Type II diabetes is characterised by hyperglycemia and disturbances of fat, carbohydrate and protein metabolism. It occurs mainly in adults, with obesity being the most modifiable risk factor. This project utilised the Israeli Sand Rat (Psammomys obesus) and some of the latest molecular biology technology including differential display, membrane microarray and real-time PCR to detect genes in the liver that may be associated with the development of Type II diabetes and/or obesity. This study showed calpain, a proteolytic inhibitor and calpastatin, its natural inhibitor to be disregulated in the liver during the diabetic state.

Energy expenditure and substrate utilisation were measured in Psammomys obesis to identify metabolic abnormalities potentially contributing to the development of obesity and diabetes. Furthermore two genes, thyroxine binding globulin and site 1 protease, were identified as differentially regulated in the liver of obese and diabetic Psammomys obesis.

The prevalence of type 2 diabetes (T2D) is increasing as obesity increases worldwide and insulin resistance (IR) remains the most important factor in its development. The resulting hyperglycemia leads to complications including retinopathy, stroke and amputations. Life style changes and treatments have not been successful in elevating the progression of IR into diabetes nor preventing co-morbidities with cardiovascular involvement. Despite compelling evidence that susceptibility to obesity and T2D is highly heritable and considerable progress with gene identification, most susceptibility genes continue to elude discovery. We used mouse models of diet-induced metabolic disease to facilitate gene discovery and better characterize the underlying genetic architecture of T2D. Analysis of the C57BL/6JA/J panel of Chromosome substitution strains (CSS) identified 8 chromosomes with at least 1 QTL affecting glucose homeostasis. First, we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains of CSS-6 defining Obrq2, a QTL for body weight, and measures of IR. Pathway analysis of global gene expression patterns in liver identified expression level differences between 6C1 and 6C2 in pathways related to mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain. This data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance. Next, we developed two consecutive subcongenic panels for Obrq2. Through genetic and phenotypic analysis of congenic, subcongenic and subsubcongenic strains, we uncovered a complex genetic architecture for metabolic traits associated with T2D. Multiple closely linked QTLs demonstrated strong effects with considerable phenotypic heterogeneity. Analysis of one of them, Obrq2a1, identified the solute receptor Slc35b4 as a potential regulator of obesity and insulin resistance. Slc35b4 mRNA expression level differences in liver were associated with the phenotype. Finally, we provided first evidence for a non-imprinting transgenerational paternal effect on body weight and food intake using crosses between obesity resistant congenic strain 6C2d and obesity sensitive strain B6. The phenotype was transmitted through the paternal lineage for at least 3 generations, but was lost if passed through the female lineages.

Metabolism in Psammomys obesis, a polygenic animal model of obesity and type 2 diabetes is associated with dysregulated nocturnal fat oxidation in diabetic animals. Furthermore, a new gene called AGT-203 has been identified. Evidence indicates that AGT-203 is involved in abnormal glucose metabolism leading to the proposition that AGT-203 is a new candidate gene for type 2 diabetes.

Obesity is officially recognised as a major worldwide public health problem. "Progress in Obesity Research: 9" fulfils the need for an accessible and fundamental research, highly recommended towards a better understanding of obesity. It will prove an indispensable resource for all those involved in the research, prevention and treatment of obesity.

""Frontiers in Medicinal Chemistry" is an Ebook series devoted to the review of areas of important topical interest to medicinal chemists and others in allied disciplines. "Frontiers in Medicinal Chemistry" covers all the areas of medicinal chemistry, incl"

More than 18 million people in the United States have diabetes mellitus, and about 90% of these have the type 2 form of the disease. This book attempts to dissect the complexity of the molecular mechanisms of insulin action with a special emphasis on those features of the system that are subject to alteration in type 2 diabetes and other insulin resistant states. It explores insulin action at the most basic levels, through complex systems.