Evidence against a Physiologic Role for Acute Changes in CNS Insulin Action in the Rapid Regulation of Hepatic Glucose Production

Ramnanan, Christopher J.; Edgerton, Dale S.; Cherrington, Alan D.

doi:10.1016/j.cmet.2012.03.006

Cited by 49 publications

(47 citation statements)

References 70 publications

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“…However, the second observation of enhanced whole-body insulin sensitivity after intranasal insulin application holds true. Of note, this effect is rapid and corresponds to the time course observed in rodents (3,6,14) but not in dogs (11).…”

Section: Discussionmentioning

confidence: 99%

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Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

et al. 2014

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Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on wholebody insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

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Section: Discussionmentioning

confidence: 99%

“…Particularly, the action of insulin in the brain modulates insulin sensitivity in other organs such as liver (2,3,6,7), muscle (8), and adipose (1,9,10) tissue. However, at least for the liver, the relevance of this mechanism is still under debate (11,12).…”

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confidence: 99%

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

et al. 2014

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“…It has been reported that insulin still suppresses HGP partially even in mice with PI3K signal transduction inhibition in the liver [8,9]. Further, in an investigation of the changes in HGP after intravenous and intraportal insulin administration, it was shown that the differences in portal blood insulin level, that is, the direct insulin action on hepatocytes, do not necessarily correlate with the effect of insulin on HGP suppression [10].Indirect suppression of HGP by insulin is accomplished through the reduction of the release of glycerol and free fatty acids from the adipose tissue, which are the substrates and energy source of gluconeogenesis, and the decrease in the expression of hepatic gluconeogenic genes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [11]. Actually, in an investigation using dogs, maintenance of blood free fatty acid at a constant level by the intravenous administration of fat emulsion and heparin is reported to inhibit suppression of HGP during hyperinsulinemic-euglycemic clamp [12].…”

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confidence: 99%

“…Indirect suppression of HGP by insulin is accomplished through the reduction of the release of glycerol and free fatty acids from the adipose tissue, which are the substrates and energy source of gluconeogenesis, and the decrease in the expression of hepatic gluconeogenic genes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [11]. Actually, in an investigation using dogs, maintenance of blood free fatty acid at a constant level by the intravenous administration of fat emulsion and heparin is reported to inhibit suppression of HGP during hyperinsulinemic-euglycemic clamp [12].…”

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Central insulin-mediated regulation of hepatic glucose production [Review]

Inoue

2016

Endocr J

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Abstract. Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.Key words: Hypothalamus, Insulin, Liver, Vagus nerve, STAT3 THE LIVER plays a central role in the maintenance of whole-body glucose homeostasis, by adjusting glucose production according to the energy balance. The master regulator of hepatic glucose production (HGP) is insulin, as the liver is exposed to portal blood, which displays high insulin concentrations of approximately three times that in venous blood [1]. Indeed, in diabetes mellitus, the increase of HGP is closely related to the rise of fasting blood level [2]. HGP is strongly controlled by direct actions of insulin on hepatocytes [3]. When bound to its receptor, insulin suppresses HGP via the activation of phosphoinositide 3-kinase (PI3K) signal transduction pathway consisting of insulin receptor substrate (IRS), PI3K, phosphoinositide-dependent kinase 1 (PDK1) and Akt [4]. Thus, liver-specific insulin receptor knockout mice or impaired PI3K signal transduction exhibit hyperinsulinemia and glucose intolerance with impaired insulin-dependent suppression of HGP [5][6][7][8]. Meanwhile, insulin is known to control HGP not only by direct mechanisms via hepatic insulin receptors, but also by indirect mechanisms mediated by insulin actions on other organs (Fig.1). It has been reported that insulin still suppresses HGP partially even in mice with PI3K signal transduction inhibition in the liver [8,9]. Further, in an investigation of the changes in HGP after intravenous and intraportal insulin administration, it was shown that the differences in portal blood insulin level, that is, the direct insulin action on hepatocytes, do not necessarily correlate with the effect of insulin on HGP suppression [10].Indirect suppressio...

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“…Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7).…”

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confidence: 55%

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

Gancheva

Roden

2016

Diabetes

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In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of K ATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7).In humans, intranasal insulin (IN) application has been established as one approach to noninvasively examine brain insulin action in vivo. The IN spray application transiently increases the insulin concentration in liquor (8), likely due to bulk flow within the perivascular space of cerebral blood vessels (9). Using this technique, evidence for the central insulin regulation of systemic lipolysis (10), modulation of liver fat content and hepatic energy metabolism (11), and improvement in whole-body insulin sensitivity (12) has been provided. Interestingly, effects of IN on EGP seem to depend on the experimental conditions with no changes in the fasting state (11) but with reduction during pancreatic clamps (13). Modulation of energy-demanding processes might contribute to the rise in hepatic energy status after IN application. Of note, central insulin regulation of peripheral insulin sensitivity and hepatic energy metabolism was blunted in obese humans and patients with type 2 diabetes (11,12), suggesting that the presence of a combined central and peripheral IR and a dysregulation of a brain-liver cross talk in type 2 diabetes. Nevertheless, IN may have some limitations resulting from variable cerebral insulin delivery and/or peripheral insulin spillover.Another approach to mimic brain insulin action in humans is the administration of the K ATP -channel opener and sulfonylurea drug diazoxide. Dr. Hawkins' group showed that diazoxide treatment can suppress EGP in lean healthy humans, and complementary studies in rodents revealed increased hepatic STAT3 phosphorylation along with reduced hepatic gluconeogenic protein levels (14). The same group now presents a carefully planned and nicely performed follow-up study investigating the effects of diazoxide on EGP in patients with type 2 diabetes. Esterson et al. (15) combined diazoxide admini...

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Evidence against a Physiologic Role for Acute Changes in CNS Insulin Action in the Rapid Regulation of Hepatic Glucose Production

Cited by 49 publications

References 70 publications

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

Central insulin-mediated regulation of hepatic glucose production [Review]

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

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