Recent studies highlighted the significance of chronic inflammation, which is mediated in part by toll-like receptors 4 (TLR4), in islet beta cell dysfunction by high-glucose exposure. However, about it is unclear whether islet beta cell dysfunction in response to high glucose is associated with TLR4. This investigation was designed to address the effect of TLR4 deficiency on insulin secretion in mice in response to acute intravenous glucose load. Hyperglycemic clamp was used to impair insulin secretion, and intraperitoneal glucose tolerance test was carried out to analyze insulin secretion function of islet beta cells. Our results showed that TLR4 deficiency repressed insulin secretion impairment in response to acute intravenous glucose load. Compared to wild-type mice, TLR4(-/-) mice did not exhibit increase of IL-1 beta and TNF-alpha level in plasma and pancreatic tissue in response to acute intravenous load of high glucose. However, recombinant IL-1 beta or TNF-alpha administration restored insulin secretion impairment induced by high glucose in TLR4(-/-) mice. Taken together, our results demonstrated that TLR4 activation and subsequent IL-1 beta and TNF-alpha production contribute to islet beta cell dysfunction in mice in response to acute intravenous load of high glucose, which may provide a theoretical basis for diabetes complication improvement by physical exercise. (C) 2020 Elsevier Inc. All rights reserved.