Variants in HSD11B1 gene modulate susceptibility to diabetes kidney disease and to insulin resistance in type 1 diabetes

Abstract

Background and aim11β‐Hydroxysteroid dehydrogenase 1 has been implicated in insulin resistance (IR) in the setting of metabolic disorders, and single nucleotide polymorphisms (SNPs) in its encoding gene (HSD11B1) have been associated with type 2 diabetes and metabolic syndrome. In type 1 diabetes (T1D), IR has been related to the development of chronic complications. We investigated the association of HSD11B1 SNPs with microvascular complications and with IR in a Brazilian cohort of T1D individuals.Materials and methodsFive SNPs were genotyped in 466 T1D individuals (57% women; median of 37 years old, diabetes duration of 25 years and HbA1c of 8.4%).ResultsThe minor allele T of rs11799643 was nominally associated with diabetic retinopathy (OR = 0.52; confidence interval [CI] 95% = 0.28‐0.96; P = .036). The minor allele C of rs17389016 was nominally associated with overt diabetic kidney disease (DKD) (OR = 1.90; CI 95% = 1.07‐3.37; P = .028). A follow‐up study revealed that 29% of the individuals lost ≥5 mL min−1 × 1.73 m2 per year of the estimated glomerular filtration rate (eGFR). In these individuals (eGFR decliners), C allele of rs17389016 was more frequent than in non‐decliners (OR = 2.10; CI 95% = 1.14‐3.89; P = .018). Finally, minor allele T of rs846906 associated with higher prevalence of arterial hypertension, higher body mass index and waist circumference, thus conferring risk to a lower estimated glucose disposal rate, a surrogate marker of insulin sensitivity (OR = 1.23; CI 95% = 1.06‐1.42; P = .004).ConclusionSNPs in the HSD11B1 gene may confer susceptibility to DKD and to IR in T1D individuals.

Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors

“…Furthermore, the minor C allele of rs17389016 of the 11β-Hydroxysteroid dehydrogenase 1 (HSD11B1) was recently associated with the “fast decliner” phenotype and overt DKD in a cohort of 466 T1DM subjects (OR = 2.10; CI 95% = 1.14–3.89; p = 0.018) [ 186 ].…”

“…Overall, the available evidence suggests that sex should be considered among the variables potentially influencing the impact of genes on DKD risk. Thus, when a sex-specific analysis was conducted, some of these genetic risk factors were exclusively or more strongly associated with DKD in either DM men or women ( Table 3 ) [ 180 , 181 , 182 , 183 , 184 , 185 , 186 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 198 , 200 , 201 , 202 , 203 , 204 , 205 , 207 ]. Future research should persevere to confirm sex-specific associations and basic research should investigate the mechanisms behind these observed results.…”

12(S)‐hydroxyeicosatetraenoic acid is significantly increased in diabetic kidney disease and associated with renal function decline

“…Extensive evidence suggested that inflammation played a key role in the development and progression of diabetic renal injury, resulted in elevated albuminuria, and decreased glomerular filtration rate (GFR) and renal fibrosis. 5,6 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) is a stable metabolite of arachidonic acid that is catalysed by 12-lipoxygenases (12LOXs). 7 Abnormalities in the arachidonic acid metabolites have been observed in both diabetic animal models and humans.…”

“…Therefore, the management of DKD has become a long‐term health cost and huge burden worldwide. Extensive evidence suggested that inflammation played a key role in the development and progression of diabetic renal injury, resulted in elevated albuminuria, and decreased glomerular filtration rate (GFR) and renal fibrosis 5,6 …”

Review of potential biomarkers of inflammation and kidney injury in diabetic kidney disease

“…More recently, Fayed et al151 found urinary mRNA levels of podocyte injury proteins (Nephrin, Podocin and Podocalyxin) to correlate with albuminuria and serum creatinine. In the study by Mori et al152 single nucleotide polymorphisms in the gene which encodes for the enzyme protein 11-beta hydroxysteroid dehydrogenase 1 was found to associate with increased risk of DKD in T1D cohort.The increasing relevance of lipid markers has led to the emergence of lipidomic, a…”