Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes.
Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2-4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056+/-62 vs 1793+/-62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8+/-0.4 vs 3.3+/-0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340+/-38 vs 916+/-25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.
Fosgerau
K
K
Rheoscience, Department of In Vivo Pharmacology, Herlev, Denmark.
Galle
P
P
Hansen
T
T
Albrechtsen
A
A
Rieper
C de Lemos
Cde L
Pedersen
B Klarlund
BK
Larsen
L Kongskov
LK
Thomsen
A Randrup
AR
Pedersen
O
O
Hansen
M Bagge
MB
Steensberg
A
A
D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000276:immunology*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged
D001323:Autoantibodies; D015850:Interleukin-6