Effects of elevated fatty acid and glucose concentrations on pancreatic islet function in vitro

The aims of this study were to elucidate long-term effects of increased fatty acids and glucose concentrations on islet hormone secretion, triglyceride (TG) accumulation and fuel metabolism, and to determine the role of insulin on glucagon secretion.

Isolated normal mouse islets were exposed to palmitate (0.6 mM) in the presence of high glucose (16.7 mM). After 48 h culture, glucagon secretion and content, insulin secretion and content, TG content and glucose oxidation were measured. The impact of etomoxir, an inhibitor of carnitine palmitoyl transferase-1, as well as of insulin, and alterations in gene expression were also investigated.

In the presence of palmitate, (i) high glucose caused no statistically significant suppression of glucagon while this was seen in the absence of palmitate; (ii) the insulin response to high glucose was impaired and (iii) an accumulation of TG and a decline in glucose oxidation were detected, whereas the glucagon content remained unchanged. However, etomoxir was capable of reducing glucagon secretion. Addition of exogenous insulin (10(-10)-10(-6) M) failed to restore alpha cell response to normal. Furthermore, 0.6 mM palmitate reduced the mRNA levels of acetyl-CoA carboxylase-1 and sterol regulatory element-binding protein-1c.

In summary, high concentrations of palmitate and glucose cause a relative increase in glucagon secretion, a decline in insulin secretion, a loss of alpha cell sensitivity to glucose and an accumulation of TG. The inability of insulin to suppress glucagon may be because of insulin resistance of alpha cells.