Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.

The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis. Pgc1alpha is unable to induce gluconeogenesis in Foxo1-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin.