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Stogios N, Wu S, Hahn M, Emami Z, Navagnanavel J, Korann V, PrasannaKumar A, Remington G, Graff-Guerrero A, Agarwal SM. Exploring the effects of an insulin challenge on neuroimaging outcomes: A scoping review. Front Neuroendocrinol 2025; 77:101187. [PMID: 39971163 DOI: 10.1016/j.yfrne.2025.101187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/27/2025] [Accepted: 02/15/2025] [Indexed: 02/21/2025]
Abstract
Emerging evidence demonstrates that insulin has a modulating effect on metabolic and cognitive function in the brain, highlighting the potential role of aberrant brain insulin signaling in the pathogenesis of various neuropsychiatric illnesses. Neuroimaging paradigms using intranasal insulin (INI) as a pharmacological challenge have allowed us to study the effects of insulin in the human brain. In this scoping review, we conducted a systematic database search to identify relevant research studies that employed an INI-based neuroimaging assay of brain insulin signaling. Thirty-six studies met inclusion criteria for this review. INI was found to significantly modulate activity and cerebral blood flow in brain regions related to homeostatic/hedonic control of food intake, as well as cognition. This review highlights the putative role of insulin signaling in the brain and the potential therapeutic value of INI in patients with mental health, addiction, and co-morbid metabolic disorders.
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Affiliation(s)
- Nicolette Stogios
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda
| | - Sally Wu
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda
| | - Margaret Hahn
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda; Department of Psychiatry, University of Toronto, Toronto, ON, Cananda; Banting and Best Diabetes Centre (BBDC), University of Toronto, Toronto, ON, Cananda
| | - Zahra Emami
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Cananda
| | - Janani Navagnanavel
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Cananda
| | - Vittal Korann
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda
| | | | - Gary Remington
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda; Department of Psychiatry, University of Toronto, Toronto, ON, Cananda
| | - Ariel Graff-Guerrero
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda; Department of Psychiatry, University of Toronto, Toronto, ON, Cananda
| | - Sri Mahavir Agarwal
- Institute of Medical Science, University of Toronto, Toronto, ON, Cananda; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Cananda; Department of Psychiatry, University of Toronto, Toronto, ON, Cananda; Banting and Best Diabetes Centre (BBDC), University of Toronto, Toronto, ON, Cananda.
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2
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Frank-Ito DO. Olfaction and drug delivery to the human olfactory airspace: current challenges and recent advances. Expert Opin Drug Deliv 2025; 22:511-524. [PMID: 39955085 DOI: 10.1080/17425247.2025.2467784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/01/2024] [Accepted: 02/12/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Olfactory function, despite its critical role in human survival and quality of life, is often underappreciated. This could be associated with the fact that symptoms of olfactory dysfunction rarely occur in isolation as they are frequently concomitant with comorbidities. Furthermore, effective treatments for olfactory dysfunction largely remain elusive, and no standardized clinical practice for treating this dysfunction currently exist, thus complicating the initiation of appropriate therapeutic modalities. Intranasal administration of topical medication targeting the olfactory cleft represents a safe, noninvasive and potentially efficacious approach, but several challenges impede effective drug delivery. AREAS COVERED This review highlights the importance of human olfaction, assessment of olfactory function, underlying sources of olfactory dysfunction, and challenges involved in developing long-term and effective treatment modalities, particularly in the administration of topical medication to the olfactory cleft intranasally. Advancements in both device-related and administration-related modalities designed to enhance intranasal drug delivery are discussed. EXPERT OPINION Clinical management typically prioritizes comorbid conditions, relegating symptoms pertaining olfactory dysfunction to ancillary concerns. Device manufacturers for intranasal administration likewise underestimate the complexity and variabilities of the nasal cavity, and how these impact drug transport. Synergistic implementation of device and formulation strategies can potentially yield enhanced olfactory cleft drug delivery.
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Affiliation(s)
- Dennis Onyeka Frank-Ito
- Department of Head and Neck Surgery & Communication Sciences, Duke University Medical Center, Durham, North Carolina, USA
- Department of Mechanical Engineering and Materials Science, Duke University, Durham, North Carolina, USA
- Computational Biology & Bioinformatics PhD Program, Duke University, Durham, North Carolina, USA
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3
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Au E, Panganiban KJ, Wu S, Sun K, Humber B, Remington G, Agarwal SM, Giacca A, Pereira S, Hahn M. Antipsychotic-Induced Dysregulation of Glucose Metabolism Through the Central Nervous System: A Scoping Review of Animal Models. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2025; 10:244-257. [PMID: 39461717 DOI: 10.1016/j.bpsc.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024]
Abstract
The use of antipsychotic drugs is associated with adverse metabolic effects. Disruptions in glucose metabolism such as hyperglycemia and insulin resistance have been shown to occur with antipsychotic use, independent of changes in body weight or adiposity. The regulation of whole-body glucose metabolism is partly mediated by the central nervous system. In particular, the hypothalamus and brainstem are responsive to peripheral energy signals and subsequently mediate feedback mechanisms to maintain peripheral glucose homeostasis. In this scoping review of preclinical in vivo studies, we aimed to explore central mechanisms through which antipsychotics dysregulate glucose metabolism. A systematic search for animal studies identified 29 studies that met our eligibility criteria for qualitative synthesis. The studies suggest that antipsychotic-induced changes in autonomic nervous system activity, certain neurotransmitter systems, expression of neuropeptides, and central insulin action mediate impairments in glucose metabolism. These findings provide insight into potential targets for the mitigation of the adverse effects of antipsychotics on glucose metabolism.
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Affiliation(s)
- Emily Au
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Kristoffer J Panganiban
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Sally Wu
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Kira Sun
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - Bailey Humber
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Gary Remington
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Sri Mahavir Agarwal
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Adria Giacca
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Sandra Pereira
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Margaret Hahn
- Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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4
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Buettner C, Sakamoto K, Butera MA. Why do some individuals with obesity remain metabolically healthy? Trends Endocrinol Metab 2025; 36:1-3. [PMID: 38960837 PMCID: PMC11693770 DOI: 10.1016/j.tem.2024.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.
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Affiliation(s)
- Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Mary A Butera
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
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Bruce K, Garrido AN, Zhang SY, Lam TKT. Regulation of Energy and Glucose Homeostasis by the Nucleus of the Solitary Tract and the Area Postrema. Endocrinol Metab (Seoul) 2024; 39:559-568. [PMID: 39086274 PMCID: PMC11377841 DOI: 10.3803/enm.2024.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 06/07/2024] [Indexed: 08/02/2024] Open
Abstract
The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.
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Affiliation(s)
- Kyla Bruce
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada
| | - Ameth N Garrido
- Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada
| | - Tony K T Lam
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, Medicine, University of Toronto, Toronto, ON, Canada
- Banting and Best Diabetes Center, University of Toronto, Toronto, ON, Canada
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6
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Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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7
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Heni M. The insulin resistant brain: impact on whole-body metabolism and body fat distribution. Diabetologia 2024; 67:1181-1191. [PMID: 38363340 PMCID: PMC11153284 DOI: 10.1007/s00125-024-06104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 12/19/2023] [Indexed: 02/17/2024]
Abstract
Insulin exerts its actions not only on peripheral organs but is also transported into the brain where it performs distinct functions in various brain regions. This review highlights recent advancements in our understanding of insulin's actions within the brain, with a specific emphasis on investigations in humans. It summarises current knowledge on the transport of insulin into the brain. Subsequently, it showcases robust evidence demonstrating the existence and physiological consequences of brain insulin action, while also introducing the presence of brain insulin resistance in humans. This pathophysiological condition goes along with an impaired acute modulation of peripheral metabolism in response to brain insulin action, particularly in the postprandial state. Furthermore, brain insulin resistance has been associated with long-term adiposity and an unfavourable adipose tissue distribution, thus implicating it in the pathogenesis of subgroups of obesity and (pre)diabetes that are characterised by distinct patterns of body fat distribution. Encouragingly, emerging evidence suggests that brain insulin resistance could represent a treatable entity, thereby opening up novel therapeutic avenues to improve systemic metabolism and enhance brain functions, including cognition. The review closes with an outlook towards prospective research directions aimed at further elucidating the clinical implications of brain insulin resistance. It emphasises the critical need to establish feasible diagnostic measures and effective therapeutic interventions.
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Affiliation(s)
- Martin Heni
- Division of Endocrinology and Diabetology, Department of Internal Medicine 1, University Hospital Ulm, Ulm, Germany.
- Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital of Tübingen, Tübingen, Germany.
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8
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Jahromi HM, Rafati A, Karbalay-Doust S, Keshavarz S, Naseh M. The combination treatment of hypothermia and intranasal insulin ameliorates the structural and functional changes in a rat model of traumatic brain injury. Brain Struct Funct 2024; 229:947-957. [PMID: 38498064 DOI: 10.1007/s00429-024-02769-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 01/26/2024] [Indexed: 03/19/2024]
Abstract
The present study aimed to investigate the combination effects of hypothermia (HT) and intranasal insulin (INS) on structural changes of the hippocampus and cognitive impairments in the traumatic brain injury (TBI) rat model. The rats were divided randomly into the following five groups (n = 10): Sham, TBI, TBI with HT treatment for 3 h (TBI + HT), TBI with INS (ten microliters of insulin) treatment daily for 7 days (TBI + INS), and TBI with combining HT and INS (TBI + HT + INS). At the end of the 7th day, the open field and the Morris water maze tests were done for evaluation of anxiety-like behavior and memory performance. Then, after sacrificing, the brain was removed for stereological study. TBI led to an increase in the total volume of hippocampal subfields CA1 and DG and a decrease in the total number of neurons and non-neuronal cells in both sub-regions, which was associated with anxiety-like behavior and memory impairment. Although, the combination of HT and INS prevented the increased hippocampal volume and cell loss and improved behavioral performances in the TBI group. Our study suggests that the combined treatment of HT and INS could prevent increased hippocampal volume and cell loss in CA1 and DG sub-regions and consequently improve anxiety-like behaviors and memory impairment following TBI.
