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Title: Treating the changing face of Western medicine : pharmacological interventions on the Jak/STAT pathway in diabetic complications and its relationship to ageing
Author: Hull, William John
ISNI:       0000 0004 7652 8848
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2017
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Ageing and diabetes are two major healthcare concerns that used to be regarded as problems of the Western world but are now of increasing concern in developing nations. Treating elderly patients with diabetes poses issues for clinicians due to often complex, preexisting drug regimes. Research targeted at the development of novel drugs that have multiple effects on diabetes could go some way towards reducing polypharmacy in these patients. Here I present evidence that the oral Jak1/3 inhibitor, baricitinib, has effects on multiple aspects of diabetes. Baricitinib has been suggested to be a strong anti-inflammatory given the role Jak plays in transducing cytokine signals to elicit immune cell activation and maturation. Baricitinib was found to reduce urinary albumin to creatinine ratio and mesangial expansion in mice on an experimental high-fat diet with a diabetic metabolic profile when compared with naïve, non-diabetic mice. This reduction in renal impairment from diabetes was not found with a large reduction in proinflammatory cytokines and instead appears to be as a result of a direct effect on the cells of the mesangium. Baricitinib also reduced the circulating levels of cholesterol with a positive effect on the LDL: HDL ratio of diabetic mice. This reduction in cholesterol appears to be because of the abolition of GLP- 1 signalling, initiating an increase in blood insulin, preventing lipid flux and inhibiting LDL formation. Both of these changes in key diabetic complications were not accompanied by an increase in sensitivity to insulin compared with vehicle treated diabetic mice. These results show that baricitinib has a beneficial effect on two key aspects of the diabetic condition but that it does not modify insulin sensitivity itself. Baricitinib may represent a potential treatment for these diabetes-associated pathologies but only in combination with traditional anti-diabetic treatments.
Supervisor: Not available Sponsor: BBSRC ; Takeda Cambridge Ltd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Ageing ; Diabetes ; cytokine signals ; Polypharmacy reduction