Over-expression of human amylin in transgenic mice as a model for the pathogenesis of gestational diabetes

Abstract

Gestational diabetes (GD) is defined as any degree of impaired glucose tolerance with onset or first recognition during pregnancy. It is characterised by β-cell dysfunction resulting in inadequate insulin supply to overcome pregnancy-induced insulin resistance, in order to maintain normal blood glucose regulation. GD has been reported to affect between 1.8 to 25.1% of all pregnancies making it one of the most common heterogeneous metabolic disorders during pregnancy. Women with GD are associated with an increased risk of short- and long-term adverse consequences for the fetus and mother, the most significant of which is a predisposition to the development of metabolic syndrome and type 2 diabetes (T2D). There are substantive studies linking human amylin (hA) aggregates i.e. amylin oligomers to β-cell dysfunction, leading to development of T2D. Emerging evidence has reported deposition of aggregated hA in organs of T2D patients, including pancreas, heart, kidney, and brain, consistent with haematogenous spread of aggregated hA from the islet. Thus, We proposed that amylin oligomers are initially formed by seeding in the pancreas, and that the seeds (small oligomers) then pass into the circulation by which they are carried to distant organs where they lodge in capillary beds and thereafter grow by the seeding/nucleation mechanism and cause damage. The aim of this research was to establish the hemizygous hA TG mouse as a valid animal model to study GD and investigate the consequences of maternal human amylin overexpression during pregnancy on offspring. Subsequently, gain a better understanding of the pathogenic role of amylin in the development of GD and the transmission of T2D between mother and offspring. TG female mice exhibited elevated blood glucose, glucose intolerance and developed T2D at ~370 days of age. Furthermore, multi-parity TG mice had exacerbated glucose intolerance and accelerated diabetes onset at ~249 days. Non-transgenic (NT) male offspring from TG mother displayed several characteristics of T2D. NT male offspring from TG mothers weighed significantly more than NT male offspring from NT mothers by 137 days of age. They also developed hyperinsulinaemia with insulin resistance, hyperleptinaemia, and glucose intolerance between 120 - 240 days. More importantly, 70% of NT male offspring from TG mothers developed diabetes, whereas none of NT male offspring from NT mothers did. Moreover, they acquire this syndrome before their mothers develop hyperglycaemia. We conclude that hA over-expression TG female mice are an informative and suitable model to study the role of hA over-expression in development of GD and subsequent T2D. Nondiabetic TG mothers transmit T2D to their NT offspring with high penetrance, whereas NT mothers do not, indicating that amylin could potentially play a role in the transmission.