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


METHODS
sKlotho 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.


RESULTS
No 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.


CONCLUSIONS
These 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.
Joris
J
van Ark
Hans-Peter
HP
Hammes
Marcory C R F
MC
van Dijk
Chris P H
CP
Lexis
Iwan C C
IC
van der Horst
Clark J
CJ
Zeebregts
Marc G
MG
Vervloet
Bruce H R
BH
Wolffenbuttel
Harry
H
van Goor
Jan-Luuk
JL
Hillebrands
D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D003925:Diabetic Angiopathies / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D005966:Glucuronidase / Q000097:blood* / Q000235:genetics; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D013997:Time Factors
D001786:Blood Glucose; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D006442:Glycated Hemoglobin; D000090265:Klotho Proteins; D012333:RNA, Messenger; C558406:HbA(1c) protein, mouse