Diabetes alters microvascular function in the vascular beds of organs, including the lungs. Cardiovascular complications of pulmonary vascular affectation may be a consequence of the overactivation of the vasoconstrictive and proliferative components of the renin-angiotensin system. We previously reported that pulmonary physiology and surfactant production is improved by the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide (LIR) in a rat model of lung hypoplasia. Because we hypothesized that streptozotocin-induced diabetes rats would show deficiencies in lung function, including surfactant proteins, and develop an imbalance of the renin-angiotensin system in the lungs. This effect would in turn be prevented by long-acting agonists of the GLP-1R, such as LIR. The induction of diabetes reduced the surfactant protein A and B in the lungs and caused the vasoconstrictor component of the renin-angiotensin system to predominate, which in turn increased angiotensin II levels, and ultimately being associated with right ventricle hypertrophy. LIR restored surfactant protein levels and reversed the imbalance in the renin-angiotensin system in this type 1 diabetes mellitus rat model. Moreover, LIR provoked a strong increase in angiotensin-converting enzyme 2 expression in the lungs of both diabetic and control rats, and in the circulating angiotensin(1-7) in diabetic animals. These effects prompted complete reversion of right ventricle hypertrophy. The consequences of LIR administration were independent of glycemic control and of glucocorticoids, and they involved NK2 homeobox 1 signaling. This study demonstrates by first time that GLP-1R agonists, such as LIR, might improve the cardiopulmonary complications associated with diabetes.

In this study, we have extended our initial molecular studies of a nonconsanguineous family with two affected siblings and one of their nephews with congenital goiter, hypothyroidism, and marked impairment of thyroglobulin synthesis. Genomic DNA sequencing revealed that the index patient (affected nephew) was heterozygous for a single base change of a cytosine to a thymine at nucleotide 886 in exon 7 (886C>T, mother's mutation) in one allele and for a novel guanine to cytosine transversion at position -1 of the splice acceptor site in intron 34 (IVS34-1G>C, father's mutation) in the other allele. The two affected siblings inherited the 886C>T mutation from their mother and a previously reported cytosine to thymine transition at nucleotide 4588 in exon 22 from their father (4588C>T). The 886C>T and 4588C>T substitutions resulted in premature stop codons at amino acids 277 (R277X) and 1511 (R1511X), respectively. In vitro transcription analysis showed that the exon 35 is skipped entirely when the IVS34-1G>C mutation is present, whereas the wild-type allele is correctly spliced. SSCP (exon 7 and 35) and restriction analysis (exon 22) using Taq I indicated that the two affected siblings, the affected nephew, his mother, and his unaffected brother were all heterozygous for the R277X mutation. The two affected siblings, their father, and three unaffected siblings were all heterozygous for the R1511X mutation, whereas the affected nephew and his father were heterozygous for the IVS34-1G>C mutation. Moreover, in this kindred, we have characterized polymorphisms (insertion/deletion, microsatellite, and single nucleotide polymorphism) located within introns 18 and 29 and exon 44 that are associated with the described mutations. Haplotype analysis with these polymorphic markers in two unrelated Brazilian families (present family studied and previously reported family) harboring the R277X mutation suggests a founder effect for the R277X mutation. In conclusion, the affected individuals of this family are either compound heterozygous for R277X/IVS34-1G>C or R277X/R1511X. This observation further supports that thyroglobulin gene mutations display significant intraallelic heterogeneity.

In a 22-yr-old healthy woman, a fetal goiter was diagnosed coincidentally by ultrasound during the sixth month of gestation, and hypothyroidism was affirmed by a high TSH (336 mU/liter) concentration after cordocentesis. A second ultrasound examination at 27 wk gestation showed further enlargement of the goiter (34/21 mm). Two intraamniotic injections of 200 microg levothyroxine were performed during the seventh month of pregnancy. Ultrasound studies revealed a fetal goiter size of 30/18 mm during the eighth month of gestation. The woman delivered at term a female infant with an Apgar score of 10 at 1 and 5 min. Cord blood analysis indicated elevated TSH (284 mU/liter) and low free T(4) (5.5 pmol/liter) levels. The serum thyroglobulin (Tg) concentration was low (0.8 ng/ml), whereas ultrasound of the neonate indicated an enlarged thyroid gland (32/15/14 mm). During the second pregnancy, ultrasound examination revealed a goiter, and fetal hypothyroidism was also confirmed after umbilical vein blood sampling (TSH, 472 mU/liter). After two intraamniotic injections of 500 microg levothyroxine, the woman delivered a male infant at 37 wk of pregnancy. In cord blood the serum TSH concentration was 39 mU/liter, and the serum Tg level was low (0.7 ng/ml). The parents were nonconsanguineous. After birth of the two affected siblings, genomic DNA sequencing identified the presence of compound heterozygous mutations of the Tg gene: the paternal mutation consists of a cytosine deletion at nucleotide 1143 in exon 9 (1143delC), resulting in a frameshift that generates a stop codon at position 382, and the maternal mutation is a guanine to adenine substitution at position 6725 in exon 38, creating the R2223H missense mutation in the acetylcholinesterase homology domain of Tg. In conclusion, we report two siblings with congenital goiter and hypothyroidism caused by compound heterozygous mutations of the Tg gene.