Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

Abstract

BackgroundDiabetes is associated with a high incidence of macrovascular disease (MVD), including peripheral and coronary artery disease. Circulating soluble-Klotho (sKlotho) is produced in the kidney and is a putative anti-aging and vasculoprotective hormone. Reduced Klotho levels may therefore increase cardiovascular risk in diabetes. We investigated if sKlotho levels are decreased in type 2 diabetes and associate with MVD in the absence of diabetic nephropathy, and whether hyperglycemia affects renal Klotho production in vitro and in vivo.MethodssKlotho levels were determined with ELISA in diabetic and non-diabetic patients with and without MVD, and healthy control subjects. Human renal tubular epithelial cells (TECs) were isolated and exposed to high glucose levels (15 and 30 mM) in vitro and Klotho levels were measured with qPCR and quantitative immunofluorescence. Klotho mRNA expression was quantified in kidneys obtained from long term (3 and 8 months) diabetic Ins2Akita mice and normoglycemic control mice.ResultsNo significant differences in sKlotho levels were observed between diabetic patients with and without MVD (527 (433–704) pg/mL, n = 35), non-diabetic MVD patients (517 (349–571) pg/mL, n = 27), and healthy control subjects (435 (346–663) pg/mL, n = 15). High glucose (15 and 30 mM) did not alter Klotho expression in TECs. Long-term hyperglycemia in diabetic Ins2Akita mice (characterized by increased HbA1c levels [12.9 ± 0.3% (3 months) and 11.3 ± 2.0% (8 months)], p < 0.05 vs. non-diabetic mice) did not affect renal Klotho mRNA expression.ConclusionsThese data indicate that sKlotho levels are not affected in type 2 diabetes patients with and without MVD. Furthermore, hyperglycemia per se does not affect renal Klotho production. As type 2 diabetes does not alter sKlotho levels, sKlotho does not seem to play a major role in the pathogenesis of MVD in type 2 diabetes.

Soluble α-Klotho as a Novel Biomarker in the Early Stage of Nephropathy in Patients with Type 2 Diabetes

“…measured circulating α-klotho levels in diabetes patients. Although they reported that circulating α-klotho levels were not changed in diabetic patients compared to control, their sample size was very small ( n  = 35) and they never mentioned the albuminuria status of their diabetic patients [11]. In the present study, plasma α-klotho levels in patients with type 2 diabetes were highest in the normoalbuminuria stage and decreased with increasing urinary albumin excretion.…”

“…Recent studies in patients with diabetes report conflicting data. One study found serum α-klotho level was not significantly different between patients with diabetes without nephropathy and non-diabetic controls [11], [12]. In contrast, another study reports a significant reduction in serum klotho levels in patients with glycated hemoglobin (HbA1c) levels ≥6.5% compared to control samples (HbA1c <6.5%) [13].…”

“…The extracellular domain of α-klotho protein is subject to ectodomain shedding and is released into the blood and urine [1]; therefore, it may function as a hormone [16]. Hyperglycemia does not affect renal α-klotho production per se, because high glucose does not alter α-klotho expression in kidney cells and diabetes does not affect renal α-klotho mRNA expression in mice [11]. The lack of an association between HbA 1c or glycated albumin with soluble α-klotho concentrations in the present study also corroborates previous observations.…”

Soluble Klotho and Fibroblast Growth Factor 23 Levels in Diabetic Nephropathy with Different Stages of Albuminuria

“…Furthermore, reduced expression of Klotho in diabetes has been reported in experimental studies 11 12. In contrast, s-Klotho levels were not significantly different between patients with diabetes without nephropathy, and healthy controls 13. In these studies, patients have relatively preserved renal function.…”

Erratum to: Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

“…After publication of this work [1], we noted that we inadvertently failed to include the complete list of all coauthors. The full list of authors has now been added and the Authors’ contributions and Competing interests section modified accordingly.…”