In obese type 2 diabetic patients inadequately controlled on MET alone, addition of rosiglitazone improves glycaemic control, insulin sensitivity and beta-cell function to a clinically important extent.

DA, Woollett LA. Multiparity leads to obesity and inflammation in mothers and obesity in male offspring. Am J Physiol Endocrinol Metab 302: E449 -E457, 2012. First published November 29, 2011; doi:10.1152/ajpendo.00487.2011.-Multiparity is an independent risk factor for obesity in parous females. In addition to being a health issue for the mother, offspring of multiparous females may also be at risk for obesity later in life. The aim of the current study was to establish a mouse model that mimics the human pathology of multiparity and determine the effects of multiparity-induced obesity (MIO) on offspring in adulthood. C57BL/6 mice were mated and studied when primiparous (1st pregnancy) or multiparous (4th pregnancy). Dams became obese with multiparity, an effect that was independent of the age of the dam. Multiparous dams also had increased markers of inflammation (JNK activation, cytokine expression) in adipose tissue and liver that was greater than inflammation in nulliparous females made obese with a high-fat diet. Placental inflammation was prevalent in multiparous vs. primiparous dams as well. Male offspring of the multiparous dams developed increased adiposity by 24 wk of age relative to the progeny of primiparous dams, although food consumption was similar in both groups. Lipid metabolism was altered in liver and fat in that mRNA levels of regulatory genes (PGC-1␣) as well as metabolic genes (CPT I) and Akt phosphorylation were decreased in offspring of multiparous dams. Thus, in mice, as in humans, multiparity increases adiposity and is associated with hepatic and placental inflammation and abnormal glucose tolerance. Importantly, MIO leads to increased body fat and metabolic dysfunction in the offspring, suggesting a role in the propagation of obesity. developmental programming; diabetes; peroxisome proliferator-activated receptor-␥ coactivator-1␣ OBESITY HAS BECOME AN EPIDEMIC in developed countries and is on the rise in underdeveloped countries. Consequently, a significant number of women in their reproductive years, including those that are pregnant, are obese or overweight (30, 31). Obesity during gestation poses a significant clinical problem since it is linked to a spectrum of maternal complications, including gestational diabetes, exaggerated inflammation, hypertension, thromboembolism, preeclamplsia, and delivery complications (26,31,55,62,69).Multiparity is a cause of weight gain in women during their reproductive years and is in fact an independent predictor of obesity (12,20). The increase in multiparity-induced obesity (MIO) has followed overall trends in obesity, since gestational weight gain is additive to prepregnancy weight and the inability to loose weight gained postpartum (51,53,54). Moreover, overweight women are more likely than leaner women to retain the weight gained during pregnancy (19). Thus, as the population becomes heavier, the effect of multiparity on body weight is amplified. Similar to obesity, pregnancy has been described as an inflammatory state, with the placenta cont...

Emerging evidence indicates that maternal events prior to birth have a powerful impact on the risk for age-related diseases. Indeed, mothers who are obese during pregnancy confer an increased risk on their offspring for developmental programming of metabolic diseases. An often-overlooked risk factor for female obesity, and thus developmental programming, is multiparity. We have developed a novel mouse model in which multiparous mice become obese and develop severe inflammation − mirroring the pathology of obese multiparous humans. We have previously reported that the adult offspring of multiparous mice exhibit increased adiposity and a reduction in expression levels of genes associated with energy expenditure when fed low fat diets, despite similar food consumption. Recent studies show that these defects are associated with reduced energy expenditure and reduced mitochondrial function in hepatocytes of these mice compared to adult offspring of primiparous mice. Since a change in mitochondrial function in cardiomyocytes can lead to abnormal heart function, we fed male offspring a high fat diet (41% calories; milk fat) to stress the metabolic system. All mice accrued the same amount of fat on the high fat diets. We then and measured cardiac function using an echocardiogram. We found that there were significant differences in the ejection time, left ventricle mass, fractional shortening, and importantly in stroke volume and cardiac output of male offspring from females in their 1 st vs 4 th (multiparous) pregnancy. No differences in heart rate and aorta diameter were observed. These data suggest that the offspring of obese multiparous females are more prone to develop reduced cardiac function on a high fat diet, possibly indicating that maternal environment may be a novel risk factor for heart disease.