Adipose Tissue as an Endocrine Organ

Obesity is the result of an increase in adipocyte size (fat storage) and number (115, 116). Obesity can be interpreted based on our current understanding of fat biology as a pathological enlargement by fat cells and a failure to adequately proliferate and differentiate in response to excessive energy intake (117-121). In addition to surplus energy, hypertrophic fat cells are challenged by chronic inflammation and perhaps insulin resistance itself, posing considerable stress to its various...

What Strategy to Use to Prevent TDM in Subjects Genetically Predisposed to TDM Lifestyle Intervention Pharmacological

It is now clear that lifestyle interventions including dietary modification and regular physical activity delay the development of T2DM in genetically predisposed individuals several excellent reviews are available (22, 23, 152, 250, 396, 399) . Large prospective trials (400-403), as well as a number of smaller ones included in reviews by Norris et al. (396), Gillies et al. (22) and Jeon et al. (250) , have confirmed this notion. In the Diabetes Prevention Program (DPP), the largest of the...

Can Weight Loss andor Exercise Reverse Muscle Insulin Resistance

It is unquestionable that cardiorespiratory fitness reduces the risk of CVD and that low rates of physical activity are associated with a greater risk of developing insulin resistance, obesity, MS, and T2DM (51, 231-233). In the midst of an epidemic of obesity and diabetes, renewed interest has developed in understanding the molecular pathways by which exercise appears to reverse defects associated with insulin resistance reviewed in-depth under .234-236) . While the role of exercise will be...

Adipose Tissue Insulin Resistance and Lipotoxicity

Type 2 diabetes is characterized by insulin resistance (at the level of skeletal muscle, adipose tissue, and liver) and by impaired P-cell function (68,129-134). Both genetic and acquired defects have been shown to play a role in affecting insulin action and insulin secretion. Among the acquired defects, obesity and glucotoxicity (135-137) have received special attention as both are believed to worsen insulin resistance and possibly contribute to the decline in P-cell function. Dissecting the...

Role Fatty Acids in the Control of Insulin Secretion

In the fasting state, plasma FFA (not glucose) is the primary energy substrate for sustaining insulin secretion (378). Following a meal, pancreatic P-cells switch from using FFA to glucose as the preferred energy source. This occurs as glucose enters the P-cell by high-capacity, low-affinity GLUT2 transporters and is rapidly phosphorylated to glucose-6-phosphate (G-6-P) by glucokinase that acts as the glucose sensor or pacemaker for insulin secretion (379). Glucokinase is the rate-limiting step...

FFAInduced Insulin Resistance Early Studies

In 1963, Randle et al. (153) demonstrated that incubation of rat muscle with fatty acids diminished insulin-stimulated glucose uptake. They proposed a glucose fatty-acid cycle (better known later as the Randle cycle) that revolved around the notion that cardiac and skeletal (diaphragm) muscle could shift readily back and forth between carbohydrate and fat as sources of energy for oxidation, depending on substrate availability. In its original formulation of the Randle cycle, oxidation of fatty...

Role of Mitochondrial Dysfunction in Muscle Insulin Resistance

Impaired muscle insulin action at an early stage in life could be the result from an intrinsic genetic inability of muscle to increase its oxidative capacity upon demand, as reported in lean FH+ subjects and or an acquired defect from excessive exogenous substrate (i.e., FFA) as in obesity and T2DM. Diminished lipid oxidative capacity has been reported by many laboratories in insulin-resistant lean FH+ and obese individuals, as well as in patients with T2DM (133, 134, 184, 206, 215-218). In...

Contemporary Diabetes

The Diabetic Foot Second Edition, edited by Aristidis Veves, md, John M. Giurini, dpm, and Frank W. LoGerfo, md, 2006 The Diabetic Kidney, edited by Pedro Cortes, md and Carl Erik Mogensen, md, 2006 Obesity and Diabetes, edited by Christos S. Mantzoros, md, 2006 Diabetic Retinopathy, edited by Elia J. Duh, md, 2008 Diabetes and Exercise edited by Judith G. Regensteiner, phd, Jane E.B. Reusch, md, Kerry J. Stewart, edd, Aristidis Veves, md, dsc, 2009

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...

Info

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...