Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion.
Toll-like receptors (TLRs) have been implicated in the pathogenesis of type 2 diabetes. We examined the function of TLR3 in glucose metabolism and type 2 diabetes-related phenotypes in animals and humans. TLR3 is highly expressed in the pancreas, suggesting that it can influence metabolism. Using a diet-induced obesity model, we show that TLR3-deficient mice had enhanced glycemic control, facilitated by elevated insulin secretion. Despite having high insulin levels, Tlr3(-/-) mice did not experience disturbances in whole-body insulin sensitivity, suggesting that they have a robust metabolic system that manages increased insulin secretion. Increase in insulin secretion was associated with upregulation of islet glucose phosphorylation as well as exocytotic protein VAMP-2 in Tlr3(-/-) islets. TLR3 deficiency also modified the plasma lipid profile, decreasing VLDL levels due to decreased triglyceride biosynthesis. Moreover, a meta-analysis of two healthy human populations showed that a missense single nucleotide polymorphism in TLR3 (encoding L412F) was linked to elevated insulin levels, consistent with our experimental findings. In conclusion, our results increase the understanding of the function of innate receptors in metabolic disorders and implicate TLR3 as a key control system in metabolic regulation.
Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Metabolism Unit, Department of Medicine, and Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet at Karolinska University Hospital Huddinge, Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Center and Center for Innovative Medicine, NOVUM, Stockholm, Sweden daniela.strodthoff@ki.se.
Daniela
D
Strodthoff
Endocrinology and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Zuheng
Z
Ma
Endocrinology and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Tina
T
Wirström
Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Rona J
RJ
Strawbridge
Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Daniel F J
DF
Ketelhuth
Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
David
D
Engel
Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, U.K.
Robert
R
Clarke
Laboratory of Pathology and Clinical Cytology, Ryhov Hospital, Jönköping, Sweden.
Sture
S
Falkmer
Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Anders
A
Hamsten
Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Göran K
GK
Hansson
Endocrinology and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Anneli
A
Björklund
Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Anna M
AM
Lundberg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D007328:Insulin; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D005947:Glucose