The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: A magnetoencephalographic study

Abstract

Animal studies have shown that the brain is an insulin-responsive organ and that central nervous insulin resistance induces obesity and disturbances in glucose metabolism. In humans, insulin effects in the brain are poorly characterized. We used a magnetoencephalography approach during a two-step hyperinsulinemic euglycemic clamp to (i) assess cerebrocortical insulin effects in humans, (ii) compare these effects between 10 lean and 15 obese subjects, and (iii) test whether the insulin receptor substrate (IRS)-1 Gly972Arg polymorphism in the insulin-signaling cascade modifies these effects. Both spontaneous and stimulated (mismatch negativity) cortical activity were assessed. In lean humans, stimulated cortical activity (P ‫؍‬ 0.046) and the beta and theta band of spontaneous cortical activity (P ‫؍‬ 0.01 and 0.04) increased with insulin infusion relative to saline. In obese humans, these effects were suppressed. Moreover, the insulin effect on spontaneous cortical activity correlated negatively with body mass index and percent body fat (all r < ؊0.4; all P < 0.05) and positively with insulin sensitivity of glucose disposal (theta band, r ‫؍‬ 0.48, P ‫؍‬ 0.017). Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P ‫؍‬ 0.01). We conclude that, in lean humans, insulin modulates cerebrocortical activity, and that these effects are diminished in obese individuals. Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene.glucose metabolism ͉ insulin resistance ͉ magnetoencephalography ͉ mismatch negativity ͉ type 2 diabetes T he human brain has been traditionally regarded as an insulininsensitive organ. However, there is now growing evidence that insulin signaling might be an important modulator of several functions of the brain. The insulin receptor and other components of the insulin-signaling chain, such as the insulin receptor substrate (IRS)-1 are ubiquitously expressed throughout the brain in animals and humans with particularly high concentrations in the hypothalamus, the hippocampus, and the cerebral cortex (1-3). Early work in animals suggested that insulin acts in the CNS and controls food intake and body weight (4). Furthermore, it was clearly shown that insulin crosses the blood-brain barrier (5) and, when given directly to the brain, suppresses food intake (6, 7) and mediates peripheral metabolic effects (8). Most important for the understanding of central nervous insulin function was the observation that brainspecific deletion of the insulin receptor in mice resulted in hyperphagia, obesity, and metabolic insulin resistance (9).In mice, insulin effects have been intensively studied in the hypothalamus. However, it is noteworthy that insulin receptors are also abundant in the cerebral cortex (2). Furthermore, intracerebroventricular insulin administration was associated with imp...

Obese men respond to cognitive but not to catabolic brain insulin signaling

“…Moreover, such effects can develop entirely independently from any acute effects of insulin on the neocortical response to sensory stimuli. 42 Going beyond the examination of acute insulin effects, our data show that long-term enhancement of brain insulin signaling, while affecting cognition and HPA axis activity in obese men in the same manner as in lean men, 9 does not reduce body weight. This pattern strongly supports the notion that primarily, central nervous insulin resistance in obese men focuses on brain structures relevant to the regulation of energy homeostasis.…”

“…42 At first glance, this outcome seems at odds with the fact that after 8 weeks of treatment, our obese subjects displayed preserved susceptibility to insulin's improving effect on delayed word list recall in as much the storage of declarative memory representations involves also neocortical brain areas. 18 However, neither in the present nor in our previous studies did intranasal insulin administration exert any acute effect on memory function in lean men.…”

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

“…Thus, augmented insulin sensitivity can promote insulin's effects in the later postprandial state. Physiologically, this biphasic response is reasonable and we therefore propose that, apart from the many other effects of insulin on the brain [11][12][13]30], the central action of the hormone regulates its own efficiency in peripheral tissues in a time-dependent manner.…”

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

“…Although it is difficult to assess the effects of insulin on the human CNS it has been suggested that insulin acts through the cerebral cortex 49 and studies have demonstrated reduced cerebrocortical response to hyperinsulinaemia in non‐diabetic, obese subjects 49. Interestingly, Tschritter et al.…”