Ingestive Classics
Mayer and the Glucostatic Hypothesis

MAYER, J. Glucostatic mechanism of regulation of food intake.
New England Journal of Medicine 249 : 13-16, 1953.

Comments by Barry Levin (November 1, 2013)

It was as if he had stepped into a time machine. In the quest to identify mechanisms by which the brain monitors peripheral energy stores as a means of regulating food intake, Jean Mayer made several incredibly prescient predictions, now known collectively as the “glucostatic hypothesis”. As he put it in this first of our “Ingestive Classics” [1], “…hunger would be integrated among the mechanisms through which the central nervous system ensures its homeostasis”. Since the brain is almost totally dependent upon glucose as an energy source [2], glucose was the obvious candidate as a signal for regulating this homeostasis.  Together with his often forgotten collaboration with Ted VanItallie [1, 3] , and informed by the recently discovered effects of ventromedial hypothalamic (VMH) [4] and lateral hypothalamic lesions [5] on feeding, Mayer postulated that “…the passage of potassium ions into the (hypothalamic*) glucoreceptor cells along with the glucose phosphate (requiring hexokinase*) represents the point at which effective glucose level is translated into an electrical or neural mechanism”… as a means of regulating food intake [1]. It was not until i16 years later that Oomura and colleagues actually identified such hypothalamic glucosensing neurons [6], another 17 years before they demonstrated that a K+ channel was involved in their function [7], and a further 4 years until Ashford and colleagues identifed the ATP-sensitive K+ (KATP) channel [8] as an important contributor to neuronal glucosensing.

As reviewed in this Ingestive Classic [1], Mayer and colleagues used differences in arterio-venous (actually between oxygenated capillary blood obtained by finger stick and antecubital vein) glucose levels, (“Δ-glucose”) as a surrogate for glucose utilization. They showed that, in most cases, Δ-glucose varied as an inverse function of self-reported hunger in humans; the greater the Δ-glucose, the less the reported hunger (Figure 1). Importantly, Mayer did not equate changes in blood glucose levels per se with changes in feeding or states of hunger. That hypothesis was later championed by Louis-Sylvestre and Le Magnen [9] but refuted by Mayer himself [1] and others [10, 11] . Rather, it was increased glucose utilization (Δ-glucose) that appeared to correlate best with decreased hunger reporting. 

Mayer’s glucostatic hypothesis and its corollaries engendered over a half century of intense research. How did they hold up? First, it is clear from a number of studies that both systemic [12] and focal, bilateral VMH glucoprivation [11] can evoke robust hunger and eating in animals and humans. But the real questions are: 1) do changes in blood glucose availability or utilization within the physiological range affect activity in hypothalamic glucosensing neurons and, 2) does such altered glucose utilization and activity in VMH glucosensing neurons act to regulate normal eating? My personal answer is “somewhat” to the first and “no” to the second question. First, glucosensing neurons clearly do respond to small incremental changes in brain glucose [13] which vary from 15-25% of blood levels [11]. But this is not an index of glucose utilization, as envisioned by Mayer, because neuronal glucose utilization is almost completely insulin-independent, unlike peripheral utilization, which is largely mediated by insulin. Further, in virtually all neurons, ATP production from glucose is highly buffered by the high capacity and high affinity for glucose uptake by Glut3 and for glucose phosphorylation by hexokinase I and varies as a function of neuronal activity but not of glucose availability, per se [14, 15] . However, in the small subpopulation of specialized glucosensing neurons scattered throughout the brain, the majority do alter their activity in response to small incremental changes in ambient glucose by utilizing the low affinity but very low abundance hexokinase, glucokinase [14]. Because of its extremely low abundance and the overwhelming production of intracellular ATP via hexokinase I, it is likely that glucokinase-mediated production of ATP occurs in a microenvironment close to membrane-bound KATP channels, where it can alter the local ATP/ADP ratio and channel activity [14]. Thus, focal subcellular, rather than total neuronal glucose utilization is likely to be the critical regulator of neuronal glucosensing. This would be in keeping with Mayer’s original ideas [1]. However, while increasing and decreasing VMH glucokinase activity have major impacts on rats’ ability to mount a counterregulatory response to hypoglycemia [16], they have no significant effects on normal diurnal feeding or longer term intake and body weight regulation [11]. On the other hand, stepped reductions in plasma glucose levels in humans increase hunger [17] and rapid lowering in rodents produces feeding [11], but in humans this occurred only at levels at which there were significant impairments of cognition and arousal. Thus, my modification of Mayer’s glucostatic hypothesis is that neuronal glucose utilization probably does play a role in the regulation of food intake, but only when brain glucose levels are pathologically low.
* My insertions

1.      Mayer, J., Glucostatic mechanism of regulation of food intake. N.Engl.J.Med., 1953. 249: p. 13-16.
2.      Sokoloff, L., et al., The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J.Neurochem, 1977. 23: p. 897-916.
3.      Mayer, J., M.W. Bates, and T.B. VanItallie, Blood sugar and food intake in rats with lesions of the anterior hypothalamus. Metabolism, 1952. 1(4): p. 340-8.
4.      Hetherington, A.W. and S.W. Ranson, Hypothalamic lesions and adiposity in the rat. Anat.Record, 1940. 78: p. 149-172.
5.      Anand, B.K. and J.R. Brobeck, Hypothalamic control of food intake in rats and cats. Yale J.Biol.Med., 1951. 24: p. 123-146.
6.      Oomura, Y., et al., Glucose and osmosensitive neurons of the rat hypothalamus. Nature, 1969. 222: p. 282-284.
7.      Minami, T., Y. Oomura, and M. Sugimori, Electrophysiological properties and glucose responsiveness of guinea-pig ventromedial hypothalamic neurones in vitro. J.Physiol., 1986. 380: p. 127-143.
8.      Ashford, M.L.J., P.R. Boden, and J.M. Treherne, Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflugers Arch., 1990. 415: p. 479-483.
9.      Louis-Sylvestre, J. and J. Le Magnen, Fall in blood glucose level precedes meal onset in free-feeding rats. Neurosci.Biobehav.Rev., 1980. 4(Suppl 1): p. 13-15.
10.     Scott, W.W., C.C. Scott, and A.B. Luckhardt, Observations on blood sugard level before, during and aftter hunger periods in humans. Am. J. Physiol. , 1938. 123`: p. 243-247.
11.     Dunn-Meynell, A.A., et al., Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. J. Neurosci., 2009. 29(21): p. 7015-7022.
12.     Smith, G.P. and A.N. Epstein, Increased feeding in response to decreased glucose utilization in the rat and monkey. Am.J.Physiol., 1969. 217(4): p. 1083-1087.
13.     Kang, L. and B.E. Levin, A single bout of hypoglycemia selectively decreases the sensitivity of glucose-excited arcuate nucleus neurons to low glucose. Diabetes, 2006. 55(Suppl 1): p. A16.
14.     Levin, B.E., et al., Role of neuronal glucosensing in the regulation of energy homeostasis. Diabetes, 2006. 55 Suppl 2: p. S122-S130.
15.     Ainscow, E.K., et al., Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K(+) channels. J Physiol, 2002. 544(Pt 2): p. 429-45.
16.     Levin, B.E., et al., Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia. Diabetes, 2008. 57(5): p. 1371-9.
17.     Mitrakou, A., et al., Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am.J.Physiol., 1991. 260(1:Pt 1): p. E67-E74.