The Acute Effects of Low-Dose TNF-α on Glucose Metabolism and β-Cell Function in Humans

Type 2 diabetes is characterized by increased insulin resistance and impaired insulin secretion. Type 2 diabetes is also associated with low-grade inflammation and increased levels of proinflammatory cytokines such as TNF-α. TNF-α has been shown to impair peripheral insulin signaling in vitro and in vivo. However, it is unclear whether TNF-α may also affect endogenous glucose production (EGP) during fasting and glucose-stimulated insulin secretion (GSIS) in vivo. We hypothesized that low-dose TNF-α would increase EGP and attenuate GSIS. Recombinant human TNF-α or placebo was infused in healthy, nondiabetic young men (n = 10) during a 4-hour basal period followed by an intravenous glucose tolerance test (IVGTT). TNF-α lowered insulin levels by 12% during the basal period (P < 0.05). In response to the IVGTT, insulin levels increased markedly in both trials, but there was no difference between trials. Compared to placebo, TNF-α did not affect EGP during the basal period. Our results indicate that TNF-α acutely lowers basal plasma insulin levels but does not impair GSIS. The mechanisms behind this are unknown but we suggest that it may be due to TNF-α increasing clearance of insulin from plasma without impairing beta-cell function or hepatic insulin sensitivity.