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Affiliation(s)
- Hadi Moatamed Jahromi
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Rafati
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saied Karbalay-Doust
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somaye Keshavarz
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Maryam Naseh
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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9
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Saedi H, Waro G, Giacchetta L, Tsunoda S. miR-137 regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in Drosophila. Proc Natl Acad Sci U S A 2024; 121:e2319475121. [PMID: 38252824 PMCID: PMC10835047 DOI: 10.1073/pnas.2319475121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/13/2023] [Indexed: 01/24/2024] Open
Abstract
miR-137 is a highly conserved brain-enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that Drosophila miR-137 null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation, miR-137 mutants exhibit reduced motivation to feed and prolonged survival. We show through genetic epistasis and rescue experiments that this starvation resistance is due to a disruption in insulin signaling. Our studies further show that miR-137 null mutants exhibit a drastic reduction in levels of the phosphorylated/activated insulin receptor, InR (InR-P). We investigated if this is due to the predicted miR-137 target, Protein Tyrosine Phosphatase 61F (PTP61F), ortholog of mammalian TC-PTP/PTP1B, which are known to dephosphorylate InR-P. Indeed, levels of an endogenously tagged GFP-PTP61F are significantly elevated in miR-137 null mutants, and we show that overexpression of PTP61F alone is sufficient to mimic many of the metabolic phenotypes of miR-137 mutants. Finally, we knocked-down elevated levels of PTP61F in the miR-137 null mutant background and show that this rescues levels of InR-P, restores normal body weight and triglyceride content, starvation sensitivity, as well as attenuates locomotor and starvation-induced feeding defects. Our study supports a model in which miR-137 is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis.
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Affiliation(s)
- Hana Saedi
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO80523
| | - Girma Waro
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO80523
| | - Lea Giacchetta
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO80523
| | - Susan Tsunoda
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO80523
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10
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Lee J, Xue X, Au E, McIntyre WB, Asgariroozbehani R, Tseng GC, Papoulias M, Panganiban K, Agarwal SM, Mccullumsmith R, Freyberg Z, Logan RW, Hahn MK. Central insulin dysregulation in antipsychotic-naïve first-episode psychosis: In silico exploration of gene expression signatures. Psychiatry Res 2024; 331:115636. [PMID: 38104424 PMCID: PMC10984627 DOI: 10.1016/j.psychres.2023.115636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/18/2023] [Accepted: 11/25/2023] [Indexed: 12/19/2023]
Abstract
Antipsychotic drug (AP)-naïve first-episode psychosis (FEP) patients display premorbid cognitive dysfunctions and dysglycemia. Brain insulin resistance may link metabolic and cognitive disorders in humans. This suggests that central insulin dysregulation represents a component of the pathophysiology of psychosis spectrum disorders (PSDs). Nonetheless, the links between central insulin dysregulation, dysglycemia, and cognitive deficits in PSDs are poorly understood. We investigated whether AP-naïve FEP patients share overlapping brain gene expression signatures with central insulin perturbation (CIP) in rodent models. We systematically compiled and meta-analyzed peripheral transcriptomic datasets of AP-naïve FEP patients along with hypothalamic and hippocampal datasets of CIP rodent models to identify common transcriptomic signatures. The common signatures were used for pathway analysis and to identify potential drug treatments with discordant (reverse) signatures. AP-naïve FEP and CIP (hypothalamus and hippocampus) shared 111 and 346 common signatures respectively, which were associated with pathways related to inflammation, endoplasmic reticulum stress, and neuroplasticity. Twenty-two potential drug treatments were identified, including antidiabetic agents. The pathobiology of PSDs may include central insulin dysregulation, which contribute to dysglycemia and cognitive dysfunction independently of AP treatment. The identified treatments may be tested in early psychosis patients to determine if dysglycemia and cognitive deficits can be mitigated.
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Affiliation(s)
- Jiwon Lee
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
| | - Xiangning Xue
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
| | - Emily Au
- Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
| | - William B McIntyre
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
| | - Roshanak Asgariroozbehani
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
| | - George C Tseng
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
| | - Maria Papoulias
- Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
| | - Kristoffer Panganiban
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
| | - Sri Mahavir Agarwal
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
| | - Robert Mccullumsmith
- Department of Neurosciences, University of Toledo, Toledo, Ohio, United States; ProMedica, Toledo, Ohio, United States.
