Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis-at least in part-through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Bilgen
B
Ekim Üstünel
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.|Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Kilian
K
Friedrich
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Adriano
A
Maida
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Xiaoyue
X
Wang
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Anja
A
Krones-Herzig
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Oksana
O
Seibert
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Anke
A
Sommerfeld
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Allan
A
Jones
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Tjeerd P
TP
Sijmonsma
Center for Clinical Research, Medical Faculty Mannheim, 68167 Mannheim, Germany.
Carsten
C
Sticht
Center for Clinical Research, Medical Faculty Mannheim, 68167 Mannheim, Germany.
Norbert
N
Gretz
Department of Medicine I and Clinical Chemistry, Heidelberg University, 69120 Heidelberg, Germany.
Thomas
T
Fleming
Department of Medicine I and Clinical Chemistry, Heidelberg University, 69120 Heidelberg, Germany.
Peter P
PP
Nawroth
Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Wolfgang
W
Stremmel
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Adam J
AJ
Rose
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Mauricio
M
Berriel-Diaz
Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.
Matthias
M
Blüher
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, and Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, 85764 Neuherberg, Germany.
Stephan
S
Herzig
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; D054834:Lipocalins; C582288:TSC22D4 protein, human; D014157:Transcription Factors