Exp Clin Endocrinol Diabetes 2013; 121 - P51
DOI: 10.1055/s-0033-1336724

Animal model of type 1 diabetes: Control of energy homeostasis and insulin sensitivity by Toll-like receptor 4, a modulator of innate immunity

AL Reinbeck 1, G Séquaris 1, HJ Partke 1, P Nowotny 1, J Kotzka 2, B Knebel 2, V Burkart 1, M Roden 1, 3
  • 1German Diabetes Center (DDZ), Leibniz Center for Diabetes Research, Heinrich-Heine University, Institute for Clinical Diabetology, Düsseldorf, Germany
  • 2German Diabetes Center (DDZ), Leibniz Center for Diabetes Research, Heinrich-Heine University, Institute for Clinical Biochemistry and Pathobiochemistry, Düsseldorf, Germany
  • 3University Clinics Düsseldorf, Department of Metabolic Diseases, Düsseldorf, Germany

Aims: Studies on the pathogenesis of type 1 diabetes implicate that mechanisms controlling energy metabolism are involved in disease development. As certain aspects of carbohydrate and lipid metabolism are under control of the toll-like receptor 4 (TLR4), we hypothesized that this receptor determines a diabetes-modulating metabolic phenotype in non-obese diabetic (NOD) mice.

Methods: Diabetes development and whole-body metabolism including indirect calorimetry were monitored in female TLR4-expressing (TLR4+/+) and TLR4-deficient (TLR4-/-) NOD mice. Glucose- and insulin-tolerance were determined in fasted mice and mitochondrial function was determined by high-resolution respirometry.

Results: When compared to TLR4+/+ mice, TLR4-/- animals developed diabetes earlier in life (TLR4+/+: 208 ± 40 days; TLR4-/-: 152 ± 25 days, p < 0.001), had a lower respiratory quotient (TLR4+/+ 0.98 ± 0.05; TLR4-/- 0.89 ± 0.3, p < 0.001) and lower glucose tolerance (area under the glucose curve: TLR4+/+ 233 ± 102 mmol/L; TLR4-/- 587 ± 152 mmol/L x h-1, x h-1, p < 0.001), but two-fold higher insulin concentrations upon ipGTT. Fasting serum free fatty acid levels were 40% higher in TLR4-/- than in TLR4+/+ mice. In TLR4-/- NOD mice, hepatic but not myocellular mitochondria showed increased O2 flux through complex I and II (TLR4-/- 54.6 ± 14.8, TLR4+/+ 29.6 ± 7.4 (pmol x mg-1 x s-1)/mtDNA copy number, p < 0.05) and higher maximal respiratory capacity (TLR4-/- 87.8 ± 18.6, TLR4+/+ 55.5 ± 22.7 (pmol x mg-1 x s-1)/mtDNA copy number, p < 0.01) when compared to TLR4+/+ NOD mice.

Conclusion: Taken together, TLR4 deficiency decreases insulin sensitivity resulting in increased substrate availability and subsequently enhanced O2-flux in liver mitochondria. This indicates that TLR4 controls the progression of immune-mediated diabetes in NOD mice by regulating insulin sensitivity.