Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation

Abstract

Excess of glucocorticoids (GCs) during pregnancy is strongly associated with the programming of glucose intolerance in the offspring. However, the impact of high GC levels on maternal metabolism is not clearly documented. This study aimed to test the hypothesis that mothers exposed to elevated levels of GCs might also display long-term disturbances in glucose homeostasis. Dexamethasone (DEX) was administered noninvasively to the mothers via drinking water between the 14th and the 19th days of pregnancy. Mothers were subjected to glucose and insulin tolerance tests at 1, 2, 3, 6, and 12 mo postweaning. Pregnant rats not treated with DEX and age-matched virgin rats were used as controls. Pancreatic islets were isolated at the 20th day of pregnancy and 12 mo postweaning in order to evaluate glucose-stimulated insulin secretion. The expression of the miR-29 family was also studied due to its responsiveness to GCs and its well-documented role in the regulation of pancreatic β-cell function. Rats treated with DEX during pregnancy presented long-term glucose intolerance and impaired insulin secretion. These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence. Our data demonstrate that the use of DEX during pregnancy results in deleterious outcomes to the maternal metabolism, hallmarked by reduced insulin secretion and glucose intolerance. This maternal metabolic programming might be a consequence of time-sustained upregulation of miR-29s in maternal pancreatic islets.

Day‐restricted feeding during pregnancy and lactation programs glucose intolerance and impaired insulin secretion in male rat offspring

“…Consistent with the present data, we previously reported that pregnant rats treated with dexamethasome present a long‐term sustained reduction in insulin secretion and syntaxin 1a levels, which are correlated with increased miR‐29a levels (Gomes et al . ).…”

“…Analysis of mRNA and miRNA expression was performed as previously described (Gomes et al . ). Briefly, the total RNA was extracted using TRIzol reagent from pools of 200 freshly isolated islets.…”

Regulatory Roles of MicroRNAs in Diabetes

“…Aside from the above, many other miRNAs are involved in pancreatic function, especially insulin secretion (e.g., miR-375 , -184, -33 , -187 , -29a , and -30a ) [28,29,30,31,32,33,34,35,36,37]. For example, although miR-29 is mentioned above in regard to its role in regulating β-cell proliferation, it has also been shown in multiple reports to negatively regulate insulin secretion by directly targeting Stx-1a , a t-SNARE protein involved in insulin exocytosis [31], and Mct1 , which may affect insulin secretion [32].…”

“…For example, although miR-29 is mentioned above in regard to its role in regulating β-cell proliferation, it has also been shown in multiple reports to negatively regulate insulin secretion by directly targeting Stx-1a , a t-SNARE protein involved in insulin exocytosis [31], and Mct1 , which may affect insulin secretion [32]. miR-124a is increased in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion by directly targeting the GTPase Rab27a [33] and Foxa2 [34], which contribute to β-cell dysfunction in T2DM.…”

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

“…Dexamethasone and prednisone/prednisolone show potent immunosuppressive, anti-inflammatory and antiallergic effects, which justify their wide prescription for the treatment of chronic autoimmune diseases, inflammatory diseases, organ transplant rejection, among others [6] . However, chronic exposure to the GCs impairs the normal metabolic homeostasis and causes deleterious adverse effects as demonstrated clinically and experimentally including hyperglycemia, glucose intolerance, dyslipidemia, peripheral insulin resistance, muscle wasting, hepatosteatosis, infertility, growth retardation, cognitive dysfunction, glaucoma, cataracts, topical skin thinning, osteoporosis and diabetes, among others [6][7][8] .…”