Orphaned No More? Glucose-Sensing Hypothalamic Neurons Control Insulin Secretion.

Well before Dr. Minkowski discovered the role of the pancreas in regulating blood glucose (1889), Dr. Bernard had discovered the role of the brain (specifically the base of the fourth ventricle) in regulating blood glucose (1849). Bernard’s basic observation has been replicated by many interventions involving pharmacological manipulations directed toward the brain stem (1). Nevertheless, the overt production of diabetes by the removal of the pancreas and the eventual discovery of the determinative role of insulin secreted by pancreatic islets in regulating blood glucose by Drs. Banting and Best (1922) led to an overwhelming emphasis in studying islet function (and later insulin sensitivity) in the study of blood glucose regulation. At about the same time, the function of the hypothalamus began to be studied extensively because of early evidence that damage to the hypothalamus in humans produced a variety of neuroendocrine disturbances, including obesity (Erdheim 1904). However the relative importance of the hypothalamus versus the pituitary in these systemic pathologies continued to be controversial until the classic study by Hetherington and Ransom (2) reported that specific lesions in the ventromedial nucleus (VMN) cause robust obesity in rats, an extremely robust effect replicated in many species, including humans. Subsequent extensions of these studies demonstrated that lesions of an area slightly lateral to the VMN (lateral hypothalamic area [LHA]) produced the opposite effect: starvation. Furthermore, lesions in the paraventricular nucleus (PVN) also produce obesity, although they do not prevent feeding induced by hypoglycemia or 2-deoxy-D-glucose (2-DG) (3). As early as 1916, Carlson proposed that glucose controlled satiety, but his proposed mechanisms involving stomach contractions as hunger signals were eventually largely discarded. However, in 1953 Mayer (4) revised the so-called glucostat hypothesis, which stated that blood glucose was a key satiety signal that acted on hypothalamic glucose-sensing neurons and it was damage to these neurons that mediated obesity after VMN lesions. A major rationale for this hypothesis was that peripheral injections of gold thioglucose produced obesity and lesions apparently specific to the VMN and, interestingly, to the nucleus tractus solitarius (NTS) of the brain stem, lesions completely dependent on the glucose moiety. Motivated in part by these studies, in 1969 Oomura et al. (5) reported that activity of different neurons in the VMN and LHA could be either excited or inhibited by glucose. Nevertheless, the glucostat hypothesis was gradually marginalized, especially after the Freidman laboratory discovered leptin and that the signaling form of the leptin receptor is largely confined to hypothalamic areas that regulate energy balance (6,7). However this marginalization left glucose-sensing neurons orphaned, in search of function(s). Addressing this issue, in 1981 Ritter et al. (8) reported that infusion of the glucose metabolism inhibitor 5-thioglucose, apparently confined to the caudal brain stem, produced hyperglycemia as well as feeding. Furthermore, the Sherwin laboratory reported that the glucose metabolism inhibitor 2-deoxyglucose, confined to the VMN, also produced hyperglycemia and associated counterregulatory responses (9), whereas infusion of glucose into the VMN prevented counterregulatory responses (10). These studies have been extensively corroborated, leading to a broad consensus that glucose-sensing neurons in the VMN and brain stem (almost certainly including the NTS) play a key role in glucose regulation. Subsequent studies supported that in at least some neurons glucose either excites (11) or inhibits (12) glucose-sensing neurons via the putative glucosesensing enzyme, the pancreatic form of glucokinase (pGK).