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
| | - Ryan W Logan
- Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States; Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States.
| | - Margaret K Hahn
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
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11
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Hummel J, Benkendorff C, Fritsche L, Prystupa K, Vosseler A, Gancheva S, Trenkamp S, Birkenfeld AL, Preissl H, Roden M, Häring HU, Fritsche A, Peter A, Wagner R, Kullmann S, Heni M. Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase. Nat Metab 2023; 5:1475-1482. [PMID: 37735274 PMCID: PMC10513929 DOI: 10.1038/s42255-023-00869-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 07/19/2023] [Indexed: 09/23/2023]
Abstract
Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2. In particular, brain insulin action increases whole-body insulin sensitivity, but these studies were mainly performed in lean men3,4. Here we investigate metabolic and hypothalamic effects of brain insulin action in women with a focus on the impact of menstrual cycle ( ClinicalTrials.gov registration: NCT03929419 ).Eleven women underwent four hyperinsulinemic-euglycemic clamps, two in the follicular phase and two in the luteal phase. Brain insulin action was introduced using nasal insulin spray5-7 and compared to placebo spray in a fourfold crossover design with change in glucose infusion rate as the primary endpoint. Here we show that during the follicular phase, more glucose has to be infused after administration of nasal insulin than after administration of placebo. This remains significant after adjustment for blood glucose and insulin. During the luteal phase, no significant influence of brain insulin action on glucose infusion rate is detected after adjustment for blood glucose and insulin (secondary endpoint). In 15 other women, hypothalamic insulin sensitivity was assessed in a within-subject design by functional magnetic resonance imaging with intranasal insulin administration8. Hypothalamus responsivity is influenced by insulin in the follicular phase but not the luteal phase.Our study therefore highlights that brain insulin action improves peripheral insulin sensitivity also in women but only during the follicular phase. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase of the menstrual cycle.
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Affiliation(s)
- Julia Hummel
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine I, Division of Endocrinology and Diabetology, University of Ulm, Ulm, Germany
| | - Charlotte Benkendorff
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Katsiaryna Prystupa
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Andreas Vosseler
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Sofiya Gancheva
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sandra Trenkamp
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Andreas L Birkenfeld
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Robert Wagner
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
- Department of Internal Medicine I, Division of Endocrinology and Diabetology, University of Ulm, Ulm, Germany.
- Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
- Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
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12
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Becerra LA, Gavrieli A, Khan F, Novak P, Lioutas V, Ngo LH, Novak V, Mantzoros CS. Daily intranasal insulin at 40IU does not affect food intake and body composition: A placebo-controlled trial in older adults over a 24-week period with 24-weeks of follow-up. Clin Nutr 2023; 42:825-834. [PMID: 37084469 PMCID: PMC10330069 DOI: 10.1016/j.clnu.2023.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/23/2023]
Abstract
Centrally administered insulin stimulates the reward system to reduce appetite in response to food intake in animal studies. In humans, studies have shown conflicting results, with some studies suggesting that intranasal insulin (INI) in relatively high doses may decrease appetite, body fat, and weight in various populations. These hypotheses have not been tested in a large longitudinal placebo-controlled study. Participants in the Memory Advancement with Intranasal Insulin in Type 2 Diabetes (MemAID) trial were enrolled in this study. This study on energy homeostasis enrolled 89 participants who completed baseline and at least 1 intervention visit (42 women; age 65 ± 9 years; 46 INI, 38 with type 2 diabetes) and 76 completed treatment (16 women, age 64 ± 9; 38 INI, 34 with type 2 diabetes). The primary outcome was the INI effect on food intake. Secondary outcomes included the effect of INI on appetite and anthropometric measures, including body weight and body composition. In exploratory analyses, we tested the interaction of treatment with gender, body mass index (BMI), and diagnosis of type 2 diabetes. There was no INI effect on food intake or any of the secondary outcomes. INI also showed no differential effect on primary and secondary outcomes when considering gender, BMI, and type 2 diabetes. INI did not alter appetite or hunger nor cause weight loss when used at 40 I.U. intranasally daily for 24 weeks in older adults with and without type 2 diabetes.
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Affiliation(s)
- Laura Aponte Becerra
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Anna Gavrieli
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Faizan Khan
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Peter Novak
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vasileios Lioutas
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Long H Ngo
- Department of Medicine, Beth Israel Deaconess Medical Center and School of Public Health, Harvard Medical School, Boston, MA, USA
| | - Vera Novak
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Boston VA Healthcare System, Boston, MA, USA.
