The Relationship between Insulin Resistance and the Atherogenic Lipoprotein Phenotype

The prevalence of the insulin resistance syndrome in a non diabetic population had been estimated to be about 25% whilst the prevalence of the atherogenic lipoprotein phenotype is thought to be about 30%. There are some evidence to suggest that there may be a close relationship between these two syndrome and that relationship was explored in this thesis. Risk factors for cardiovascular disease often show clustering that cannot be accounted for by chance occurrence. This has led to the hypothesis that clustering of risk factors such as insulin resistance and dyslipidaemia, may be an indication of an underlying metabolic disorder which increases the risk for premature atherosclerosis. Plasma triglyceride was found to be the most important determinant of LDL subfraction distribution in a group of normal individuals. The least dense species, LDL-I, decreased as the level of this plasma lipid rose. LDL-II in both men and women exhibited a positive association with plasma triglyceride in the range 0.5 to 1.3 mmol/L; it increased from about 100 to 200 mg/dL. In contrast, within this triglyceride range the LDL-III concentration was low (about 30 mg/dL) and changed little. As plasma triglyceride rose from 1.3 mmol/L to 3.0 mmol/L there was a significant fall in LDL-II concentration in males but not in females. Conversely, above the triglyceride "threshold" of 1.3 mmol/L there was a steeper rise in LDL-III concentration in males than females; 42% of men had an LDL-III in the range associated with high risk of heart disease (> 100 mg lipoprotein/dL plasma) compared with only 17% of women. In a group of young Singaporean males, the relationship of plasma triglyceride with LDL-II failed to show a biphasic pattern but rather, increasing levels of plasma triglyceride was associated with decreasing levels of LDL-II. The LDL-I showed a similar negative relationship and the LDL-III a positive relationship with plasma triglyceride. Other influences of the LDL subfraction profile were the activities of lipases and parameters indicative of the presence of insulin resistance. Males on the average had twice the hepatic lipase activity of females. This enzyme in males was not strongly associated with variation in the LDL subfraction profile whereas in the females it was correlated with LDL-III and remained a significant predictor in multivariate analysis. Increased WHR, fasting insulin and glucose were shown to be correlated with LDL-I (negatively) and LDL-III (positively), primarily, at least in the case of LDL-III, through raising plasma triglyceride. Subjects with proven coronary artery disease were also found to have impaired triglyceride metabolic capacity during the administration of an oral fat tolerance test. The triglyceride rose to a higher level when compared to age matched controls. The exaggerated hypertriglyceridaemia may be related to the preheparin lipoprotein lipase activity, which was demonstrated to be significantly lower in CAD patients compared to age matched controls. The CAD patients also demonstrated some features of insulin resistance, such as hyperinsulinaemic and hyperglycaemic response, both after the standardised fat meal as well as after a modified glucose meal carried in almost fat free yoghurt. Lipoprotein lipase activity is believed to be modulated by hormonal influence such as insulin and resistance of LPL to insulin may be responsible for the lower preheparin LPL documented in CAD patients. The metabolic implications of impaired preheparin LPL during alimentary lipaemia is presently unclear as there is no correlation with adipose tissue and skeletal muscle LPL. The prevalence of insulin resistance and the atherogenic lipoprotein phenotype in Singapore may be higher than other population because of the high prevalence of diabetes mellitus. A group of normal Singaporean male, aged 30 to 45 years old were studied and found to have a high prevalence of both syndromes. More than half of this sampled group had LDL-III concentraton that was above 100 mg lipoprotein/dL plasma and this may be related to the higher mean plasma triglyceride levels (1.8 mmol/L). Ethnic differences were noted and men with predominantly Asian ancestry had higher mean LDL-III concentrations and plasma triglyceride, while those with some European descent (Eurasians) had levels of LDL-III and plasma triglyceride similar to age matched Scottish cohort. There were also ethnic differences in markers of insulin resistance such as fasting insulin and fasting glucose and these difference paralleled that seen in LDL-III concentration. Ethnic differences suggest that genetic factors may determine manifestation of both the atherogenic lipoprotein phenotype and the insulin resistance syndrome, as socio-economic factors are similar between the various ethnic groups. The data presented in this thesis suggest a strong relationship between the atherogenic lipoprotein phenotype and the insulin resistance syndrome. The clustering of coronary risk factors such as dyslipidaemia and insulin resistance in patients with premature atherosclerosis may be an indication of an underlying metabolic dyslipidaemic syndrome