Insulin normally suppresses hepatic (liver) glucose production (HGP) among healthy individuals so that they do not experience hyperglycemia (high blood sugar) throughout the day. This function is inhibited among type 2 diabetics, but the specific molecular mechanism behind the issue has remained elusive within the research community. However, a new study led by researchers from Yale University, and published in the journal Cell, may have uncovered the reason why this dysfunctional process begins. "In the study, we set out to examine how insulin normally works to turn off production of glucose by the liver, and why this process goes awry in patients with type 2 diabetes," said Gerald I. Shulman, the George R. Cowgill professor of physiological chemistry, professor of medicine and cellular & molecular physiology at Yale School of Medicine, and an investigator with the Howard Hughes Medical Institute.
Experts have long debated how insulin suppresses HGP to limit abnormal fluxes in blood sugar. Many scientists have claimed that insulin has a direct effect on the liver, but the current study uncovered a different physiological pathway that may challenge present theories and treatment methods. The Yale researchers theorized that insulin suppresses HGP by inhibiting the breakdown of body fat, which results in a reduction in hepatic acetyl CoA. Acetyl-CoA and related coenzymes are essential to balancing carbohydrate and fat metabolism in the body. In the liver specifically, it is critical to regulating the conversion of amino acids and lactate into glucose as needed. When insulin is not properly inhibiting the breakdown of body fat due to systemic inflammation caused by relative obesity, hepatic acetyl CoA concentrations rise; HGP and blood sugar will then follow suit.
"These studies identify hepatic acetyl CoA as a key mediator of insulin action on the liver and link it to inflammation-induced hepatic insulin resistance and type 2 diabetes," Shulman explained. This new insight into insulin resistance paves the way for exploring new treatments. "None of the drugs we currently use to treat type 2 diabetes target the root cause," said Shulman. "By understanding the molecular basis for hepatic insulin resistance we now can design better and more effective drugs for its treatment."