Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Abstract

Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

Expression of the diabetes‐associated gene TCF7L2 in adult mouse brain

“…However, it is expressed at moderate levels in hypothalamic nuclei such as the dorsomedial hypothalamus (DMH) and lateral hypothalamic area (LHA), which are known to be important for energy homeostasis, and which are also targets of ARC and VMH projections. Interestingly, TCF7L2 is also moderately expressed in the basal forebrain, a region that has long been the focus of sleep research, but which recently has also been shown to be responsive to hypoglycemia (Cai et al, 2001; Tkacs et al, 2007). …”

Prevention of severe menorrhagia in oncology patients with treatment‐induced thrombocytopenia by luteinizing hormone‐releasing hormone agonist and depo‐medroxyprogesterone acetate

“…However, it is expressed at moderate levels in hypothalamic nuclei such as the dorsomedial hypothalamus (DMH) and lateral hypothalamic area (LHA), which are known to be important for energy homeostasis, and which are also targets of ARC and VMH projections. Interestingly, TCF7L2 is also moderately expressed in the basal forebrain, a region that has long been the focus of sleep research, but which recently has also been shown to be responsive to hypoglycemia (Cai et al,2001; Tkacs et al,2007).…”

Neural pathways that control the glucose counterregulatory response

“…Studies using neurotropic viruses have shown that in the perifornical hypothalamus only orexin- and MCH-containing neurons project to adrenal sympathetic premotor neurons in the RVLM (Kerman et al, 2007 ). In addition, insulin-induced hypoglycemia or neuroglucoprivation induces Fos expression in orexin neurons of the PeH suggesting a possible role in glucose sensing (Moriguchi et al, 1999 ; Briski and Sylvester, 2001 ; Cai et al, 2001 ; Paranjape et al, 2006 ; Tkacs et al, 2007 ). On the other hand, an in vitro study has shown that GI orexin neurons respond in an identical fashion to both glucose and 2DG through a K + channel-mediated mechanism.…”