Cardiovascular Consequences of Gestational Diabetes; Role of Amylin

Gestational diabetes mellitus (GDM) significantly increases the risk of developing type-2 diabetes (T2D) and cardiovascular disease later in life in both mother and offspring. While the underlying mechanisms are unknown, hyperglycemia is largely considered the critical mediator. However, numerous studies revealed that GDM has negative long term consequences even with good glycemic control in the mother. Here, we propose that systemic dyshomeostasis of the pancreatic hormone amylin is a critical contributor to the GDM-programmed metabolic and cardiovascular dysfunction. Amylin is synthesized and co-secreted with insulin by the pancreatic â-cells. Thus, secretion of amylin rises in parallel with that of insulin in obesity and insulin resistance. Human, but not rodent, amylin is amyloidogenic, i.e. amylin molecules stick to each other and to other molecules. Consequently, enhanced amylin secretion (hyperamylinemia) results in amylin oligomerization and deposition in the pancreas, leading to gradual decline in â-cell mass and T2D in humans and transgenic rats expressing human amylin specifically in the â-cells. We previously demonstrated that oversecretion of amyloidogenic amylin is also an active participant in the development of diabetic heart disease. Amylin secretion is likely enhanced in females with GDM, as a result of insulin resistance and the consequent increase in insulin secretion. This assertion is supported by our preliminary data in a rat model of GDM. The blood level of amylin is also elevated in neonates of mothers with GDM. A recent large population-based prospective study (CARDIA) found that GDM is independently associated with increased left-ventricular mass and impaired heart function later in life. In a pilot study in rats we found that heart size is elevated two months after a GDM-complicated pregnancy but not following a normal pregnancy. Based on all these data, we hypothesize that hyperamylinemia exacerbates the pathological remodeling of the maternal and offspring heart triggered by GDM. To test this overall hypothesis we will use a rat model of GDM and will assess the effect of GDM on amylin levels (in the blood, pancreas and heart) in mothers and offspring (Aim 1), probe the amylin-myocyte interaction and its role in cardiac hypertrophy and dysfunction in females with GDM and their offspring (Aim 2) and determine the independent effect of hyperamylinemia on pregnancy-induced cardiac remodeling (Aim 3). This study may be paradigm shifting by asserting amylin dyshomeostasis as a key player in the GDM-programmed cardiac remodeling, which will help design new therapeutic strategies for reducing the postpartum risk of heart disease in mothers with GDM and their offspring.