Impact of obesity on maternal and neonatal outcomes in insulin-resistant pregnancy.

OBJECTIVE: To determine the impact of obesity on pregnancies complicated by insulin resistance. STUDY DESIGN: Secondary analysis of prospective cohort of women with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM). The exclusion criteria were type 1 DM, multiple gestation, fetal anomalies, unknown prepregnancy, and body mass index (BMI). Primary maternal outcome was a composite of any of the following: severe preeclampsia, eclampsia, third- to fourth-degree laceration, readmission, wound infection, or antepartum hospitalization. Primary neonatal outcome was a composite of any of the following: hypoglycemia, preterm delivery, admission to level 3 nursery, oxygen requirement > 6 hours after birth, shoulder dystocia, 5-minute Apgar ≤3, cord pH < 7.0, and cord base excess < -12 mmol/L. Obese women (BMI ≥30.0 kg/m(2)) were compared with nonobese women (BMI < 30.0 kg/m(2)). RESULTS: Of 356 subjects with DM, 233 (66%) were obese. Obese women were not at further increased risk of the composite maternal outcome (adjusted odds ratio [AOR] = 0.68, 95% confidence interval [CI] = 0.43-1.09), the composite neonatal outcome (AOR = 0.76, 95% CI = 0.48-1.21), or cesarean (58.8 vs. 52.9%, p = 0.28, AOR = 1.47, 95% CI = 0.91-2.39). CONCLUSION: We did not find evidence that obesity worsened pregnancy outcomes in women with GDM and type 2 DM, suggesting that obese women may not require more stringent antepartum treatment strategies.

A role for ataxia telangiectasia mutated in insulin-independent stimulation of glucose transport.

Literature reports suggest that ataxia telangiectasia mutated (ATM) can activate the AMP-activated protein kinase (AMPK), a protein that can stimulate glucose transport in skeletal muscle. We hypothesized that 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, would increase glucose transport in mouse extensor digitorum longus (EDL) muscles in an ATM-dependent manner. AICAR-stimulated glucose transport was prevented by the ATM inhibitor KU-55933 despite normal stimulation of AMPK phosphorylation. Consistent with this, AICAR caused AMPK phosphorylation but not an increase of glucose transport in ATM-deficient (ATM-/-) muscles. S231 of TBC1D1 matches the sequence motif of ATM substrates, and phosphorylation of this site is known to inhibit TBC1D1 and lead to increased glucose transport. Accordingly, we assessed TBC1D1 phosphorylation and found that AICAR-stimulated phosphorylation of TBC1D1 at S231 did not occur in ATM-/- muscles. However, activation of ATM without activation of AMPK was insufficient to increase TBC1D1 phosphorylation. The data suggest that ATM plays a role in AICAR-stimulated glucose transport downstream of AMPK.

Impaired insulin-stimulated glucose transport in ATM-deficient mouse skeletal muscle.

There are reports that ataxia telangiectasia mutated (ATM) plays a role in insulin-stimulated Akt phosphorylation, although this is not the case in some cell types. Because Akt plays a key role in insulin signaling, which leads to glucose transport in skeletal muscle, the predominant tissue in insulin-stimulated glucose disposal, we examined whether insulin-stimulated Akt phosphorylation and (or) glucose transport would be decreased in skeletal muscle of mice lacking functional ATM, compared with muscle from wild-type mice. We found that in vitro insulin-stimulated Akt phosphorylation was normal in soleus muscle from mice with 1 nonfunctional allele of ATM (ATM+/-) and from mice with 2 nonfunctional alleles (ATM-/-). However, insulin did not stimulate glucose transport or the phosphorylation of AS160 in ATM-/- soleus. ATM protein level was markedly higher in wild-type extensor digitorum longus (EDL) than in wild-type soleus. In EDL from ATM-/- mice, insulin did not stimulate glucose transport. However, in contrast to findings for soleus, insulin-stimulated Akt phosphorylation was blunted in ATM-/- EDL, concomitant with a tendency for insulin-stimulated phosphatidylinositol 3-kinase activity to be decreased. Together, the findings suggest that ATM plays a role in insulin-stimulated glucose transport at the level of AS160 in muscle comprised of slow and fast oxidative-glycolytic fibers (soleus) and at the level of Akt in muscle containing fast glycolytic fibers (EDL).