Glucose output from the liver is tightly regulated by insulin. But insulin holds sway over more than the liver — an unappreciated circuit in glucose control involves the opening of ion channels in the brain.
Developed countries are currently witnessing a surge in the incidence of adult-onset (type 2) diabetes, driven by soaring levels of obesity. Insulin, the hormone that normally coordinates the disposal of glucose after a meal, becomes less effective in obesity, resulting in the high blood-glucose concentration that is the hallmark of diabetes. Insulin is known to target the liver directly, but Pocai et al.1 (page 1026 of this issue) identify an additional pathway by which the hormone, acting on the brain, sends messages via the nervous system to exert a higher level of control on glucose output from the liver.
The liver has a central role in glucose homeostasis because it extracts glucose from the bloodstream in times of plenty, and synthesizes glucose in times of need. Thus, it buffers the body from extremes in glucose concentration — the relative excess after meals, and the relative shortage between meals, particularly overnight and during periods of fasting. The liver recognizes these different energy states through changes in the blood insulin concentration; insulin binds to its receptor in the liver and directly inhibits glucose production. But this well-established pathway is far from the whole story.
In recent years, the idea that glucose metabolism throughout the body is coordinated by the brain has gained growing support2. It is increasingly evident, for example, that the liver receives control signals from the hypothalamus, an area of the brain known to detect and integrate metabolic signals. Now, Pocai et al.1 intriguingly show that insulin, in addition to its direct effects on the liver, also acts on specialized ion channels called KATP channels in the hypothalamus to control glucose production (Fig. 1). These channels, which lie in the outer membranes of hypothalamic neurons, were named for their ability to release potassium ions from cells in response to a drop in ATP (a molecule that provides energy for many cellular reactions and which is produced as glucose is metabolized). The authors' results link two findings that had previously been viewed in isolation: that insulin can modulate liver glucose output through an unknown action in the hypothalamus3, and that it opens KATP channels in an unidentified set of neurons in a part of the hypothalamus that monitors blood metabolites and hormones4.
KATP channels are generally known for their ability to convert metabolic signals into changes in electrical activity in excitable cells such as neurons, cardiac muscle cells and some endocrine cells — including the insulin-producing β-cells of the pancreas. The channels close in response to ATP and sulphonylureas (a class of drugs used in the treatment of type 2 diabetes), and are opened by ADP (a metabolic product of ATP) and by certain lipids and insulin. KATP channels regulate both the resting membrane potential and cell excitability. Opening the channels — by, for example, decreasing the relative amount of ATP in response to falling glucose levels — allows potassium ions to leave the cell, resulting in membrane hyperpolarization and reduced membrane excitability, which dampens its electrical activity.
It is known that insulin exploits a KATP-channel-dependent mechanism to electrically silence a subgroup of glucose-responsive neurons in the hypothalamus4. It seems contradictory that insulin, the hormonal indicator of nutrient excess, should have the same effect as glucose deprivation on KATP-channel activity and neuronal excitability. However, Pocai et al.1 show convincingly in rats that opening KATP channels in the hypothalamus by infusing the KATP-channel opener diazoxide causes a neurally mediated reduction in liver glucose production, typical of the response to high rather than low nutrient availability. To substantiate the physiological relevance of this finding, they performed an exhaustive series of experiments on rats and mice. They infused insulin into the cerebral ventricles, hypothalamus or peripheral bloodstream, in the presence or absence of KATP-channel inhibitors in the brain, or in animals lacking subunits of the KATP channel, and arrive at a simple conclusion: a rise in physiological insulin concentrations can switch off liver glucose production by opening hypothalamic KATP channels.
The implications of these findings deserve reflection, although the contribution of this pathway to the control of hepatic glucose output in intact animals, and in humans in particular, remains to be established. There are several inherited insulin-secretion disorders that are caused by altered KATP-channel activity in pancreatic β-cells, and assessment of liver glucose handling in such disorders would be of great interest. The authors raise the possibility that hypothalamic resistance to insulin might contribute to the raised liver glucose output typical of type 2 diabetes, suggesting that agents targeting such resistance (or even targeting hypothalamic KATP channels themselves) might be useful in treating this condition. On a more sobering note, however, KATP-channel inhibitors are used routinely to increase insulin secretion in type 2 diabetes, and it may be that, if these oral hypoglycaemic agents gain access to and inhibit hypothalamic KATP channels, they might adversely affect glucose handling in the liver. There are clearly a number of critical studies needed to address these issues.
Pocai, A. et al. Nature 434, 1026–1031 (2005).
Schwartz, M. W. & Porte, D. Jr Science 307, 375–379 (2005).
Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Nature Med. 8, 1376–1382 (2002).
Spanswick, D., Smith, M. A., Mirshamsi, S., Routh, V. H. & Ashford, M. L. Nature Neurosci. 3, 757–758 (2000).
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