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.