| Summary: | Growing evidence exists for an association between fetal and early growth restriction and the subsequent development of various adult degenerative diseases such as type 2 diabetes and the insulin resistance syndrome. At highest risk are those individuals that were growth restricted in very early life but are obese in adult life. These factors have been addressed in the thrifty phenotype hypothesis. Central to this theory is that the malnourished fetus adapts its metabolism to aid short- and long-term survival but that this adaptation becomes detrimental to health later in life with adequate or overnutrition. The work described in this thesis attempted to model and test the thrifty phenotype hypothesis in the rat. Any role that the deposition of pancreatic amyloid, the most characteristic pancreatic lesion in individuals with type 2 diabetes, may have in the pathogenesis of type 2 diabetes through a thrifty phenotype was investigated by using rats which were transgenic for human amylin (the equivalent native peptide in the rat not precipitating as pancreatic amyloid). Initially a new immunoenzymometric assay for amylin was investigated. Monoclonal antibodies used in this assay were then labelled with eu ropium to establish new sensitive time resolved fluorescence immunoassays for rat amylin and human amylin-like peptides. These assays were used to characterise the human amylin transgenic rats. As well as being genotypically transgenic for human amylin, these rats were shown to make and secrete human amylin in concentrations which are broadly equivalent to concentrations seen in the plasma of individuals with type 2 diabetes. Of all the organs studied the pancreata of the transgenic rats were shown to have the highest human amylin contents. In modelling and testing the thrifty phenotype hypothesis fetal and early growth restriction was achieved by feeding a low protein diet to a pregnant rat and her offspring. At this stage the offspring had better glucose tolerances than equivalent control rats. The low protein offspring became obese in adult life by feeding them a cafeteria-style highly palatable diet. Up to twelve months of age obese rats had worse glucose tolerances than non-obese rats but there was no apparent effect of early growth restriction. Both early growth retardation due to protein restriction and obesity were associated with hypertension at this age. These associations were independent and additive. Between twelve and sixteen months of age there was a relative worsening of glucose tolerance in the low protein, early growth restricted rats. Impaired glucose tolerance was also still evident in obese rats in comparison to non-obese rats. Although the low protein rats had impaired glucose tolerance and were hypertensive they were not hyperlipidaemic. Obese rats, in contrast, were hyperlipidaemic. No pancreatic amyloid deposition was found in any of the rats. In summary, the low protein rat model with dietary-induced obesity exhibits a number of metabolic alterations which are consistent with changes pertaining to the thrifty phenotype hypothesis.
|
|---|
