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"Joseph, L A"
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The Causal Role of Ectopic Fat Deposition in the Pathogenesis of Metabolic Syndrome
Consuming a “modern” Western diet and overnutrition may increase insulin secretion. Additionally, nutrition-mediated hyperinsulinemia is a major driver of ectopic fat deposition. The global prevalence of metabolic syndrome is high and growing. Within this context, people with congenital lipodystrophy often experience a severe form of metabolic syndrome. Evidence is increasingly supporting that subtle partial lipodystrophy plays an important role in the development of metabolic syndrome in the general population. In individuals in the general population with subtle partial lipodystrophy, as well as in those with congenital lipodystrophy, the subcutaneous adipose tissues are unable to accommodate surplus energy intake. In both conditions, (excess) fat is directed toward the liver, pancreas, and muscles, where it is deposited as ectopic fat, as this fat can no longer be stored in the “safe” subcutaneous fat depots. Ectopic fat depositions cause insulin resistance in the liver and muscles, as well as β-cell dysfunction in the pancreas. Support of a direct pathological role of ectopic fat deposition in this condition is further provided by the rapid normalization of hepatic insulin sensitivity and improvement in pancreatic β-cell function after marked reductions in ectopic fat depositions. Thus, ectopic fat deposition in the liver, pancreas, and muscles may play a causal role in the pathogenesis of metabolic syndrome even in the general population. As such, the prevention of ectopic fat deposition may reduce the risk of metabolic syndrome and mitigate its effects.
Journal Article
Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes
The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic β-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.
Journal Article
The Pivotal Role of the Western Diet, Hyperinsulinemia, Ectopic Fat, and Diacylglycerol-Mediated Insulin Resistance in Type 2 Diabetes
Genetic background, the “Western diet”, and environment may all contribute to hyperinsulinemia. Hyperinsulinemia can precede and cause insulin resistance. In situations of fuel overload, insulin resistance limits the amount fuel (glucose and fatty acids) entering insulin-sensitive tissues. When energy intake is chronically greater than energy expenditure, the capacity of the subcutaneous fat tissues to store fat can be overpowered. If subcutaneous fat tissues are no longer able to accommodate excess energy, there will be spillover of lipids. Excess calories will be stored as ectopic fat (triglycerides) in the liver, pancreas, and skeletal muscle. Growing evidence suggests that ectopic fat deposition directly causes insulin resistance and pancreatic beta cell dysfunction. Overnutrition and ectopic fat increase diacylglycerol (DAG) accumulation in fat cells, hepatocytes, and skeletal muscle cells. A unifying hypothesis proposes that translocated DAG into the plasma membrane induces insulin resistance in all these three cell types. In addition, ectopic fat accumulation in the pancreas induces beta-cell dysfunction. Introducing a negative energy balance by bariatric surgery or a very low-calorie diet (VLCD) reduces ectopic fat depositions from the liver and pancreas and decreases intracellular DAG content: both are effective treatments to restore insulin sensitivity, normalize metabolism, and put type 2 diabetes in remission.
Journal Article
The Impact of Westernization on the Insulin/IGF-I Signaling Pathway and the Metabolic Syndrome: It Is Time for Change
The metabolic syndrome is a cluster of overlapping conditions resulting in an increased incidence of type 2 diabetes, cardiovascular disease, and cancer. In the last few decades, prevalence of the metabolic syndrome in the Western world has reached epidemic proportions and this is likely due to alterations in diet and the environment as well as decreased physical activity. This review discusses how the Western diet and lifestyle (Westernization) has played an important etiological role in the pathogenesis of the metabolic syndrome and its consequences by exerting negative effects on activity of the insulin–insulin-like growth factor-I (insulin–IGF-I) system. It is further proposed that interventions that normalize/reduce activity of the insulin–IGF-I system may play a key role in the prevention and treatment of the metabolic syndrome. For successful prevention, limitation, and treatment of the metabolic syndrome, the focus should be primarily on changing our diets and lifestyle in accordance with our genetic make-up, formed in adaptation to Paleolithic diets and lifestyles during a period of several million years of human evolution. Translating this insight into clinical practice, however, requires not only individual changes in our food and lifestyle, starting in pediatric populations at a very young age, but also requires fundamental changes in our current health systems and food industry. Change is needed: primary prevention of the metabolic syndrome should be made a political priority. New strategies and policies should be developed to stimulate and implement behaviors encouraging the sustainable use of healthy diets and lifestyles to prevent the metabolic syndrome before it develops.
Journal Article
Structural design for the stage
\"The follow-up to the 2000 Golden Pen Award-winning Structural Design for the Stage, this second edition provides the theater technician with a foundation in structural design, allowing an intuitive understanding of \"why sets stand up.\" It introduces the basics of statics and the study of the strength of materials as they apply to typical scenery, emphasizing conservative approaches to real world examples. This is an invaluable reference for any serious theatre technician throughout their career, from the initial study of the fundamental concepts, to the day-to-day use of the techniques and reference materials.Now in hardcover, with nearly 200 new pages of content, it has been completely revised and updated to reflect the latest recommended practices of the lumber and steel industries, while also including aluminum design for the first time. \"-- Provided by publisher.
Book
Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer
For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.
Journal Article