Obesity and type 2 diabetes are modern epidemics, closely associated with the development of insulin resistance. While lipid induced mitochondrial dysfunction plays an important role in skeletal muscle insulin resistance, it is unclear whether a similar etiology is responsible for hepatic insulin resistance. The purpose of this thesis is to investigate whether impaired mitochondrial function plays a role in hepatic insulin resistance, and if so, whether it is a cause or consequence of insulin resistance. I further put forth the hypothesis that increased fat delivery either by diet or by genetic defect results in elevated hepatic triglyceride storage, induction of hepatic TCA cycle flux and poorly controlled gluconeogenesis in the insulin resistant liver. In order determine in vivo hepatic metabolism, we first developed a stable isotope tracer method to estimate hepatic fat oxidation and integrated it with other standard techniques to measure hepatic glucose production. These methods were used to determine in vivo hepatic mitochondrial pathways in a diet induced obese and diabetic mouse model and in a severe genetic model of diabetes (ZDF rats). Additionally, a pharmacological intervention in ZDF rats was used as an attempt to correct the dysfunctional metabolic pathways. The findings from this study suggest that mitochondrial dysfunction is not a cause, but the consequence of hepatic insulin resistance. The data further indicate that only selected mitochondrial pathways are impaired during severe insulin resistance, while others are induced and that interventions that target mitochondrial metabolism may not completely normalize hepatic metabolism if they indiscriminately induce all mitochondrial pathways.

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.

Due to the resultant health consequences and considerable increase in prevalence, obesity has become a major worldwide health problem. “Obesity and Lipotoxicity” is a comprehensive review of the recent researches to provide a better understanding of the lipotoxicity-related mechanisms of obesity and the potential for the development of new treatment strategies. This book overviews the biochemical pathways leading to obesity-related metabolic disorders that occur subsequent to lipotoxicity. Chapters examine the deleterious effects of nutrient excess at molecular level including the cellular and molecular aspects of breast cancer, resistance to leptin, insulin, adiponectin, and interconnection between the circadian clock and metabolic pathways during high-fat feeding. “Lipotoxicity and Obesity” will be a useful resource for clinicians and basic science researchers, such as biochemists, toxicologists, immunologists, nutritionists, adult and pediatric endocrinologists, cardiologists, as well as students who are thought in this field.

The first edition of this book. Published in 1993, was very well received as providing a comprehensive review of the digestion and metabolism of ruminant animals. Since its publication, much new research has been conducted in the subject and knowledge has increased. This new edition includes Dr. Dijkstra as an additional editor and four completely new chapters. These cover: the gas production technique in feed evaluation; the relationship between pasture characteristics and animal performance; calorimetry; and feed processing. Other chapters have been expanded or updated as appropriate.

The liver is an exceptionally complex and diverse organ that functions both as an exocrine and an endocrine gland. It secretes bile, which contains many con stituents in addition to bile salts, and it synthesizes and releases many substances in response to the body's demands, including prohormones, albumin, clotting factors, glucose, fatty acids, and various lipoproteins. It has a dual blood supply providing a rich mixture of nutrients and other absorbed substances via the portal vein and oxygen-rich blood via the hepatic artery. This functional heterogeneity is accompanied by cellular heterogeneity. The liver contains many cell types including hepatic parachymal cells, Kiipffer cells, Ito cells, and endothelial cells. The most abundant cell type, the parenchymal cells, are biochemically and structurally heterogeneous. The cells in the oxygen-rich areas of the portal triad appear more dependent on oxidative metabolism, whereas those around the central vein (pericentral, perivenous, or centrolobular areas) are more dependent upon an anaerobic mechanism. Throughout this volume the latter three terms are used synonymously by various authors to indicate the five to eight layers of cells radiating from the central vein. Structural and metabolic heterogeneity of hepatic parenchymal cells has been demonstrated by a variety of approaches, including histochemical, ultra structural, and ultramicrobiochemical studies. This microheterogeneity is linked to the physiological functions of the liver and its response to injurious substances.

Thoroughly revised and updated, this Third Edition encompasses the most recent advances in molecular and cellular research and describes the newest therapeutic modalities for type 1 and type 2 diabetes mellitus. Chapters by leading experts integrate the latest basic science and clinical research on diabetes mellitus and its complications. The text is divided into ten major sections, including extensive sections on therapeutics, diabetes during pregnancy, and complications. New chapters cover stem cell therapy for type 1 diabetes; genetics and treatment of obesity; new therapies to promote insulin action; vasculopathy; islet cell protocols; triglycerides in muscle; hypoglycemia in the adult; and the Diabetes Prevention Program.

Liver disease in children is increasing in prevalence, placing a huge burden on healthcare systems and often requiring long-term management. Offering an integrative approach to the science and clinical practice of pediatric hepatology, this is the definitive reference text for improved diagnosis and treatment strategies. In the new edition of this authoritative text, chapters have been thoroughly revised in line with major advances in the field, such as recognizing the increased frequency of fatty liver disease, and how genetic testing has the potential to establish earlier diagnoses for a variety of diseases. Disorders covered include cholestasis, metabolic disorders and hepatitis, with their presentation across the spectrum of infancy, childhood and adolescence discussed. The indications and surgical aspects of liver transplant are explained and post-transplant care is described in detail. This is a valuable resource for pediatricians, hepatologists, gastroenterologists and all clinicians involved in the care of children with liver diseases.