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

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          Abstract

          Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes.

          Abstract

          Abstract

          GHRH neurons in the arcuate nucleus are activated by glucose deprivation; however, repeated hypoglycemia blunts activation, remodels inputs, and disrupts mitochondrial fusion.

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          Most cited references80

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          The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus

          Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
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            iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging.

            The visualization of molecularly labeled structures within large intact tissues in three dimensions is an area of intense focus. We describe a simple, rapid, and inexpensive method, iDISCO, that permits whole-mount immunolabeling with volume imaging of large cleared samples ranging from perinatal mouse embryos to adult organs, such as brains or kidneys. iDISCO is modeled on classical histology techniques, facilitating translation of section staining assays to intact tissues, as evidenced by compatibility with 28 antibodies to both endogenous antigens and transgenic reporters like GFP. When applied to degenerating neurons, iDISCO revealed unexpected variability in number of apoptotic neurons within individual sensory ganglia despite tight control of total number in all ganglia. It also permitted imaging of single degenerating axons in adult brain and the first visualization of cleaved Caspase-3 in degenerating embryonic sensory axons in vivo, even single axons. iDISCO enables facile volume imaging of immunolabeled structures in complex tissues. PAPERCLIP:
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              Oligodendroglia metabolically support axons and contribute to neurodegeneration

              Summary Oligodendroglia support axon survival and function through mechanisms independent of myelination and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been hypothesized. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and utilization. We show the most abundant lactate transporter in the CNS, monocarboxylate transporter 1 (MCT1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and mouse models of, amyotrophic lateral sclerosis (ALS), suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.
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                Author and article information

                Contributors
                Journal
                JCI Insight
                JCI Insight
                JCI Insight
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                5 November 2020
                5 November 2020
                5 November 2020
                : 5
                : 21
                : e133488
                Affiliations
                [1 ]Diabetes, Obesity and Metabolism Institute,
                [2 ]Nash Family Department of Neuroscience and Friedman Brain Institute, and
                [3 ]Tisch Cancer Institute and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
                Author notes
                Address correspondence to: Sarah A. Stanley, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, New York, USA. Phone: 212.241.1728; Email: sarah.stanley@ 123456mssm.edu .

                Authorship note: AA and KD contributed equally to the work.

                Author information
                http://orcid.org/0000-0003-0868-8578
                http://orcid.org/0000-0002-4374-4670
                http://orcid.org/0000-0002-2605-634X
                http://orcid.org/0000-0002-7678-9058
                http://orcid.org/0000-0002-1517-3903
                Article
                133488
                10.1172/jci.insight.133488
                7710320
                33148883
                fbfe2942-6d12-45a5-a024-e66ee0845834
                © 2020 Bayne et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 September 2019
                : 24 September 2020
                Funding
                Funded by: American Diabetes Association, https://doi.org/10.13039/100000041;
                Award ID: #1-17-ACE-31
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: U01 MH105941
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: R01 NS097184
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: OT2 OD024912
                Funded by: Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, https://doi.org/10.13039/100012301;
                Award ID: P30 DK020541
                Funded by: American Heart Association, https://doi.org/10.13039/100000968;
                Award ID: 18PRE33960254
                Funded by: Charles Revson Foundation
                Award ID: 18-25
                Funded by: National Science Foundation, https://doi.org/10.13039/100000001;
                Award ID: 1930157
                This work was supported by the American Diabetes Association Pathway to Stop Diabetes Grant ADA #1-17-ACE-31
                K.D. is supported by a predoctoral fellowship from the American Heart Association
                A.A. is supported by a postdoctoral fellowship from the Charles H Revson Foundation
                Categories
                Research Article

                metabolism,neuroscience,diabetes
                metabolism, neuroscience, diabetes

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