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13
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Omori NE, Malys MK, Woo G, Mansor L. Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders. Front Psychiatry 2023; 14:1142682. [PMID: 37139329 PMCID: PMC10149735 DOI: 10.3389/fpsyt.2023.1142682] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/28/2023] [Indexed: 05/05/2023] Open
Abstract
In recent times, advances in the field of metabolomics have shed greater light on the role of metabolic disturbances in neuropsychiatric conditions. The following review explores the role of ketone bodies and ketosis in both the diagnosis and treatment of three major psychiatric disorders: major depressive disorder, anxiety disorders, and schizophrenia. Distinction is made between the potential therapeutic effects of the ketogenic diet and exogenous ketone preparations, as exogenous ketones in particular offer a standardized, reproducible manner for inducing ketosis. Compelling associations between symptoms of mental distress and dysregulation in central nervous system ketone metabolism have been demonstrated in preclinical studies with putative neuroprotective effects of ketone bodies being elucidated, including effects on inflammasomes and the promotion of neurogenesis in the central nervous system. Despite emerging pre-clinical data, clinical research on ketone body effectiveness as a treatment option for psychiatric disorders remains lacking. This gap in understanding warrants further investigating, especially considering that safe and acceptable ways of inducing ketosis are readily available.
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Affiliation(s)
- Naomi Elyse Omori
- Health Via Modern Nutrition Inc. (H.V.M.N.), San Francisco, CA, United States
- *Correspondence: Naomi Elyse Omori,
| | - Mantas Kazimieras Malys
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, United Kingdom
| | - Geoffrey Woo
- Health Via Modern Nutrition Inc. (H.V.M.N.), San Francisco, CA, United States
| | - Latt Mansor
- Health Via Modern Nutrition Inc. (H.V.M.N.), San Francisco, CA, United States
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14
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Malin SK, Stewart NR, Ude AA, Alderman BL. Brain insulin resistance and cognitive function: influence of exercise. J Appl Physiol (1985) 2022; 133:1368-1380. [PMID: 36269295 PMCID: PMC9744647 DOI: 10.1152/japplphysiol.00375.2022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/12/2022] [Accepted: 10/12/2022] [Indexed: 12/15/2022] Open
Abstract
Exercise has systemic health benefits in people, in part, through improving whole body insulin sensitivity. The brain is an insulin-sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. Although brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.
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Affiliation(s)
- Steven K Malin
- Department of Kinesiology & Health, Rutgers University, New Brunswick, New Jersey
- Division of Endocrinology, Metabolism & Nutrition, Rutgers University, New Brunswick, New Jersey
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, New Jersey
- Institute of Translational Medicine and Science, Rutgers University, New Brunswick, New Jersey
| | - Nathan R Stewart
- Department of Kinesiology & Health, Rutgers University, New Brunswick, New Jersey
| | - Andrew A Ude
- Department of Kinesiology & Health, Rutgers University, New Brunswick, New Jersey
| | - Brandon L Alderman
- Department of Kinesiology & Health, Rutgers University, New Brunswick, New Jersey
- Center of Alcohol and Substance Use Studies, Rutgers University, New Brunswick, New Jersey
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15
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Investigating the effects of antipsychotics on brain insulin action: Study protocol for a multi-modality magnetic resonance imaging (MRI) study in healthy controls. PLoS One 2022; 17:e0277211. [PMID: 36441736 PMCID: PMC9704670 DOI: 10.1371/journal.pone.0277211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/29/2022] Open
Abstract
Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2-6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.
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16
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Zakharova IO, Bayunova LV, Derkach KV, Ilyasov IO, Morina IY, Shpakov AO, Avrova NF. Effects of Intranasally Administered Insulin and Gangliosides on Hypothalamic Signaling and Expression of Hepatic Gluconeogenesis Genes in Rats with Type 2 Diabetes Mellitus. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022060072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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17
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Kullmann S, Goj T, Veit R, Fritsche L, Wagner L, Schneeweiss P, Hoene M, Hoffmann C, Machann J, Niess A, Preissl H, Birkenfeld AL, Peter A, Häring HU, Fritsche A, Moller A, Weigert C, Heni M. Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese. JCI Insight 2022; 7:161498. [PMID: 36134657 DOI: 10.1172/jci.insight.161498] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUNDInsulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODSIn this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21-59 years; BMI range 27.5-45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTSThe exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSIONOur study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATIONClinicalTrials.gov (NCT03151590).FUNDINGBMBF/DZD 01GI0925.
