Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia

Stanley, Sarah A.; Moheet, Amir; Seaquist, Elizabeth R.

doi:10.1210/er.2018-00226

Cited by 72 publications

(87 citation statements)

References 230 publications

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“…This central adaptation of the brain to tolerate lower peripheral concentrations of glucose may be mediated through increased expression of brain glucose transporters allowing for enhanced cerebral utilization of glucose, a shift in brain fuel utilization to alternative substrates such as lactate 49 (circulating levels of which increase during insulin-mediated hypoglycemia), or some combination of these mecha-nisms as has recently been reviewed. 50 While such adaptation is undoubtedly beneficial for tolerating prolonged fasting, this becomes maladaptive in the setting of insulin-induced hypoglycemia where the window is lost for correcting the development of even further reduction in blood glucose before cognitive function is affected and results in the experience of severe hypoglycemia. The mechanisms for central adaptation converge on altered brain glucose sensing in the ventromedial hypothalamus (VMH) leading to increased GABA that impairs activation of the ANS required for the counterregulatory response against low blood glucose ( Fig.…”

Section: Mechanisms For Haaf In T1dmentioning

confidence: 99%

Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

Rickels

2019

Annals of the New York Academy of Sciences

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Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin-dependent type 1 diabetes (T1D). Both the loss of β cells and an accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.

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Section: Mechanisms For Haaf In T1dmentioning

confidence: 99%

Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

Rickels

2019

Annals of the New York Academy of Sciences

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“…Similar to parasites, cancer cells manipulate the metabolism of the host organism, thereby receiving a larger portion of glucose than the host cells (1,2). To prevent glucose starvation dangerous to such glucose-sensitive organs as the brain, the host organism uses glucose sensors capable of maintaining normoglycemia in response to deficient or excess glucose (3). The mechanism of cancer-mediated manipulation of the host glucose metabolism is unknown.…”

Section: Introductionmentioning

confidence: 99%

A View on Pathogenesis of ≪Vicious Cancer Progression Cycle≫

Schwartsburd

2020

Front. Oncol.

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Unrestricted tumor growth requires a permanent supply of glucose that can be obtained from cancer-stimulated hepatic glucose production and/or glucose redirecting from host insulin resistant tissues to cancer cells. This study proposes a mechanism based on metabolic and hormonal changes that may provoke glucose delivery to cancer cells through two interconnected "vicious cycles" whose continuous activity drives cancer progression. As follows from the proposed here feedback model, these "vicious cycles" result from cancer-mediated manipulation of host glucose sensors. The derived conclusions contribute to a better understanding of cancer pathogenesis and identifying potential therapeutic targets.

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“…Under normal circumstances, plasma glucose levels are maintained within a narrow range. In healthy individuals, hypoglycemia rapidly triggers the counterregulatory response (CRR) to restore blood glucose (8). These responses occur via direct actions of low glucose on peripheral organs such as the pancreas and indirectly via the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

“…Glucose-sensing neurons are found in many brain regions, including hypothalamic arcuate nucleus (ARC) (8). The ARC includes both GE and GI neurons, which express putative glucose sensors such as glucokinase (Gck) (10), glucose transporter type 2 (11), and ATP-sensitive potassium channels (12).…”

Section: Introductionmentioning

confidence: 99%

Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness

Bayne¹,

Alvarsson²,

Devarakonda³

et al. 2020

JCI Insight

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Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia

Cited by 72 publications

References 230 publications

Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

A View on Pathogenesis of ≪Vicious Cancer Progression Cycle≫

Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness

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