Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

K Fosgerau; P Galle; T Hansen; A Albrechtsen; C de Lemos Rieper; B Klarlund Pedersen; L Kongskov Larsen; A Randrup Thomsen; O Pedersen; M Bagge Hansen; A Steensberg; K Fosgerau; Pia Søndergaard Galle; T Hansen; A Albrechtsen; C de Lemos Rieper; Bente Klarlund Pedersen; L Kongskov Larsen; Allan Randrup Thomsen; O Pedersen; M Bagge Hansen; Adam Steensberg

doi:10.1677/JOE-09-0413

Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

K Fosgerau, P Galle, T Hansen, A Albrechtsen, C de Lemos Rieper, B Klarlund Pedersen, L Kongskov Larsen, A Randrup Thomsen, O Pedersen, M Bagge Hansen, A Steensberg, K Fosgerau, Pia Søndergaard Galle, T Hansen, A Albrechtsen, C de Lemos Rieper, Bente Klarlund Pedersen, L Kongskov Larsen, Allan Randrup Thomsen, O PedersenM Bagge Hansen, Adam Steensberg

21 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Endocrinology
Volume	204
Issue number	3
Pages (from-to)	265-73
Number of pages	9
ISSN	0022-0795
DOIs	https://doi.org/10.1677/JOE-09-0413 https://doi.org/10.1677/JOE-09-0413
Publication status	Published - 1 Mar 2010

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Fosgerau, K., Galle, P., Hansen, T., Albrechtsen, A., Rieper, C. D. L., Pedersen, B. K., Larsen, L. K., Thomsen, A. R., Pedersen, O., Hansen, M. B., Steensberg, A., Fosgerau, K., Galle, P. S., Hansen, T., Albrechtsen, A., Rieper, C. D. L., Pedersen, B. K., Larsen, L. K., Thomsen, A. R., ... Steensberg, A. (2010). Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes. Journal of Endocrinology, 204(3), 265-73. https://doi.org/10.1677/JOE-09-0413, https://doi.org/10.1677/JOE-09-0413

Fosgerau, K, Galle, P, Hansen, T, Albrechtsen, A, Rieper, CDL, Pedersen, BK, Larsen, LK, Thomsen, AR, Pedersen, O, Hansen, MB, Steensberg, A, Fosgerau, K, Galle, PS, Hansen, T, Albrechtsen, A, Rieper, CDL, Pedersen, BK, Larsen, LK, Thomsen, AR, Pedersen, O, Hansen, MB & Steensberg, A 2010, 'Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes', Journal of Endocrinology, vol. 204, no. 3, pp. 265-73. https://doi.org/10.1677/JOE-09-0413, https://doi.org/10.1677/JOE-09-0413

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title = "Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes",

abstract = "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.",

author = "K Fosgerau and P Galle and T Hansen and A Albrechtsen and Rieper, {C de Lemos} and Pedersen, {B Klarlund} and Larsen, {L Kongskov} and Thomsen, {A Randrup} and O Pedersen and Hansen, {M Bagge} and A Steensberg and K Fosgerau and Galle, {Pia S{\o}ndergaard} and T Hansen and A Albrechtsen and Rieper, {C de Lemos} and Pedersen, {Bente Klarlund} and Larsen, {L Kongskov} and Thomsen, {Allan Randrup} and O Pedersen and Hansen, {M Bagge} and Adam Steensberg",

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T1 - Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

AU - Fosgerau, K

AU - Galle, P

AU - Hansen, T

AU - Albrechtsen, A

AU - Rieper, C de Lemos

AU - Pedersen, B Klarlund

AU - Larsen, L Kongskov

AU - Thomsen, A Randrup

AU - Pedersen, O

AU - Hansen, M Bagge

AU - Steensberg, A

AU - Fosgerau, K

AU - Galle, Pia Søndergaard

AU - Hansen, T

AU - Albrechtsen, A

AU - Rieper, C de Lemos

AU - Pedersen, Bente Klarlund

AU - Larsen, L Kongskov

AU - Thomsen, Allan Randrup

AU - Pedersen, O

AU - Hansen, M Bagge

AU - Steensberg, Adam

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

U2 - 10.1677/JOE-09-0413

DO - 10.1677/JOE-09-0413

M3 - Journal article

C2 - 20016056

SN - 0022-0795

VL - 204

SP - 265

EP - 273

JO - Journal of Endocrinology

JF - Journal of Endocrinology

IS - 3

ER -

Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

Abstract

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