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Affiliation(s)
- Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Thomas Goj
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Institute for Clinical Chemistry and Pathobiochemistry and
| | - Ralf Veit
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Lore Wagner
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Patrick Schneeweiss
- Department of Sports Medicine, University Hospital Tübingen, Germany.,Interfaculty Research Institute for Sport and Physical Activity, University of Tübingen, Tübingen, Germany
| | - Miriam Hoene
- Institute for Clinical Chemistry and Pathobiochemistry and
| | | | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Radiology, Section on Experimental Radiology, University Hospital Tübingen, Germany
| | - Andreas Niess
- Department of Sports Medicine, University Hospital Tübingen, Germany.,Interfaculty Research Institute for Sport and Physical Activity, University of Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany.,Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Andreas L Birkenfeld
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Institute for Clinical Chemistry and Pathobiochemistry and
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Anja Moller
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Cora Weigert
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Institute for Clinical Chemistry and Pathobiochemistry and
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany.,Institute for Clinical Chemistry and Pathobiochemistry and.,Division of Endocrinology and Diabetology, Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
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18
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Henkel ND, Wu X, O'Donovan SM, Devine EA, Jiron JM, Rowland LM, Sarnyai Z, Ramsey AJ, Wen Z, Hahn MK, McCullumsmith RE. Schizophrenia: a disorder of broken brain bioenergetics. Mol Psychiatry 2022; 27:2393-2404. [PMID: 35264726 DOI: 10.1038/s41380-022-01494-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
Abstract
A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.
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Affiliation(s)
- Nicholas D Henkel
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
| | - Xiajoun Wu
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Sinead M O'Donovan
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Emily A Devine
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jessica M Jiron
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Laura M Rowland
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Zoltan Sarnyai
- Laboratory of Psychiatric Neuroscience, Australian Institute for Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia
| | - Amy J Ramsey
- Department of Pharmacology and Toxicology, Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Zhexing Wen
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Margaret K Hahn
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Robert E McCullumsmith
- Department of Neurosciences, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
- Neurosciences Institute, ProMedica, Toledo, OH, USA
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19
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Kullmann S, Hummel J, Wagner R, Dannecker C, Vosseler A, Fritsche L, Veit R, Kantartzis K, Machann J, Birkenfeld AL, Stefan N, Häring HU, Peter A, Preissl H, Fritsche A, Heni M. Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial. Diabetes Care 2022; 45:398-406. [PMID: 34716213 PMCID: PMC8914418 DOI: 10.2337/dc21-1136] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/20/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.
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Affiliation(s)
- Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Julia Hummel
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Robert Wagner
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Corinna Dannecker
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Andreas Vosseler
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Ralf Veit
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Konstantinos Kantartzis
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Department of Diagnostic and Interventional Radiology, Section of Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.,Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Interfaculty Center for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany.,Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
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20
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Stahel P, Xiao C, Nahmias A, Tian L, Lewis GF. Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks. Endocr Rev 2021; 42:815-838. [PMID: 33743013 PMCID: PMC8599201 DOI: 10.1210/endrev/bnab008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Indexed: 12/15/2022]
Abstract
Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease. Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut [glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), ghrelin, cholecystokinin (CCK), peptide YY], adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks. In addition, the gut microbiome and bile acids influence lipoprotein secretion in humans and animal models. Several nutritional factors modulate hepatic lipoprotein secretion through effects on the central nervous system. Vagal afferent signaling from the gut to the brain and efferent signals from the brain to the liver and gut are modulated by hormonal and nutritional factors to influence TRL secretion. Some of these factors have been extensively studied and shown to have robust regulatory effects whereas others are "emerging" regulators, whose significance remains to be determined. The quantitative importance of these factors relative to one another and relative to the key regulatory role of lipid availability remains largely unknown. Our understanding of the complex interorgan regulation of TRL secretion is rapidly evolving to appreciate the extensive hormonal, nutritional, and neural signals emanating not only from gut and liver but also from the brain, pancreas, and adipose tissue.
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Affiliation(s)
- Priska Stahel
- Division of Endocrinology and Metabolism, Departments of Medicine and Physiology, Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Changting Xiao
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Avital Nahmias
- Division of Endocrinology and Metabolism, Departments of Medicine and Physiology, Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Lili Tian
- Division of Endocrinology and Metabolism, Departments of Medicine and Physiology, Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Gary Franklin Lewis
- Division of Endocrinology and Metabolism, Departments of Medicine and Physiology, Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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21
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Kullmann S, Blum D, Jaghutriz BA, Gassenmaier C, Bender B, Häring HU, Reischl G, Preissl H, la Fougère C, Fritsche A, Reimold M, Heni M. Central Insulin Modulates Dopamine Signaling in the Human Striatum. J Clin Endocrinol Metab 2021; 106:2949-2961. [PMID: 34131733 DOI: 10.1210/clinem/dgab410] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. RESEARCH DESIGN AND METHODS We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial. RESULTS In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin. CONCLUSIONS This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.
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Affiliation(s)
- Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Dominik Blum
- Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Benjamin Assad Jaghutriz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Christoph Gassenmaier
- Department of Internal Medicine, Division of Hematology, Oncology, Clinical Immunology and Rheumatology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Benjamin Bender
- Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Gerald Reischl
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Christian la Fougère
- Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard-Karls-University Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Matthias Reimold
- Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard-Karls-University Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany
- German Center for Diabetes Research (DZD), Tübingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
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22
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Zhang SY, Li RJW, Lim YM, Batchuluun B, Liu H, Waise TMZ, Lam TKT. FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats. Gut 2021; 70:1675-1683. [PMID: 33087489 DOI: 10.1136/gutjnl-2020-321757] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown. DESIGN We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel. RESULTS We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance. CONCLUSION Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.
