Metabolic effects of dipeptyl peptidase 4 inhibitor in type 2 diabetes

MD ThesisInsulin resistance and abnormal insulin secretion are central to type 2 diabetes. The relationships have been established between lipid accumulation in the liver and muscle and insulin resistance, and that of lipid accumulation in the pancreas and β cell dysfunction. Therefore it is vital to assess the effect of therapies on intra-organ lipid concentration. DPP-4 inhibitor vildagliptin is a new therapeutic agent in type 2 diabetes. Its known primary mechanism of action is to delay GLP-1 and GIP degradation, and enhance their endogenous concentration. GLP-1 and GIP increase the sensitivity of the α- and β-cells to glucose concentration. Although DPP-4 inhibitors have been found to decrease postprandial triglyceride levels and lipolysis, the effect on intra-organ lipid concentration is unknown. Glycogen storage in the liver and muscle in type 2 diabetes is subnormal, nonetheless, the extent of glycogen storage abnormality after a whole day of normal eating has not been previously examined. Although abnormal β cell function has been recognised as a feature of type 2 diabetes, the whole pancreas has not been extensively studied previously. To test the hypothesis that DPP-4 inhibitors modulate intra-organ lipid accumulation, 44 well-controlled type 2 diabetes subjects treated only with metformin were randomised in a double-blinded manner to receive either vildagliptin or placebo for 6 months. In order to assess the extent of change, in intra-organ lipid content, and abnormal glycogen storage, and to provide comparative data for pancreas morphology, 14 normal glucose tolerant subjects matched for weight, BMI, sex and age were studied. A clinically significant decrease in liver triglyceride content after 6 months treatment with vildagliptin was observed. Additionally, the studies demonstrate that the pancreas volume in type 2 diabetes was smaller compared to match controls, and that muscle did not contribute to glycogen storage during normal daily eating in type 2 diabetes.Novartis Novartis Pharma A

Novel approaches for image analysis of in vitro epithelial cultures with application to silver nanoparticle toxicity

A novel imaging approach was developed for the purpose of counting cells from phase contrast microscopy images of laboratory grown (in vitro} cultures of epithelial cells. Validation through comparison with standard laboratory cell counting techniques showed this approach provided consistent and comparable results, whilst overcoming limitations of these existing techniques, such as operator variability and sample destruction. The imaging approach was subsequently applied to investigate the effects of silver nanoparticles (AgNP} on H400 oral keratinocytes. Concurrent investigations into antimicrobial effects of AgNP were performed on Escherichia coli, Staphylococcus aureus and Streptococcus mutans to provide models for Gram-positive and Gram-negative infection, and to compare with the literature and oral keratinocyte toxicity. It was found that AgNP elicit size-, dose- and time-dependent growth inhibition in both human cells and bacteria, although bacterial inhibition was not achieved without significant cytotoxicity at the same concentrations