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Insulin Resistance: Intra-Uterine Growth Retardation, Life Style, Genetic Susceptibility, Prevention and Treatment pp. 277-302 $100.00
Authors:  (Ir. Vincent van Ginneken, Robert E. Poelmann, Department of Anatomy & Embryology, Leiden University Medical Center (LUMC), Leiden, The Netherlands)
Overweight (BMI > 25) and obesity (BMI > 30), in our modern world of food abundance has become epidemic and is associated with a whole range of health problems like hypertension, type 2 diabetes, and an excess of cardiovascular and renal diseases. We will describe intra-uterine growth retardation due to maternal undernutrition, life-style and genetic susceptibility as causes for insulin resistance and -cell dysfunction. The 'fetal' or 'early' origins of adult disease hypothesis provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance , and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. In this review we give some epidemiological examples from the "Dutch Hunger Winter" a war induced famine between August 1944 and April 1946 in Amsterdam with less than 1,000 calories per day from government food rations. Epidemiological studies demonstrate that exposure to famine during gestation resulted in increases in impaired glucose tolerance, obesity, coronary heart diseases, atherogenic lipid profile, hypertension, microalbuminuria, schizophrenia, antisocial personality and affective disorders. Maternal undernutrition during gestation has important effects on health in later life, but it is hypothesized that the timing of the nutritional insult determines which organ system is affected. Maternal undernutrition can express itself in the second or third generation. Obesity due to diet and a sedentary lifestyle may result in excess adipose tissue which actively participates in the integration of whole-body energy and fuel metabolism by the secretion of many hormones like leptin, adiponectin and resistin. Life style features like a) disturbance in the autonomous nervous system (biological clock), b) gender, c) socioeconomic status, d) race and e) stress all may be contributing factors in the origin of metabolic syndrome and insulin resistance. Genetic factors influence the different components of the Metabolic Syndrome. Type 2 diabetes is a polygenic disorder. The "thrifty gene theory" states that it can be inherited from our ancestors living in an environment with unstable food supplies and famine. For them it could increase their probability of survival if they could maximize their storage of food surpluses. With the term "thrifty genes" one can think about underlying hormonal pathways and metabolic routes like growth hormone and insulin. Inflammation, a second characteristic of insulin resistance, can be caused by Interleukin-6 (IL-6) and Tumor necrosis factor- (TNF-). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a transcription factor involved in regulating genes in adipogenesis and, by implication, insulin action. Diet, exercise and preventing stress are the first-line strategies in the management of type 2 diabetes. Exciting results for medical glycaemic control are found in (thiazolidinediones (TZD eg. Pioglitazone). They are agonist for the PPAR and also have an effect on the recently discovered hormone resistin which probably can link obesity to diabetes-2. However, recently a meta-analysis study and two clinical trials gave for thiazolidinedione-therapy with Rosiglitazone (Avandia) strongly evidence for increased cardiovascular risk and possible cardiotoxicity. Unless no new data are available of ungoing trials it is recommended to chose for other therapies to treat type 2 diabetes. 

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Insulin Resistance: Intra-Uterine Growth Retardation, Life Style, Genetic Susceptibility, Prevention and Treatment pp. 277-302