Background. Adverse maternal environments may predispose the offspring to metabolic syndrome in adulthoods, but the underlying mechanism has not been fully understood. Methods. Maternal hyperglycemia was induced by streptozotocin (STZ) injection while control (CON) rats received citrate buffer. Litters were adjusted to eight pups per dam and then weaned to standard diet. Since 13 weeks old, a subset of offspring from STZ and CON dams were switched to high fat diet (HFD) for another 13 weeks. Glucose and insulin tolerance tests (GTT and ITT) and insulin secretion assay were performed; serum levels of lipids and leptin were measured. Hepatic fat accumulation and islet area were evaluated through haematoxylin and eosin staining. Results. STZ offspring exhibited lower survival rate, lower birth weights, and growth inhibition which persisted throughout the study. STZ offspring on HFD showed more severe impairment in GTT and ITT, and more profound hepatic steatosis and more severe hyperlipidemia compared with CON-HFD rats. Conclusions. Offspring from diabetic dams would be prone to exhibit low birth weight and postnatal growth inhibition, but could maintain normal glucose tolerance and insulin sensitivity. HFD accelerates development of insulin resistance in the offspring of diabetic dams mainly via a compensatory response of islets. 1. Introduction Metabolic syndrome (MetS) is a clustering of metabolic disorders including hyperglycemia, hypertension, dyslipidemia, overweight, and central obesity, with insulin resistance as the central feature of this syndrome [1]. A global increase in the prevalence of MetS has been found in the last decades due to the worldwide epidemic of obesity [2, 3]. The risk of the MetS depends on genetic susceptibility but is modulated by pre- and postnatal environmental factors. A growing body of evidence suggests that adverse environmental conditions during crucial periods of development may predispose individuals to develop different components of the MetS in adulthood [4]. Of particular note is maternal diabetes, including type 1 and type 2 diabetes and gestational diabetes mellitus (GDM). An overall increasing prevalence of diabetes indicates an emergence of diabetes among childbearing women. During pregnancy, especially during critical window periods for organogenesis and fetal development, unsatisfactory glycemic control is known to increase the incidence of severe obstetrical complications, including preeclampsia, macrosomia, and Caesarean section. Additionally, intrauterine exposure to a hyperglycemic environment predisposes
A. Mozumdar and G. Liguori, “Persistent increase of prevalence of metabolic syndrome among U.S. adults: NHANES III to NHANES 1999–2006,” Diabetes Care, vol. 34, no. 1, pp. 216–219, 2011.
S. Lim, H. Shin, J. H. Song et al., “Increasing prevalence of metabolic syndrome in Korea: the Korean National Health and Nutrition Examination Survey for 1998–2007,” Diabetes Care, vol. 34, no. 6, pp. 1323–1328, 2011.
K. Shankar, P. Kang, A. Harrell et al., “Maternal overweight programs insulin and adiponectin signaling in the offspring,” Endocrinology, vol. 151, no. 6, pp. 2577–2589, 2010.
D. Dabelea, R. L. Hanson, R. S. Lindsay et al., “Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a Study of Discordant Sibships,” Diabetes, vol. 49, no. 12, pp. 2208–2211, 2000.
T. D. Clausen, E. R. Mathiesen, T. Hansen et al., “High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia,” Diabetes Care, vol. 31, no. 2, pp. 340–346, 2008.
T. D. Clausen, E. R. Mathiesen, T. Hansen et al., “Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 7, pp. 2464–2470, 2009.
M. E. Symonds, S. P. Sebert, M. A. Hyatt, and H. Budge, “Nutritional programming of the metabolic syndrome,” Nature Reviews Endocrinology, vol. 5, no. 11, pp. 604–610, 2009.
H. Boerschmann, M. Pflüger, L. Henneberger, A. G. Ziegler, and S. Hummel, “Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus,” Diabetes Care, vol. 33, no. 8, pp. 1845–1849, 2010.
T. L. Crume, L. Ogden, N. A. West et al., “Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the Exploring Perinatal Outcomes among Children (EPOCH) Study,” Diabetologia, vol. 54, no. 1, pp. 87–92, 2011.
N. C. Bush, P. C. Chandler-Laney, D. J. Rouse, W. M. Granger, R. A. Oster, and B. A. Gower, “Higher maternal gestational glucose concentration is associated with lower offspring insulin sensitivity and altered β-cell function,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 5, pp. E803–E809, 2011.
A. Yessoufou, K. Moutairou, and N. A. Khan, “A model of insulin resistance in mice, born to diabetic pregnancy, is associated with alterations of transcription-related genes in pancreas and epididymal adipose tissue,” Journal of Obesity, vol. 2011, Article ID 654967, 11 pages, 2011.
F. H. Saito, D. C. Damasceno, W. G. Kempinas et al., “Repercussions of mild diabetes on pregnancy in Wistar rats and on the fetal development,” Diabetology and Metabolic Syndrome, vol. 2, no. 1, article 26, 2010.
E. M. Segar, A. W. Norris, J. R. Yao et al., “Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats,” Clinical Science, vol. 117, no. 3, pp. 129–138, 2009.
J. Han, J. Xu, S. L. Yun, P. N. Epstein, and Y. Q. Liu, “Rat maternal diabetes impairs pancreatic β-cell function in the offspring,” American Journal of Physiology, vol. 293, no. 1, pp. E228–E236, 2007.