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Affiliation(s)
- Song-Yang Zhang
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada
| | - Rosa J W Li
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.,Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Yu-Mi Lim
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.,Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | | | - Huiying Liu
- Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - T M Zaved Waise
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada .,Physiology, University of Toronto, Toronto, Ontario, Canada.,Medicine, University of Toronto, Toronto, Ontario, Canada.,Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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23
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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24
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Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1. Sci Rep 2021; 11:15490. [PMID: 34326413 PMCID: PMC8322102 DOI: 10.1038/s41598-021-94849-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.
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25
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Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab 2021; 321:E156-E163. [PMID: 34056920 PMCID: PMC8321819 DOI: 10.1152/ajpendo.00642.2020] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.
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Affiliation(s)
- Rahul Agrawal
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Candace M Reno
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Sunny Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Camille Christensen
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Yiqing Huang
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Simon J Fisher
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah
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26
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Edgerton DS, Moore MC, Gregory JM, Kraft G, Cherrington AD. Importance of the route of insulin delivery to its control of glucose metabolism. Am J Physiol Endocrinol Metab 2021; 320:E891-E897. [PMID: 33813879 PMCID: PMC8238128 DOI: 10.1152/ajpendo.00628.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic insulin secretion produces an insulin gradient at the liver compared with the rest of the body (approximately 3:1). This physiological distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiological conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.
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Affiliation(s)
- Dale S Edgerton
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Mary C Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Justin M Gregory
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Guillaume Kraft
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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27
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Li RJW, Batchuluun B, Zhang SY, Abraham MA, Wang B, Lim YM, Yue JTY, Lam TKT. Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats. iScience 2021; 24:102366. [PMID: 33870148 PMCID: PMC8044434 DOI: 10.1016/j.isci.2021.102366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/08/2021] [Accepted: 03/24/2021] [Indexed: 11/22/2022] Open
Abstract
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.
DVC oleic acid infusion lowers hepatic secretion of VLDL-TG in chow but not HF rats Inhibition of ACSL in the DVC negates lipid sensing DVC glucose infusion lowers hepatic glucose production in chow but not HF rats Inhibition of FXR in the DVC enhances oleic acid but not glucose sensing in HF rats
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Affiliation(s)
- Rosa J W Li
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.,Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada
| | - Battsetseg Batchuluun
- Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada
| | - Mona A Abraham
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.,Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada
| | - Beini Wang
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.,Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada
| | - Yu-Mi Lim
- Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada.,Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Jessica T Y Yue
- Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Tony K T Lam
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.,Toronto General Hospital Research Institute, UHN, MaRS Center, TMDT 101 College Street, 10-705, Toronto, ON M5G 1L7, Canada.,Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.,Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada
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28
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Lewis GF, Carpentier AC, Pereira S, Hahn M, Giacca A. Direct and indirect control of hepatic glucose production by insulin. Cell Metab 2021; 33:709-720. [PMID: 33765416 DOI: 10.1016/j.cmet.2021.03.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/23/2021] [Accepted: 03/05/2021] [Indexed: 01/08/2023]
Abstract
There is general agreement that the acute suppression of hepatic glucose production by insulin is mediated by both a direct and an indirect effect on the liver. There is, however, no consensus regarding the relative magnitude of these effects under physiological conditions. Extensive research over the past three decades in humans and animal models has provided discordant results between these two modes of insulin action. Here, we review the field to make the case that physiologically direct hepatic insulin action dominates acute suppression of glucose production, but that there is also a delayed, second order regulation of this process via extrahepatic effects. We further provide our views regarding the timing, dominance, and physiological relevance of these effects and discuss novel concepts regarding insulin regulation of adipose tissue fatty acid metabolism and central nervous system (CNS) signaling to the liver, as regulators of insulin's extrahepatic effects on glucose production.
