Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure

Abstract

Key points summary Prenatal alcohol exposure has the potential to affect fetal development and program chronic disease in offspring. Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour. In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring. Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6-month old male offspring exposed to prenatal alcohol, suggestive of a pre-diabetic state. This result suggests that even a relatively low-dose, acute exposure to alcohol during pregnancy can still program metabolic dysfunction in a sex-specific manner.Abstract 1 Alcohol consumption is highly prevalent amongst women of reproductive age. Given 2 that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect 3 fetal development and program chronic disease in offspring. We examined the effect of 4 an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid 5 levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-6 Dawley rats received an oral gavage of ethanol (1g/kg maternal body weight, n=9 dams) 7 or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. 8 PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. 9 Fasting blood glucose concentration was not affected by PAE in offspring at any age, 10 nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month old 11 offspring (P>0.5). However, there was evidence of insulin resistance in PAE male 12 offspring at 6 months of age, with significantly elevated fasting plasma insulin (P = 13 0.001), a tendency for increased first phase insulin secretion during the GTT and 14 impaired glucose clearance following an insulin challenge (P = 0.007). This was 15 accompanied by modest alterations in protein kinase B (AKT) signalling in adipose 16 tissue. PAE also resulted in reduced calorie consumption by offspring compared to 17 controls (P = 0.04). These data suggest that a relatively low-level, acute PAE programs 18 metabolic dysfunction in offspring in a sex-specific manner. These results highlight that 19 alcohol consumption during pregnancy has the potential to affect the long-term health 20 of offspring. 21 Key words: fetal programming, glucose metabolism, insulin resistance, food preference, 22 gene expression 23 24 25 33 development of other organs deemed relatively unnecessary, such as the kidneys, liver 34 and pancreas, can be compromised (Heindel & Vandenberg, 2015). This can result in 35 long-term adverse health outcomes in offspring associated with the altered function in 36 these organs. Although both clinical studies and animal models suggest that the timing 37 of exposure can be important, organs requiring a prolong...

The proof of the pudding is in the eating: Metabolic consequences of moderate alcohol exposure before birth

“…Although glucose control measured as fasting blood glucose concentration and glucose tolerance during a glucose tolerance test were not impaired in male or female young adult offspring, there was evidence of insulin resistance in the males (Nguyen et al . ). This included higher fasting circulating insulin, suggesting that more insulin is required to maintain normal glucose levels, and a smaller glucose response to insulin administration in PAE males compared to controls (Nguyen et al .…”

“…This included higher fasting circulating insulin, suggesting that more insulin is required to maintain normal glucose levels, and a smaller glucose response to insulin administration in PAE males compared to controls (Nguyen et al . ). Expression and activation (phosphorylation) of Akt, a proximal component of the insulin signalling pathway, was similar in liver and skeletal muscle of PAE and control males.…”

“…Gene expression of the insulin receptor and of the main glucose transporter ( Glut4 ) in skeletal muscle and adipose tissue was also unaffected by PAE (Nguyen et al . ). Curiously, protein levels of total (pan‐AKT) and activated (pAKT Thr308 ) were higher in adipose tissue from PAE than control males, suggesting that PAE alters insulin signalling in fat (Nguyen et al .…”

“…As reported in this issue of the Journal of Physiology , Nguyen et al . () therefore assessed the metabolic health of rat progeny whose mothers consumed moderate levels of alcohol for only 2 days during mid‐pregnancy. Blood alcohol concentrations peaked at ∼0.05%, 1 h after alcohol was given to the pregnant dams, and were less than 0.005% at 5 h after alcohol consumption (Nguyen et al .…”

“…Curiously, protein levels of total (pan‐AKT) and activated (pAKT Thr308 ) were higher in adipose tissue from PAE than control males, suggesting that PAE alters insulin signalling in fat (Nguyen et al . ), although these changes would be expected to enhance rather than impair insulin action in this tissue. Whether the insulin resistance observed in young adult males after PAE progresses to glucose intolerance or diabetes with ageing or other challenges such as obesity, or whether metabolic phenotypes emerge in females, remains to be assessed.…”