Congratulations to Nicolas Musi, MD on his publication in JCI!
Dr. Nicolas Musi is a Professor in the Division of Diabetes, Department of Medicine, Long School of Medicine and the Director of the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Effect of acute TLR4 inhibition on insulin resistance in human subjects
Hanyu Liang, Nattapol Sathavarodom, Claudia Colmenares, Jonathan Gelfond, Sara E Espinoza, Vinutha Ganapathy, Nicolas Musi.
J Clin Invest. 2022 Sep 6;e162291. doi: 10.1172/JCI162291. Online ahead of print.
Background: Studies in cell cultures and rodents suggest that toll-like receptor (TLR)4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.
Methods: In Protocol I, 10 lean, healthy subjects received the following 72-h intravenous (I.V.) infusions in a randomized crossover design: saline (30 ml/h)+vehicle; Intralipid® (30 ml/h)+vehicle; or Intralipid® (30 ml/h)+eritoran (12 mg I.V. every 12 h). In Protocol II, 9 obese, non-diabetic subjects received eritoran (12 mg I.V. every 12 h) or vehicle for 72 h, also in a randomized crossover design. The effects of eritoran were assessed with a euglycemic, hyperinsulinemic clamp.
Results: In Protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG), fasting plasma insulin (FPI) and HOMA insulin resistance index (HOMA-IR) by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations in these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in obese, insulin-resistant subjects (Protocol II).
Conclusions: Acute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 on metabolic dysfunction in humans.
Clinicaltrials: gov NCT02321111, NCT02267317FUNDING. NIH grants R01DK080157, P30AG044271, P30AG013319 and UL1TR002645.
Keywords: Diabetes; Endocrinology; Metabolism; Obesity.