Preconception Alcohol Exposure Increases the Susceptibility to Diabetes in the Offspring

Heavy alcohol drinking alters glucose metabolism, but the inheritability of this effect of alcohol is not well understood. We used an animal model of preconception alcohol exposure in which adult female rats were given free access to 6.7% alcohol in a liquid diet and water for about 4 weeks, went without alcohol for 3 weeks, and then were bred to generate male and female offspring. Control animals were either ad lib–fed rat chow or pair-fed an isocaloric liquid diet during the time of alcohol-feeding in the experimental animals. Our results show that the female rats fed with alcohol in the liquid diet, but not with the isocaloric liquid diet, prior to conception had an altered stress gene network involving glucose metabolism in oocytes when compared with those in ad lib–fed chow diet controls. The offspring born from preconception alcohol-fed mothers showed significant hyperglycemia and hypoinsulinemia when they were adults. These rats also showed increased levels of inflammatory cytokines and cellular apoptosis in the pancreas, altered insulin production and actions in the liver, and a reduced number of proopiomelanocortin neurons in the hypothalamus. Replenishment of proopiomelanocortin neurons in these animals normalized the abnormal glucose to restore homeostasis. These data suggest that preconception alcohol exposures alter glucose homeostasis by inducing proopiomelanocortin neuronal functional abnormalities. Our findings provide a novel insight into the impact of high doses of alcohol on the female gamete that may cause inheritance of an increased susceptibility to diabetes.