Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study
Authors: Blanchard Anne , Vallet Marion , Dubourg Laurence , Hureaux Marguerite , Allard Julien , Haymann Jean-Philippe , de la Faille Renaud , Arnoux Armelle , Dinut Aurelie , Bergerot Damien , Becker Pierre-Hadrien , Courand Pierre-Yves , Baron Stéphanie , Houillier Pascal , Tack Ivan , Devuyst Olivier , Jeunemaitre Xavier , Azizi Michel , Vargas-Poussou Rosa 
Published: July 2019

Significance Statement
About 1% of the population is heterozygous for loss-of-function variants in SLC12A3, which encodes the thiazide-sensitive sodium-chloride cotransporter. Biallelic SLC12A3 mutations are responsible for Gitelman syndrome, a salt-losing tubulopathy. In a cross-sectional study of 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome of similar age, body mass index, and sex ratio, the authors assessed findings from home BP monitoring, oral glucose tolerance testing, and assays of plasma and urine electrolyte and hormone levels. They found evidence for a subtle intermediate phenotype in heterozygous carriers and demonstrated a resistance to insulin in the patients with Gitelman syndrome. These findings indicate that counseling of such patients is warranted to reduce their risk of type 2 diabetes and to reassure them about the health of their heterozygous relatives.

Background
Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers.

Methods
To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test.

Results
We enrolled 242 participants, aged 18–75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers.

Conclusions
Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.