High-dose salsalate improves fasting glucose; holds potential for preventing type 2 diabetes

Targeting inflammation with salicylate therapy to inhibit nuclear factor κB (NF- κB) activity may represent a novel strategy to prevent diabetes, said Peter Reaven, MD.
     In humans, activation of the NF-κB pathway can promote inflammation and induce insulin resistance in adipose and other key tissues that control glucose metabolism and abnormalities such as dyslipidemia and vascular disease. Therefore, chronic inflammation mediated by NF- κB may contribute to the pathogenesis of type 2 diabetes and associated metabolic abnormalities. In previous studies, high-dose salicylates have been shown to effectively inhibit the NF- κB pathway, said Reaven, Director of the Diabetes Program, and Professor of Medicine at the University of Arizona, Tucson.        
     His group assessed whether high-dose salsalate therapy could treat metabolic/vascular abnormalities and prevent the development of type 2 diabetes in 70 veterans (67 men; mean body mass index 32 kg/m²) with impaired fasting glucose/impaired glucose tolerance. They were randomized to 12 weeks of salsalate, 3 to 4 g/day, or placebo to examine effects on glucose metabolism.
     In the group assigned to salsalate, triglyceride levels declined from baseline by 55 mg/dL at 8 weeks and by 35 mg/dL at 12 weeks; there was no effect of placebo on triglyceride levels. Although there was a slight increase in low-density lipoprotein cholesterol in the salsalate-treated patients, the ratio of total cholesterol to high-density lipoprotein cholesterol decreased.
     Salsalate significantly lowered fasting plasma glucose level by 8%, which was accompanied by a decrease in fasting C-peptide level, “perhaps consistent with decreased beta cell burden,” said Reaven. It had no effect on glucose excursion (as measured by oral glucose tolerance test) or whole-body insulin.
     “Insulin levels were preserved despite a decline in insulin secretion as estimated by C-peptide,” he said. Glucose utilization and insulin levels during euglycemic-hyperinsulinemic clamps were similar in the salsalate and placebo groups at baseline and did not change with therapy in either group.
     There were no changes in markers of inflammation (C-reactive protein, interleukin-6, vascular cell adhesion molecule [VCAM], and soluble VCAM), and there was an increase in adiponectin in the salsalate-treated group.
     Higher salicylate concentrations were associated with greater declines in fasting glucose and may modestly enhance glucose utilization. The modest effects on glucose utilization suggest that improvement in fasting glucose with high-dose salsalate may be due to reduced endogenous glucose production, he concluded.