traditionally thought of as a hypothalamic peptide, during pregnancy, kisspeptin is produced by the placenta and levels in the peripheral blood rise 7,000 fold across the trimesters of pregnancy compared to non-pregnant women. A failure to increase kisspeptin levels across pregnancy, might contribute to less glucose-stimulated insulin secretion, post-prandial hyperglycemia, and ultimately GDM. Recent work suggests that kisspeptin levels might be lower in women with GDM.

To explore the feasibility of using kisspeptin in women to stimulate insulin secretion with a particular interest in modeling the effect of kisspeptin in pregnancy, this project will:< br> 1: To establish the effect of kisspeptin, at levels normally found in pregnancy, on insulin secretion in healthy, normal weight women in both the fasted and fed state.
2: To establish the effect of sex steroids on kisspeptin modulation of insulin secretion in healthy, normal weight women by examining women in different phases of the menstrual cycle.

Each aim is accomplished by healthy, normal weight women undergo two paired liquid mixed meal tolerance tests during either a kisspeptin infusion or a placebo infusion after an overnight fast. These paired studies will allow for the examination of primary outcomes: changes in Disposition Index or Matsuda Insulin Sensitivity Index in response to kisspeptin. These studies have been appropriately powered (80% power) with 10 follicular phase, and 10 luteal phase women to examine both aims. The kisspeptin infusions will approximate kisspeptin levels seen in pregnancy based on prior published literature. By defining kisspeptin’s role in glucose homeostasis in pregnancy, this grant will refine our understanding of pregnancy physiology and may inform a potential pathomechanism of gestational diabetes mellitus. The long-term objective is to develop novel treatments for gestational diabetes mellitus.

Relevance to Public Health:
Identifying novel pathways that regulate insulin secretion can help inform the how diabetes develops and how to best treat diabetes. This project studies how kisspeptin, which is naturally produced during pregnancy, can increase insulin secretion. Our goal is to better understand, and perhaps even treat, gestational diabetes which can harm both mother and baby for a lifetime.