Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study

Abstract

BackgroundGitelman 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.MethodsTo 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.ResultsWe 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.ConclusionsHeterozygous 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.

Enemy Action in the Distal Convoluted Tubule

“…Thus, it seems likely that plasma aldosterone concentrations are higher in SLC12A3 heterozygotes than in healthy subjects, even though this difference was not "statistically significant" in the paper by Blanchard et al 9 We often think of aldosterone as a pathogenic factor, especially when it coexists with high BP. Yet, it seems that SLC12A3 heterozygotes may also have a slightly lower systolic pressure (mean systolic BP 118 mm Hg in healthy subjects and 116 mm Hg in heterozygous subjects, see table 1 in Blanchard et al 9 ), which should be protective. This small difference, played out across 7 billion people with a gene frequency of 1.5%, could have mammoth beneficial public health implications.…”

“…Genetic diagnosis, in addition to clarifying syndromic features, permits investigators to estimate mutation frequencies in populations and define phenotypes better. A paper by Blanchard et al 9 in this issue of JASN does just that. Although prior estimates of Gitelman mutation gene frequency have ranged from 1% 10 to 3%, 11 Blanchard et al, using a very recent and large database, estimate that 1.14% of the population is heterozygous for well established pathogenic mutations in SLC12A3, and that 3.6% are heterozygous when nonclassified variants of very low frequency (suggestive of being pathogenic) are included.…”

“…Given the relative frequency of heterozygosity in the general population, Blanchard et al tested whether heterozygous individuals exhibit an intermediate phenotype. 9 Gitelman syndrome results from dysfunction of salt transport; thus it is not surprising that it has been associated with low BP. 12 Several groups have previously tested the hypothesis that individuals carrying a single mutation in SLC12A3 might exhibit a forme fruste of Gitelman syndrome; in this case, the mutations might be maintained in the gene pool because they help protect individuals from hypertension.…”

“…The work by Blanchard et al in this issue again tests the hypothesis that SLC12A3 heterozygosity affects BP and electrolyte homeostasis, but uses a larger group of genetically defined individuals who were phenotyped carefully; it finds largely for the null, suggesting that heterozygosity for Gitelman-causing SLC12A3 mutations is not associated with a substantial phenotype. 9 The results benefit from several factors that make this data set the most authoritative to date; these include the use of home BP monitoring, the derivation of heterozygous patients as relatives of a population of individuals documented to have Gitelman syndrome, and the careful approach to biochemical analysis. So, then, is this the last word?…”

“…The manuscript by Blanchard et al does not dismiss the possibility of a modest intermediate phenotype resulting from SLC12A3 heterozygosity, but it suggests that any such phenotype is very mild. 9 One approach to gain additional insight into this issue is to study animal models of human disease. Unlike some disease classes, where mouse models do not provide highly relevant information regarding human processes, monogenic kidney diseases of electrolyte transport are often faithfully recapitulated by mouse models.…”