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Title: Extra-pancreatic effects of sulphonylureas in diabetes mellitus, with particular reference to platelet function and cellular receptors for insulin
Author: Bautista, A. P.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1983
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Abstract:
The extra-pancreatic effects of sulphonylureas on platelet function, haemostatic mechanisms and insulin receptors on erythrocytes and monocytes in diabetes mellitus have been investigated. Platelet function was assessed in terms of platelet survival time using ¹¹¹In-oxine as a radiotracer, and in terms of β-thrombo-globulin (βTG) release in vivo. Platelet life span was not grossly abnormal in patients with non-insulin-dependent diabetes mellitus (NIDDM) compared with other patients with known platelet abnormality not associated with diabetes as observed in primary thrombocythaemia. Plasma βTG concentrations in NIDDM were not abnormal either. Prolonged platelet life span and reduced plasma STG concentration were observed during the administration of chlorpropamide and more so with gliclazide, compared with tolazamide and dietary treatments. Despite the normal pattern of platelet function in these patients, prolonged euglobulin lysis time, increased Factor VIII coagulant activity and related antigen and plasma fibrinogen concentrations were noted in some patients, which were not significantly altered during the administration of chlorpropamide or gliclazide. The second aspect of this work was concerned with the effect of sulphonylureas on the insulin receptors on erythrocytes and monocytes in NIDDM. Decreased insulin binding to erythrocytes from diet-controlled-NIDDM patients was observed and thought to be age-related, and probably not associated with insulin resistance at cellular level. The total number of insulin receptor sites on monocytes from the same patients was not significantly different from that of the normal group. Gliclazide and chlorpropamide did not increase the total number of insulin receptors on erythrocytes and monocytes. However, there was an increase in concentration of high affinity sites with a corresponding decrease in number of low affinity receptors on erythrocytes. On monocytes, increased Kd of the low affinity sites and average affinity constants (K) were observed during the administration of chlorpropamide or gliclazide. These observations suggest that sulphonylureas might enhance the control of diabetes in these patients by increasing the number of high affinity sites and the average affinity constant. In chemical gestational diabetes mellitus (GDM) total receptor sites on erythrocytes increased significantly within 8 weeks of treatment with chlorpropamide. However, ¹²⁵I-insulin binding to erythrocytes (cord and maternal) and placental membranes in chlorpropamide-GDM was not significantly different from that of the normal group. Elevated number of binding sites for insulin on erythrocytes (cord and maternal) and placental membranes in 2 GDM patients on metformin were also noted. In rat hepatocytes, increased binding of ¹²⁵I-insulin in the presence of another sulphonylurea (Na tolbutamide) was observed. These studies suggest that sulphonylureas might affect the binding of insulin to its receptor sites on target and non-target cells, possibly enhancing further the control of diabetes. The possible beneficial effects of sulphonylureas on platelet function and insulin receptors have been analysed. These findings might have an important implication on the prevention or rate of development of vascular occlusive disorders, and the enhancement of insulin sensitivity of target and non-target cells in non-insulin-dependent diabetes mellitus.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.592115  DOI: Not available
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