I. López-Soldado and E. Herrera, “Different diabetogenic response to moderate doses of streptozotocin in pregnant rats, and its long-term consequences in the offspring,” Experimental Diabesity Research, vol. 4, no. 2, pp. 107–118, 2003.
K. Holemans, R. T. Gerber, K. Meurrens, F. De Clerck, L. Poston, and F. A. Van Assche, “Streptozotocin diabetes in the pregnant rat induces cardiovascular dysfunction in adult offspring,” Diabetologia, vol. 42, no. 1, pp. 81–89, 1999.
E. A. Ryan, D. Liu, R. C. Bell, D. T. Finegood, and J. Crawford, “Long term consequences in offspring of diabetes in pregnancy: studies with syngeneic islet-transplanted streptozotocin-diabetic rats,” Endocrinology, vol. 136, no. 12, pp. 5587–5592, 1995.
H. Merzouk, S. Madani, D. C. Sari, J. Prost, M. Bouchenak, and J. Belleville, “Time course of changes in serum glucose, insulin, lipids and tissue lipase activities in macrosomic offspring of rats with streptozotocin-induced diabetes,” Clinical Science, vol. 98, no. 1, pp. 21–30, 2000.
L. Aerts, L. Vercruysse, and F. A. Van Assche, “The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats,” Diabetes Research and Clinical Practice, vol. 38, no. 1, pp. 9–19, 1997.
I. F. Casson, C. A. Clarke, C. V. Howard et al., “Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study,” British Medical Journal, vol. 315, no. 7103, pp. 275–278, 1997.
Q.-H. Yang, S.-P. Hu, Y.-P. Zhang et al., “Effect of berberine on expressions of uncoupling protein-2 mRNA and protein in hepatic tissue of non-alcoholic fatty liver disease in rats,” Chinese Journal of Integrative Medicine, vol. 17, no. 3, pp. 205–211, 2011.
T. R. Moore, “Fetal exposure to gestational diabetes contributes to subsequent adult metabolic syndrome,” American Journal of Obstetrics and Gynecology, vol. 202, no. 6, pp. 643–649, 2010.
S. O. Rocha, G. N. Gomes, A. L. L. Forti et al., “Long-term effects of maternal diabetes on vascular reactivity and renal function in rat male offspring,” Pediatric Research, vol. 58, no. 6, pp. 1274–1279, 2005.
A. Plagemann, T. Harder, U. Janert et al., “Malformations of hypothalamic nuclei in hyperinsulinemic offspring of rats with gestational diabetes,” Developmental Neuroscience, vol. 21, no. 1, pp. 58–67, 1999.
K. Amri, N. Freund, J. Vilar, C. Merlet-Bénichou, and M. Lelièvre-Pégorier, “Adverse effects of hyperglycemia on kidney development in rats: in vivo and in vitro studies,” Diabetes, vol. 48, no. 11, pp. 2240–2245, 1999.
S. M. Steculorum and S. G. Bouret, “Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring,” Endocrinology, vol. 152, no. 11, pp. 4171–4179, 2011.
V. Grill, B. Johansson, P. Jalkanen, and U. J. Eriksson, “Influence of severe diabetes mellitus early in pregnancy in the rat: effects on insulin sensitivity and insulin secretion in the offspring,” Diabetologia, vol. 34, no. 6, pp. 373–378, 1991.
M. Vercheval, R. De Hertogh, S. Pampfer et al., “Experimental diabetes impairs rat embryo development during the preimplantation period,” Diabetologia, vol. 33, no. 4, pp. 187–191, 1990.
B. Blondeau, B. Joly, C. Perret et al., “Exposure in utero to maternal diabetes leads to glucose intolerance and high blood pressure with no major effects on lipid metabolism,” Diabetes and Metabolism, vol. 37, no. 3, pp. 245–251, 2011.
R. R. Rodríguez, A. Renauld, D. Celener, R. L. Pérez, and M. C. Susemihl, “Offspring of streptozotocin diabetic rats: Size changes in Langerhans islets with time after birth,” Diabetes Research and Clinical Practice, vol. 41, no. 2, pp. 95–100, 1998.
P. Serradas, M. N. Gangnerau, M. H. Giroix, C. Saulnier, and B. Portha, “Impaired pancreatic β cell function in the fetal GK rat: impact of diabetic inheritance,” Journal of Clinical Investigation, vol. 101, no. 4, pp. 899–904, 1998.
E. J. Keely, J. C. Malcolm, S. Hadjiyannakis, I. Gaboury, G. Lough, and M. L. Lawson, “Prevalence of metabolic markers of insulin resistance in offspring of gestational diabetes pregnancies,” Pediatric Diabetes, vol. 9, no. 1, pp. 53–59, 2008.
D. J. Pettitt, S. McKenna, C. McLaughlin, C. C. Patterson, D. R. Hadden, and D. R. McCance, “Maternal glucose at 28 weeks of gestation is not associated with obesity in 2-year-old offspring: the Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) family study,” Diabetes Care, vol. 33, no. 6, pp. 1219–1223, 2010.
T. L. Jetton, J. Lausier, K. LaRock et al., “Mechanisms of compensatory β-cell growth in insulin-resistant rats: roles of Akt kinase,” Diabetes, vol. 54, no. 8, pp. 2294–2304, 2005.
