Nagi, Dinesh K.; (1995) Cardiovascular risk factors in Asian and Caucasian subjects with and without type 2 diabetes: Studies using new highly specific assays for insulin, intact proinsulin and des 31,32 split proinsulin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hyperinsulinaemia is implicated in the pathogenesis of coronary artery disease and is related to a number of risk factors for coronary artery disease. However, the biological significance of the role of hyperinsulinaemia and insulin resistance in the pathogenesis of coronary artery disease remains controversial and for from estabilished. It has been speculated for a long time that proinsulin-like molecules may cross-react in radioimmunoassays for insulin though this has not been demonstrated. In this dissertation an effort has been made to analyse the relationships of cardiovascular risk factors, blood pressure, dyslipidaemia and of plasminogen activator inhibitor (PAI-1 ) activity, with concentrations of insulin, intact proinsulin and des 31,32 proinsulin. Insulin, proinsulin and des 31,32 proinsulin were assayed employing highly specific monoclonal antibody-based assays. In a preliminary study sera from 51 subjects with type 2 diabetes (non-insulin-dependent) mellitus was analysed to measure insulin concentrations by a conventional radioimmunoassay using a polyclonal antibody and also by a highly specific monoclonal-antibody based assay. This study revealed that proinsulin-like molecules cross-react in conventional radioimmunoassay for insulin with a potency very similar to that of insulin. In this study, cardiovascular risk factors also correlated with concentrations of immunoreactive insulin, but some of these relationships became weaker or insignificant when insulin concentrations measured by a highly specific assay was employed to study these relationships. Both intact proinsulin and des 31,32 proinsulin concentrations were related to a number of cardiovascular risk factors including PAI-1 activity. These observations raised the possibility that proinsulin-like molecules may have role in the pathogenesis of macrovascular disease in type 2 diabetic subjects. Asian subjects with type 2 diabetes had higher concentrations of des 31,32 proinsulin. Based on these preliminary results. 17 further studies were performed to reanalyse these observed relationship, with inclusion of non-diabetic and diabetic subjects from two different ethnic groups (Asians and Caucasian). Subsequently intervention studies using metformin (Diethyl biguanide) and insulin treatment in subjects with type 2 diabetes were performed to study the effect of these treatments on insulin resistance, insulin and proinsulin-like molecules, plasminogen activator inhibitor and on risk factors for cardiovascular disease. These studies revealed that non-diabetic Asian subjects had a preferential central distribution of fat, lower levels of physical activity and higher prevalence of ischaemic heart disease than age- and sex-matched Caucasian subjects. Asian subjects showed significant 2-hr post glucose load hyperinsulinaemia compared to Caucasian non diabetic subjects. Concentrations of intact proinsulin but not of des 31,32 split proinsulin were also significantly higher in Asian non-diabetic subjects than Caucasians, however the ratio of proinsulin-like molecules to insulin was similar in both ethnic groups. There was no ethnic differences in PAI-1 activity or other cardiovascular risk factors among diabetic and non-diabetic subjects from two ethnic groups. Significant and consistent relationships were observed between the concentrations of proinsulin like-molecules and levels of certain risk factors for cardiovascular disease in all the studies. The relationships of intact proinsulin and des 31,32 proinsulin with risk factors for cardiovascular disease were either similar to or stronger in magnitude than insulin concentrations measured by a specific assay. These relationships were highly significant in subjects with type 2 diabetes. No ethnic differences were noted in the relationship of insulin and proinsulin-like molecules to cardiovascular risk factors. There was no significant association of insulin or proinsulin-like molecules to electrocardiographic evidence of coronary artery disease, however the number of subjects with coronary artery disease was small. 18 Using a specific assay for insulin, subjects with type 2 diabetes who are treated with diet alone, had significantly higher fasting insulin concentrations than non-diabetic subjects. The relationship of fasting insulin concentrations with fasting and 2-hr plasma glucose however was inverted U shaped, suggesting a declining p-ceW function as hyperglycaemia worsens. Subjects with diabetes had significantly lower 30-min post load insulin concentrations compared to non-diabetic subjects suggesting a defective beta cell response in subjects who have type 2 diabetes. We have confirmed that concentrations of proinsulin and des 31,32 proinsulin are elevated in diet treated subjects with type 2 diabetes, though the proportion of these molecules varied in different studies. Likely explanations for these results are the heterogeneity of diabetes and different population of subjects included in these studies. Intervention studies demonstrated that conventional treatment modalities such as insulin or metformin treatment in type 2 diabetic subjects is associated with a reduction in the concentrations of proinsulin-like molecules. In both intervention studies the reduction in proinsulin-like molecules was significantly related to each other suggesting a close relationship in the mechanisms which control their processing and secretion. Metformin treatment was associated with improvements in insulin sensitivity, and reduction in the concentrations of proinsulin-like molecules, cardiovascular risk factors and of PAI-1 activity, but there were no significant associations between reductions in concentrations of proinsulin-like molecules and those of cardiovascular risk factors. However during insulin treatment, reductions in PAI-1 activity was significantly associated with changes in concentrations proinsulin- like molecules. The associations observed between proinsulin-like molecules and cardiovascular risk factors especially PAI-1 activity in these studies raise the possibility of a role of proinsulin-like molecules in the pathogenesis of cardiovascular disease particularly in subjects with type 2 diabetes and warrants further studies.

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