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      Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia

      Author(s): 1 , 2 , 2
      Publication date Created:
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      Journal: Endocrine Reviews
      Publisher: The Endocrine Society

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          Abstract

          Glucose homeostasis requires an organism to rapidly respond to changes in plasma glucose concentrations. Iatrogenic hypoglycemia as a result of treatment with insulin or sulfonylureas is the most common cause of hypoglycemia in humans and is generally only seen in patients with diabetes who take these medications. The first response to a fall in glucose is the detection of impending hypoglycemia by hypoglycemia-detecting sensors, including glucose-sensing neurons in the hypothalamus and other regions. This detection is then linked to a series of neural and hormonal responses that serve to prevent the fall in blood glucose and restore euglycemia. In this review, we discuss the current state of knowledge about central glucose sensing and how detection of a fall in glucose leads to the stimulation of counterregulatory hormone and behavior responses. We also review how diabetes and recurrent hypoglycemia impact glucose sensing and counterregulation, leading to development of impaired awareness of hypoglycemia in diabetes.

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          The thioredoxin antioxidant system.

          Jun Lu, Arne Holmgren (2014)
          The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate. Trx antioxidant functions are also shown by involvement in DNA and protein repair by reducing ribonucleotide reductase, methionine sulfoxide reductases, and regulating the activity of many redox-sensitive transcription factors. Moreover, Trx systems play critical roles in the immune response, virus infection, and cell death via interaction with thioredoxin-interacting protein. In mammalian cells, the cytosolic and mitochondrial Trx systems, in which TrxRs are high molecular weight selenoenzymes, together with the glutathione-glutaredoxin (Grx) system (NADPH, glutathione reductase, GSH, and Grx) control the cellular redox environment. Recently mammalian thioredoxin and glutathione systems have been found to be able to provide the electrons crossly and to serve as a backup system for each other. In contrast, bacteria TrxRs are low molecular weight enzymes with a structure and reaction mechanism distinct from mammalian TrxR. Many bacterial species possess specific thiol-dependent antioxidant systems, and the significance of the Trx system in the defense against oxidative stress is different. Particularly, the absence of a GSH-Grx system in some pathogenic bacteria such as Helicobacter pylori, Mycobacterium tuberculosis, and Staphylococcus aureus makes the bacterial Trx system essential for survival under oxidative stress. This provides an opportunity to kill these bacteria by targeting the TrxR-Trx system. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity.

            Laura E Parton, Chian Ping Ye, Roberto Coppari … (2007)
            A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
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              Activity-dependent regulation of energy metabolism by astrocytes: an update.

              Luc Pellerin, Anne-Karine Bouzier-Sore, Agnes Aubert … (2007)
              Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and lactate consumption by neurons provides a heuristically valid framework for experimental studies. In this context, it is necessary to provide a survey of recent developments and data pertaining to this model. Thus, here, we review very recent experimental evidence as well as theoretical arguments strongly supporting the original model and in some cases extending it. Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, lactate as a preferential oxidative substrate for neurons, and the notion of net lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron lactate shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.
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                Author and article information

                Journal
                Title: Endocrine Reviews
                Publisher: The Endocrine Society
                ISSN (Print): 0163-769X
                ISSN (Electronic): 1945-7189
                Publication date Created: June 2019
                Publication date Created: June 01 2019
                Publication date Created: January 22 2019
                Publication date Other: June 2019
                Publication date (Print): June 01 2019
                Publication date (Electronic): January 22 2019
                Volume: 40
                Issue: 3
                Pages: 768-788
                Affiliations
                [1 ]Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York
                [2 ]Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
                Article
                DOI: 10.1210/er.2018-00226
                PMC ID: 6505456
                PubMed ID: 30689785
                SO-VID: 5fbe9e41-c937-4c88-82ba-b3a9edc10eea
                Copyright © © 2019
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