Is Insulin Action in the Brain Clinically Relevant?

Last year marked the ninetieth anniversary of the discovery of insulin by Nobel Laureates Frederick Banting and John Macleod, as well as Charles Best and James Bertram Collip. The initial success of insulin’s ability to lower glucose levels in type 1 diabetes is now shadowed by the urgent need to characterize insulin resistance and secretion defects in type 2 diabetes and obesity. Insulin triggers signaling pathways in liver, muscle, and fat that inhibit glucose production and increase glucose uptake (1). However, it has only been in recent years that the brain has received attention for being an insulin-sensitive organ that regulates food intake (2) and glucose (3) and lipid (4) homeostasis in animals (Fig. 1). Circulating insulin crosses the blood-brain barrier and acts on its receptor in the hypothalamus to lower food intake and body weight (2). Infusion of insulin into the central nervous system (CNS) lowers food intake in rats (5), mice (6), and baboons (7), whereas hyperphagia is detected in neuronal insulin receptor knockout mice (8). Further, high-fat feeding induces hypothalamic insulin resistance in rodents (9). Although these animal studies expand the role of insulin to regulate appetite and suggest that characterizing insulin signaling pathways may reveal novel targets that reverse brain insulin resistance in obesity, a central question remains, Is insulin action in the brain clinically relevant? To address this question, an intranasal peptide delivery method was developed in humans (10). This method enables selective elevation of peptide levels in the cerebrospinal fluid without altering plasma peptide levels (10). Using this method, intranasal injection of insulin was found to inhibit food intake in normal fasting men but not women (11). This is consistent with the fact that central insulin lowers food intake in male but not female rats (5); however, hyperphagia is detected in neuronal insulin receptor knockout female but not male mice (8). While CNS insulin does not appear to affect appetite in women, intranasal insulin alters their brain activity under food-stimulated conditions (12). Furthermore, CNS insulin action regulates food reward circuitry in rodents (13). Together, these studies underscore the possibility that the anorectic effect of insulin may be amplified in postprandial conditions in women. In the current issue of Diabetes, Hallschmid et al. (14) carried out well-controlled and designed studies in women to test this hypothesis. Two sets of experiments permit distinguishing the effects of intranasal insulin administration in postprandial versus fasting conditions. In the first set, the postprandial effects of insulin were assessed in young, lean, healthy women who were given lunch (1230–1245 h) followed by intranasal insulin versus placebo delivery at 1300 h. Appetite rating and blood samples were then collected, and a snack intake test was assessed at 1505 h. In the second set of experiments, women who fasted overnight were given intranasal insulin versus placebo at 1000 h, followed by the same sampling and snack testing protocol. Of note, snack testing involved giving the blinded subjects three types of cookies: butter, coconut, and chocolate chip. The authors show that intranasal insulin delivery reduced appetite in the postprandial but not the fasted women. In addition, intranasal insulin selectively reduced the intake and the palatability of chocolate cookies among the postprandial women, but failed to alter intake or palatability of other cookies or total calories associated with cookie intake. These interesting findings illustrate the potential clinical relevance in and support the working hypothesis put forward by studies in rodents that CNS insulin action inhibits the hedonic food reward system via dopamine neurons in the ventral tegmental area (13,15). Unfortunately, the current study did not offer mechanistic insights responsible for the differential anorectic responses induced by CNS insulin in women and men (11), as well as in fasting and postprandial conditions. Nonetheless, the data in this report, together with previous literature, highlight a potential role of insulin action in the brain that serves as a physiological satiety factor inhibiting palatable food in postprandial humans. The working hypothesis, of course, remains to be tested. Another important finding made by the authors was that within ;30–40 min of intranasal insulin injection (i.e., time 1345 h), while appetite was yet to be affected, plasma glucose level was lowered by ;1 mmol/L in the postprandial women. Importantly, this significant reduction in plasma glucose occurred independently of changes in circulating plasma insulin, C-peptide, leptin, and ghrelin levels at this time point. It is not known whether a change in plasma glucagon level was detected. Nonetheless, given that intranasal insulin delivery in 30 min is sufficient to elevate insulin levels in cerebrospinal fluid (10), these findings are in line with previous reports in rats (3) and dogs (16,17), suggesting that direct brain insulin infusion lowers plasma glucose levels independently of changes in food intake. Only when the liver is removed does central insulin fail to lower glucose levels in dogs (17), suggesting that brain insulin action lowers glucose levels through a modulation of hepatic glucose metabolism. In fact, insulin triggers signaling cascades and activates ATP-sensitive potassium (KATP) channels in the hypothalamus to inhibit glucose production in rodents (3), while activation of hypothalamic From the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; the Department of Medicine, University of Toronto, Toronto, Ontario, Canada; the Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and the Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada. Corresponding author: Tony K.T. Lam, [email protected]. DOI: 10.2337/db12-0048 B.M.F. and P.I.M. contributed equally to this work. 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 782.