Neural pathways that control the glucose counterregulatory response

Verberne, Anthony J.M.; Sabetghadam, Azadeh; Korim, Willian S.

doi:10.3389/fnins.2014.00038

Cited by 116 publications

(120 citation statements)

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“…the many sites that participate in glucose sensing (5,19,20) and how difficult it is to prevent recovery from hypoglycemia (owing to redundancy inherent in the CRR), it seems improbable that the entire response should hinge on activation of a select population of neurons in a relatively small brain area. To test this hypothesis, we first determined whether optogenetic inactivation of VMN SF1 neurons during insulin-induced hypoglycemia blocks increased glucagon and corticosterone secretion, inhibition of glucoseinduced insulin secretion, and recovery of normal blood glucose levels.…”

Section: Significancementioning

confidence: 99%

Functional identification of a neurocircuit regulating blood glucose

Meek

Nelson

Matsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

153

187

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Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN SF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN SF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN SF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN SF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN SF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN SF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN SF1 →aBNST neurocircuit.glucoregulatory circuit | counter regulation | ventromedial nucleus | bed nucleus of the stria terminalis | hyperglycemia B ecause the brain relies exclusively on glucose as a fuel source, brain function is rapidly compromised when circulating glucose levels drop below the normal range. Consequently, hypoglycemia elicits a robust, integrated, and redundant set of counterregulatory responses (CRRs) that ensure the rapid and efficient recovery of plasma glucose concentrations into the normal range (1). Components of the CRR include increased secretion of the hormones glucagon, epinephrine, and glucocorticoids, inhibition of glucoseinduced insulin secretion, increased sympathetic nervous system (SNS) outflow to the liver, and increased food intake (1-3). Owing to this redundancy, recovery from hypoglycemia is difficult to block in normal humans and animal models, even when adrenal or glucagon responses are prevented. Only when multiple responses are blocked is the ability to recover from hypoglycemia significantly compromised (4). This arrangement is perhaps unsurprising, given the threat to survival posed by hypoglycemia.Although glucose sensing can occur at peripheral (e.g., neurons innervating the hepatic portal vein) as well as central sites (3, 5), the brain is the organ responsible both for transducing this information into effective glucose counterregulation and for terminating this response once euglycemia is restored. Of the many brain areas that have been investigated, the hypothalamic ventromedial nucleus (VMN) has emerged as potentially being both necessary and sufficient to elicit this powerful response. This assertion is based on evidence that, whereas electrical stimulation of the VMN activates the CRR and thereby raises circulating glucose levels (6), glucose infusion directly into the VMN can suppress the CRR during hypoglycemia (7) and thereby impair recovery of normal blood glucose levels (8). Moreover, two recent papers identified a circuit comprise...

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Section: Significancementioning

confidence: 99%

Functional identification of a neurocircuit regulating blood glucose

Meek

Nelson

Matsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

153

187

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“…Such an interaction complements the central scheme presented in the review by Verberne et al (2014). Meanwhile, Browning (2013) presents a perspective article on the role of glucose in modulating gastrointestinal vagal afferent reflex function.…”

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confidence: 74%

“…Diepenbroek et al (2013) present original research indicating that deep brain stimulation of the nucleus accumbens shell in rats alters blood glucose and glucagon, a mechanism that may be mediated via the lateral hypothalamus, a site that receives strong innervation from the nucleus accumbens. Such an interaction complements the central scheme presented in the review by Verberne et al (2014). Meanwhile, Browning (2013) presents a perspective article on the role of glucose in modulating gastrointestinal vagal afferent reflex function.…”

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confidence: 74%

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Central control of autonomic functions in health and disease

2015

Frontiers Research Topics

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There is a lack of knowledge about the neurophysiology of disease states such as obesity and related disorders. Recognizing this, basic scientists are actively investigating and learning more about how the brain controls energy homeostasis from the perspective of autonomic function.The central nervous system controls many fundamental systems including whole body metabolism, body temperature and blood pressure. Autonomic reflexes are mediated by neural pathways in the brainstem and spinal cord and generally regulate organ and system performance very rapidly (ms). Autonomic control is also mediated by specific brain regions, such as the hypothalamus, which is responsible for mid-term (min) and long-term (hours/days) regulation of internal organ systems. Importantly, autonomic reflexes are dynamic, where adaptations can alter rapid homeostatic control over longer time scales. In this respect, an understanding of the basic neurophysiology is required to subsequently discover how these processes contribute to, or are impacted by, disease states -ranging from diabetes mellitus to hypertension.The field of autonomic neuroscience research concentrates on those neural pathways and processes that ultimately modulate parasympathetic and sympathetic output to alter peripheral organ function. In the following eBook, laboratories from across the field have contributed reviews and original research to summarize current views on the role of the brain in tuning peripheral organ performance to regulate body temperature, glucose homeostasis and blood pressure. These mechanisms include experimental approaches ranging from the whole system to synaptic levels.One of the most basic requirements for mammalian life is the maintenance of core body temperature and as such, this factor is tightly regulated. Tupone et al. (2014) review the central nervous system nuclei and circuitry involved in brown adipose tissue thermogenesis, a sympathetically driven mechanism to increase body temperature that has been demonstrated in species from rodents to adult humans. The Morrison laboratory has been consistently at the forefront in unraveling the brain regions involved in this mechanism and in this review, the authors also discuss the potential advantages of activation or inhibition of brown adipose tissue thermogenesis for the treatment of obesity or cardiac ischemia.A second basic requirement for life is energy availability, with glucose as the basic substrate in mammals. Verberne et al. (2014) review the current understanding of the neural pathways that control glucose homeostasis with specific emphasis on the counter-regulatory response to hypoglycemia. This mechanism highlights the coordination between endocrine and neural outflows in regulating the supply of glucose. Diepenbroek et al.(2013) present original research indicating that deep brain stimulation of the nucleus accumbens shell in rats alters blood glucose and glucagon, a mechanism that may be mediated via the lateral hypothalamus, a site that receives strong innervation from the nucl...

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“…The glucoregulatory response to nutritive substances applied in the intestine is prevented by blocking ionotropic glutamate receptors in the NTS Wang et al 2008), suggesting that glutamatergic, vagal afferent activation of NTS neurons is required for this response. Blockade of NMDA receptors in the vagal complex prevents the positive effect of bariatric surgery on systemic blood glucose levels, an effect hypothesized to occur by inhibiting a "gut-brainstem-liver" circuit in the vagal complex (Verberne et al 2014). …”

Section: Effect Of Gck Inhibition On Synaptic Input To Nts Neurons Gmentioning

confidence: 99%

Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes

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Neural pathways that control the glucose counterregulatory response

Cited by 116 publications

References 176 publications

Functional identification of a neurocircuit regulating blood glucose

Functional identification of a neurocircuit regulating blood glucose

Central control of autonomic functions in health and disease

Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes

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