In type 1 and type 2 diabetes (T1/T2DM), beta cell destruction by apoptosis results in decreased beta cell mass and progression of the disease. In this study, we found that the interferon gamma-inducible protein 10 plays an important role in triggering beta cell destruction. Islets isolated from patients with T2DM secreted CXCL10 and contained 33.5-fold more CXCL10 mRNA than islets from control patients. Pancreatic sections from obese nondiabetic individuals and patients with T2DM and T1DM expressed CXCL10 in beta cells. Treatment of human islets with CXCL10 decreased beta cell viability, impaired insulin secretion, and decreased insulin mRNA. CXCL10 induced sustained activation of Akt, JNK, and cleavage of p21-activated protein kinase 2 (PAK-2), switching Akt signals from proliferation to apoptosis. These effects were not mediated by the commonly known CXCL10 receptor CXCR3 but through TLR4. Our data suggest CXCL10 as a binding partner for TLR4 and as a signal toward beta cell failure in diabetes.