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Title: Novel therapeutic approaches to the alleviation of type 2 diabetes
Author: Taylor, Ashley Ian
ISNI:       0000 0004 2718 8250
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2010
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Summary As the field of molecular endocrinology advances, more genes, enzymes and receptors are being defined as possible therapeutic targets for therapy in type 2 diabetes, obesity, and the metabolic syndrome as a whole. These novel therapeutics are hoped to rival and surpass current pharmacological compounds in efficacy and duration of action; but also minimise the contraindications and the side-effects involved. Given the wide range of drug targets in the literature, it was decided that this thesis would focus on two active research areas - glucocorticoids and K-cell derived therapies. High levels of l lb-hydroxysteroid dehydrogenase type 1 in adipose and liver are associated with type2 diabetes and the metabolic syndrome. Non-specific inhibition of 11~-HSDl utilising carbenoxolone, a naturally occurring 11~-HSDl inhibitor in mice with high-fat diet induced insulin resistance and obesity, had no effect on food intake, but significantly lowered body weight and non -fasting plasma glucose levels without reduction in circulating plasma corticosterone levels. Insulin sensitivity and glucose tolerance in these mice were also improved, while 11~-HSDl gene expression was significantly down-regulated in liver. Glucocorticoid receptor gene expression was increased in both liver and adipose tissue following carbenoxolone treatment. These results support current findings for the potential value of specific 11~-HSDl inhibition as a new target for the development of selective drugs for the treatment of type 2 diabetes, obesity and related metabolic disorders. As such, we employed a compound designed by Biovitrum (named BVT.2733) to test the effects of specific inhibition of l1~-HSDl in a chronic genetic model of obesity and diabetes. Twice daily treatment in ob/ob mice with BVT.2733 had no effect on food intake or bodyweight while non-fasting blood glucose levels were attenuated from day 1 of the study; however these results were independent of improvement in insulin sensitivity or glucose tolerance. PEPCK gene expression was attenuated in liver, whereas glucocorticoid receptor and 11~-HSDl gene expression was not affected in either liver of adipose tissue following treatment. Taken together, these studies highlight the potential value of selective 11 ~-HSD 1 inhibition as a new target for the treatment of type 2 diabetes and obesity. XXll The glucocorticoid receptor is another attractive therapeutic target, and as such we employed the glucocorticoid receptor antagonist RU486 to block glucocorticoid action. Results in BRIN-BDll cells showed that incubation with RU486 protected from the inhibitory effects of dexamethasone on insulin secretion, which may be in part due to a reduction in glucokinase expression. Long-term results in obese diabetic mice receiving RU486 daily over 28 days showed a significant reduction in blood glucose, improved glucose tolerance and insulin sensitivity, independent of changes in food intake and body weight. Gene expression analysis revealed a significant reduction in hepatic mRNA PEPCK, G6Pase and l1~-HSDl, while in adipose tissue 11 ~- HSD 1 and LPL were reduced. These data demonstrate wide ranging effects of glucocorticoid receptor antagonism on gene expression and metabolism, illustrating the therapeutic potential of specific glucocorticoid receptor in obesity-diabetes. Glucose-dependent insulinotropic polypeptide (GIP) is a major physiological incretin with important insulin releasing and glucose-lowering properties both within and outside the pancreatic islets. Antagonism of GIP in this situation through the use of (Pr03)GIP has proven beneficial, attenuating hyperinsulinemia, hyperglycaemia, and body weight. Therefore a study was designed to characterise the actions of novel truncated (Pro3) based GIP antagonist peptides. At the cellular level (Pro3)GIP(2- 42), (Pr03)GIP(3-42) and (P2•3)GIP(2-42) had no significant effects, however (p1•2•3)GIP was resistant to the actions of DPP-IV, attenuated the insulin-stimulatory effects of native GIP and inhibited GIP stimulated cAMP production. In vivo, (p1•2•3)GIP acutely elevated overall glucose concentration over 60-minutes when compared to GIP control long-term dosing of (p1•2•3)GIP did not however significantly affect the 'diabesity' syndrome observed in leptin deficient ob/ob mice. These data demonstrate that although (p1,2,3)GIP was established as a novel antagonist of the GIP receptor in vitro, and acutely in vivo, it did not improve upon the biological effectiveness of the established GIP receptor antagonist (Pr03)GIP in a genetic model of diabetes and obesity. Xenin-25 is eo-secreted from the GIP producing K-cell but its effects on glucose homeostasis have been poorly examined. Results in this thesis demonstrated that in BRIN-BDll cells, xenin-25 has a stimulatory effect on insulin secretion at IIlM at nonno and hyper-glycaemic glucose levels, as well as an additive effect to GIP, GLP-l and neurotensin mediated insulin secretion. Xenin-25 did not have a stimulatory effect on cAMP, which is contrary to the effects of GIP. Ex vivo and in vivo studies showed xenin-25 to be degraded rapidly over 6 hours in murine plasma, to have short acting satiety effects at high concentrations, as well as having acute glucose homeostatic properties in normal mice in fed and fasted states. These effects were however found to be short acting as a similar response to glucose bolus was not observed dosed l h previously with xenin-25. Collectively these results will hopefully prompt further investigation into longer-acting and more potent mimetics and degradation products ofxenin in models of diabetes and obesity. As a whole this thesis demonstrates the attractive qualities of glucocorticoid blockade and the use ofK-cell derived factors in the treatment of type 2 diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available