Activation of KATP channels suppresses glucose production in humans

Kishore, Preeti; Boucai, Laura; Zhang, Kehao; Li, Weijie; Koppaka, Sudha; Kehlenbrink, Sylvia; Schiwek, Anna; Esterson, Yonah B.; Mehta, Deeksha; Bursheh, Samar; Su, Yongmei; Gutiérrez‐Juárez, Roger; Muzumdar, Radhika; Schwartz, Gary J.; Hawkins, Meredith

doi:10.1172/jci63915

Cited by 10 publications

(15 citation statements)

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“…Although C-peptide levels were slightly higher with the onset of hyperglycaemia during HY and HY-NEFA, compared with EU, they were comparable and would therefore not be expected to contribute to differences between these groups ( Table 1). The portal insulin levels attained with this protocol are likely to reproduce physiological fasting conditions, given an anticipated portal/systemic insulin ratio of ∼2.4:1, as previously described [20,21]. With fasting systemic insulin levels of ∼80 pmol/l in our participants, corresponding fasting portal levels would approximate 192 pmol/l, which is consistent with the systemic levels observed during the final hour of these clamp studies.…”

Section: General Clamp Study Conditionssupporting

confidence: 80%

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

et al. 2012

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Aims/hypothesis Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP. Methods We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-2 H 2 ] glucose) and hepatic glycogen concentrations ( 13 C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA). Results EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ∼14% with prolonged fasting during euglycaemia and increased by ∼12% with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ∼23% reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA. Conclusions/interpretation Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.

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Section: General Clamp Study Conditionssupporting

confidence: 80%

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

et al. 2012

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“…Consistent with findings in rodents that ICV infusion of the K ATP channel activator diazoxide decreased EGP (12), our group recently reported the first studies in humans suggesting central regulation of EGP (78). We performed euglycemic "pancreatic clamp" studies, using somatostatin to inhibit endogenous insulin secretion along with replacement of basal insulin and glucoregulatory hormones following administration of diazoxide in healthy subjects.…”

Section: Evidence From Human Studies Supporting Cns Regulation Of Metsupporting

confidence: 52%

“…Of note, complementary studies in rats (78) showed that diazoxide crosses the blood-brain barrier and confirmed the suppression of EGP during euglycemic pancreatic clamp studies following oral diazoxide, along with decreases in glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expression and increased hepatic STAT3 phosphorylation. When the K ATP channel blocker glibenclamide was administered ICV in rats, the effects of oral diazoxide on EGP, gluconeogenic enzyme expression, and hepatic STAT3 phosphorylation were completely abolished (78). Together, these studies strongly suggest that hypothalamic K ATP channels regulate EGP, at least in part, in humans as well as in rodents.…”

Section: Evidence From Human Studies Supporting Cns Regulation Of Metmentioning

confidence: 81%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

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Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

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“…The current study demonstrates that the activation of MBH K ATPchannels, per se, attenuates hepatic VLDL-TG secretion and plasma TG levels in a model of HFD-induced hypertriglyceridemia. Given that orally administered diazoxide, which increased CSF levels of diazoxide and activated brain K ATPchannels in parallel complementary studies in rodents, lowers glucose production in humans 51 , it would be important to assess whether diazoxide lowers VLDL-TG secretion in humans and alternative experimental rodent models with obesity, diabetes and lipid disorders such as the fructose-fed hamster and the apoEdeficient and/or LDLR-deficient mice. Diazoxide inhibits b-cell insulin secretion 52 , and since circulating insulin negatively regulates hepatic VLDL-TG release 14 , systemic diazoxide may not reduce VLDL-TG secretion.…”

Section: Discussionmentioning

confidence: 99%

A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

et al. 2015

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The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-d-K ATP -channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-d or K ATP -channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.

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Activation of KATP channels suppresses glucose production in humans

Abstract: The anti-Fpn and anti-Jak2 rows in Figure 2A Figure 3B of that manuscript.The authors regret the error.

Cited by 10 publications

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Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

Evidence for Central Regulation of Glucose Metabolism

A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

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