New research is shedding light on the ways metabolism in the liver is affected by obesity and by two of the most widely prescribed medications for people with diabetes. Insulin, produced naturally by the body in response to elevated sugar in the blood, is prescribed to all patients with type 1 diabetes because they cannot make the vital hormone themselves. It is also prescribed to many people with type 2 diabetes in cases where other medications cannot make up for lost insulin production capacity and their bodies’ increased needs for the hormone. The most widely prescribed medication for type 2 diabetes, however, is metformin, which works by reducing the amount of glucose fed into the bloodstream by the liver. A hormone called glucagon triggers the liver to release glucose during periods of fasting. For reasons that have not been fully understood, liver glucose production occurs even in the absence of fasting in people with diabetes, contributing to elevated blood glucose. One of insulin’s key effects is to blunt the impact of glucagon, stopping its release of liver glucose, and accounting for one of its most serious side effects. Overly high doses of insulin not only send glucose levels too low, they also limit the ability of glucagon to bring glucose back up again. The result is hypoglycemia, dangerously low blood glucose. Metformin also counteracts glucagon, but rarely causes hypoglycemia by itself, because it does not directly lower blood glucose by signaling cells to take up sugar as insulin does.
New research in obese mice fed a high fat diet clarifies the pathway that leads to excessive production of glucose from the liver in type 2 diabetes, and pinpoints the ways in which metformin and insulin interrupt the process. One group of researchers found that a complex of proteins acts to boost glucose output and is triggered both by fasting signals (glucagon) and by a cellular condition that can result from obesity, called the “ER (endoplasmic reticulum) stress response.” Another group of researchers found that both insulin and metformin lead to a modification of one of the proteins in this complex—a protein called CBP. The modification of CBP causes the complex to fall apart so that it no longer supports glucose production. Although the impact on CBP and glucose production is the same, metformin and insulin work through different pathways to modify CBP, which helps explain why metformin is effective even in patients who are resistant to insulin’s effects. Understanding the molecular pathways by which the healthy liver promotes glucose control, as well as how insulin and metformin work in disease, has the potential to help improve glucose control in diabetes patients, preventing both hypoglycemia, and the long-term complications of hyperglycemia (high blood sugar). Because metformin is currently the only approved drug in its class, this research may also help to identify new and better therapeutic strategies to help people with diabetes control their blood glucose.
Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S, Wondisford FE. Cell. 2009 May 15; 137(4):635-46.
The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Wang Y, Vera L, Fischer WH, Montminy M. Nature. 2009 Jul 23; 460(7254):534-7.