Why do Obesity TDM and Nafld Cluster The Liver as the Metabolic Sensor of Lipotoxicity

Lifespan of patients with NAFLD is significantly shortened not only by a liver-related morbidity but also by a higher incidence of CVD (285, 286). As with obesity and T2DM, there is also considerable concern that NAFLD and NASH are reaching epidemic proportions (287) . However, the true magnitude of the disease is not appreciated by many clinicians because the majority ( 70 ) of patients affected have normal liver enzymes (279, 288-290). It has been recently estimated that fatty liver disease...

Is NASH a Mitochondrial Disease

There is an increasing consensus that the inability of the mitochondria to adapt to insulin resistance and lipotoxicity play a key role in the development of fatty liver disease and NASH reviewed in-depth by (223, 320-322) . Adipose tissue insulin resistance, oversupply of FFA to the liver and the development of a state of local and systemic chronic inflammation are at center stage in the development of steatosis and liver damage in NAFLD. A key determinant for hepatic fat accumulation is the...

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Free fatty acids induce skeletal muscle insulin resistance in humans by inhibition of insulin signaling. induce multiple defects in the insulin signaling cascade, at the level of glycogen synthesis, insulin-induced glucose transport and phosphorylation of the insulin receptor, insulin receptor substrate IRS-1, IRS-1-associated phosphatidylinositol PI 3-kinase activity, and of Akt 142, 151, 166, 171-175 , but this did not happen when lipid was infused to already insulin-resistant obese...

The Epidemic of Type Diabetes Mellitus Its Links to Obesity Insulin Resistance and Lipotoxicity

The Epidemic of Type 2 Diabetes Mellitus Metabolic Consequences of Obesity Why Does it Predispose to T2DM Role of Lipotoxicity in the Development of Skeletal Muscle Insulin Resistance FFA and the Liver Pancreatic P-Cell Lipotoxicity and the Development of T2DM References The epidemic of type 2 diabetes T2DM is a public health problem that threatens to spiral out of control in the twenty-first century. Early intervention can greatly mitigate the serious socioeconomic impact of the disease,...

Predisposed to TDM

The potential for fatty acids to cause P-cell lipotoxicity in vitro and in vivo, in many cases with subsequent apoptosis depending on the cell line or animal model has generated substantial interest as an explanation for the development of T2DM 372-376 . The concept of P-cell lipotoxicity was championed initially by Unger in a series of elegant experiments in islets of leptin-unresponsive Zucker diabetic ZDF rats 147, 148 . In brief, excess palmitoyl CoA would enter the ceramide pathway as it...

FFA and Hepatic Insulin Resistance

Insulin tightly regulates the rate of endogenous glucose production EGP . Hepatic glucose production accounts for the majority gt 90 of glucose output in the fasting state, except for a small proportion arising from renal gluconeogenesis 254 . The rate of EGP is important under fasting conditions to provide glucose for the metabolic needs of glucose-dependent tissues such as the brain and red blood cells. In lean insulin-sensitive healthy subjects, modest increases in the plasma insulin...

Humana Press

Regensteiner, PhD Divisions of General Internal Medicine and Cardiology Department of Medicine University of Colorado Denver, Aurora, CO, USA Kerry J. Stewart, EDD Division of Cardiology Department of Medicine Johns Hopkins School of Medicine Baltimore, MD, USA Jane E.B. Reusch, MD Division of Endocrinology Metabolism and Diabetes Department of Medicine Aurora, CO, USA Joslin-Beth Israel Deaconess Foot Center Beth Israel Deaconess Medical Center ISBN 978-1-58829-926-0 e-ISBN...

Can Weight Loss and Exercise Improve NAFLD

In general studies examining the effect of weight loss in fatty liver disease have been uncontrolled or of short duration, providing limited guidance for long-term management. Most have not used sophisticated measurements to assess insulin secretion or action, nor performed liver biopsies before and after to correlate weight loss with histological improvement, but have rather used surrogate markers such as liver transaminases or imaging. It is also unclear what kind of exercise would best...