Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents

Carey, Michelle A.; Lontchi-Yimagou, Eric; Mitchell, William; Reda, Sarah; Zhang, Kehao; Kehlenbrink, Sylvia; Koppaka, Sudha; Maginley, Sylvan Roger; Aleksić, Sandra; Bhansali, Shobhit; Huffman, Derek M.; Hawkins, Meredith

doi:10.2337/db19-1256

Cited by 22 publications

(13 citation statements)

References 53 publications

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“…The hypothalamus detects amino acids (Arrieta-Cruz et al, 2013;Su et al, 2012), oleic acids (Obici et al, 2002b;Pocai et al, 2006), and glucose to regulate hepatic glucose production. Hypothalamic K ATP channels is required for glucose sensing , and such a finding was recently replicated in rodents as well as implicated in humans (Carey et al, 2020). Further, genetic manipulation of glucose-sensitive hypothalamic pro-opiomelanocortin neurons impairs glucose tolerance (Parton et al, ll OPEN ACCESS 2007), while hypothalamic infusion of glucose blunts counter-regulation during hypoglycemia (Borg et al, 1997;Frizzell et al, 1993).…”

Section: Introductionmentioning

confidence: 98%

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

Batchuluun

Zhang

et al. 2021

iScience

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Summary Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.

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Section: Introductionmentioning

confidence: 98%

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

Batchuluun

Zhang

et al. 2021

iScience

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“…Ample evidence also points to a role for the brain in control of glucose handling by the liver. Recent work shows that in both humans and rodents, intact brain K ATP channel activity is required for the ability of hyperglycaemia to suppress endogenous glucose production (a key component of 'glucose effectiveness', the ability of glucose to promote its own disposal independent of insulin action) [2]. In addition to its influence over islet function, discussed below, control of glucose effectiveness is emerging as an important mechanism whereby the brain controls glucose homeostasis.…”

Section: Cns Control Of Islet Functionmentioning

confidence: 99%

“…As ingested nutrients are absorbed into the circulation following a meal, increased insulin secretion promotes glucose disposal into muscle and fat and inhibits endogenous glucose production by the liver, thereby minimising changes in blood glucose levels. The brain helps to coordinate not only the magnitude and timing of the insulin response [1] but also insulin-independent mechanisms that reduce glucose production while enhancing disposal [2]. Here, we review interactions between brain and pancreas that establish the defended blood glucose level and present evidence from humans and animals that both organs must sense the circulating glucose level for this process to function normally.…”

Section: Introductionmentioning

confidence: 99%

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

2020

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Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level.

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“…153,154 Insulin and leptin signalling also shares ATP-sensitive potassium channels, 155,156 which is one of targeted pathways for treating diabetes. 157 In line with the fact that insulin and leptin share several cellular signalling pathways, leptin injection improves not only peripheral, but also hypothalamic insulin sensitivity. 148 Insulin and leptin can modulate neuronal activity in the same AgRP neurone.…”

Section: Synerg Is Ti C Inter Ac Ti On S B E T Ween In Sulin and Lep Tin Ac Ti On Smentioning

confidence: 96%

Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner

Fujikawa

2021

J Neuroendocrinology

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The central nervous system (CNS) contributes significantly to glucose homeostasis.The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism.Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes. K E Y W O R D Sglucose metabolism, insulin, leptin, central nervous system, hypothalamus How to cite this article: Fujikawa T. Central regulation of glucose metabolism in an insulin-dependent and -independent manner.

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Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents

Cited by 22 publications

References 53 publications

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner

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