Do free fatty acids induce insulin resistance in alpha cells?

Thirty years ago, Unger and Orci proposed the bihormonal-abnormality hypothesis, which highlighted that both deficient insulin secretion and excessive glucagon levels contributed to the hyperglycemic state in type 2 diabetes. The plasma free fatty acid (FFAs) concentrations are higher in patients with diabetes and prediabetes, suggesting that FFAs may be involved in the pathophysiology of diabetes. In type 2 diabetes, at least in the obese form, insulin does not seem to correct the exaggerated alpha cell responses. This phenomenon suggests that the inability of insulin to suppress the glucagon level could be caused by alpha cell insulin resistance. However, it has remained unclear whether alpha cell insulin resistance is caused by FFAs. Recent studies have demonstrated that long-term exposure to elevated FFA levels leads to hypersecretion of glucagon and accumulation of triglycerides (TG) in clonal alpha-TC1-6 cells, but the mechanism of FFA-induced alpha cell insulin resistance is unclear. We hypothesize that long-term exposure to FFAs reduces AMP-activated protein kinase (AMPK) activity and increases TG accumulation in alpha cells, leading to impaired insulin signaling of alpha cells and hypersecretion of glucagon. This hypothesis provides the first detailed examination of the effects of FFAs on alpha cells with glucagon hypersecretion. It potentially suggests that improving alpha cell insulin resistance as well as reversing lipotoxicity will normalize alpha cell function and may benefit glucose control. Consequently, AMPK and insulin-related pathways in alpha cells could be potential targets for controlling glucagon secretion and glucose counter-regulation.