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Affiliation(s)
- Gary F Lewis
- Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
| | - Andre C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sandra Pereira
- Centre for Addiction and Mental Health and Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Margaret Hahn
- Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Adria Giacca
- Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
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29
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Abstract
The intranasal (IN) route enables the delivery of insulin to the central nervous system in the relative absence of systemic uptake and related peripheral side effects. Intranasally administered insulin is assumed to travel along olfactory and adjacent pathways and has been shown to rapidly accumulate in cerebrospinal fluid, indicating efficient transport to the brain. Two decades of studies in healthy humans and patients have demonstrated that IN insulin exerts functional effects on metabolism, such as reductions in food intake and body weight and improvements of glucose homeostasis, as well as cognition, ie, enhancements of memory performance both in healthy individuals and patients with mild cognitive impairment or Alzheimer's disease; these studies moreover indicate a favourable safety profile of the acute and repeated use of IN insulin. Emerging findings suggest that IN insulin also modulates neuroendocrine activity, sleep-related mechanisms, sensory perception and mood. Some, but not all studies point to sex differences in the response to IN insulin that need to be further investigated along with the impact of age. "Brain insulin resistance" is an evolving concept that posits impairments in central nervous insulin signalling as a pathophysiological factor in metabolic and cognitive disorders such as obesity, type 2 diabetes and Alzheimer's disease, and, notably, a target of interventions that rely on IN insulin. Still, the negative outcomes of longer-term IN insulin trials in individuals with obesity or Alzheimer's disease highlight the need for conceptual as well as methodological advances to translate the promising results of proof-of-concept experiments and pilot clinical trials into the successful clinical application of IN insulin.
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Affiliation(s)
- Manfred Hallschmid
- Institute of Medical Psychology and Behavioural Neurobiology, University of Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
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Fujikawa T. Central regulation of glucose metabolism in an insulin-dependent and -independent manner. J Neuroendocrinol 2021; 33:e12941. [PMID: 33599044 DOI: 10.1111/jne.12941] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/17/2022]
Abstract
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.
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Affiliation(s)
- Teppei Fujikawa
- Center for Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
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Ladyman SR, Brooks VL. Central actions of insulin during pregnancy and lactation. J Neuroendocrinol 2021; 33:e12946. [PMID: 33710714 PMCID: PMC9198112 DOI: 10.1111/jne.12946] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/24/2021] [Accepted: 01/27/2021] [Indexed: 12/17/2022]
Abstract
Pregnancy and lactation are highly metabolically demanding states. Maternal glucose is a key fuel source for the growth and development of the fetus, as well as for the production of milk during lactation. Hence, the maternal body undergoes major adaptations in the systems regulating glucose homeostasis to cope with the increased demand for glucose. As part of these changes, insulin levels are elevated during pregnancy and lower in lactation. The increased insulin secretion during pregnancy plays a vital role in the periphery; however, the potential effects of increased insulin action in the brain have not been widely investigated. In this review, we consider the impact of pregnancy on brain access and brain levels of insulin. Moreover, we explore the hypothesis that pregnancy is associated with site-specific central insulin resistance that is adaptive, allowing for the increases in peripheral insulin secretion without the consequences of increased central and peripheral insulin functions, such as to stimulate glucose uptake into maternal tissues or to inhibit food intake. Conversely, the loss of central insulin actions may impair other functions, such as insulin control of the autonomic nervous system. The potential role of low insulin in facilitating adaptive responses to lactation, such as hyperphagia and suppression of reproductive function, are also discussed. We end the review with a list of key research questions requiring resolution.
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Affiliation(s)
- Sharon R Ladyman
- Centre for Neuroendocrinology and Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Virginia L Brooks
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, USA
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Torabi N, Noursadeghi E, Shayanfar F, Nazari M, Fahanik-Babaei J, Saghiri R, Khodagholi F, Eliassi A. Intranasal insulin improves the structure-function of the brain mitochondrial ATP-sensitive Ca 2+ activated potassium channel and respiratory chain activities under diabetic conditions. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166075. [PMID: 33444710 DOI: 10.1016/j.bbadis.2021.166075] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/06/2020] [Accepted: 12/30/2020] [Indexed: 11/21/2022]
Abstract
Although it is well established that diabetes impairs mitochondrial respiratory chain activity, little is known of the effects of intranasal insulin (INI) on the mitochondrial respiratory chain and structure-function of mitoBKCa channel in diabetes. We have investigated this mechanism in an STZ-induced early type 2 diabetic model. Single ATP-sensitive mitoBKCa channel activity was considered in diabetic and INI-treated rats using a channel incorporated into the bilayer lipid membrane. Because mitoBKCa channels have been involved in mitochondrial respiratory chain activity, a study was undertaken to investigate whether the NADH, complexes I and IV, mitochondrial ROS production, and ΔΨm are altered in an early diabetic model. In this work, we provide evidence for a significant decrease in channel open probability and conductance in diabetic rats. Evidence has been shown that BKCa channel β2 subunits induce a left shift in the BKCa channel voltage dependent curve in low Ca2+ conditions,; our results indicated a significant decrease in mitoBKCa β2 subunits using Western blot analysis. Importantly, INI treatment improved mitoBKCa channel behaviors and β2 subunits expression up to ~70%. We found that early diabetes decreased activities of complex I and IV and increased NADH, ROS production, and ΔΨm. Surprisingly, INI modified the mitochondrial respiratory chain, ROS production, and ΔΨm up to ~70%. Our results thus demonstrate an INI improvement in respiratory chain activity and ROS production in brain mitochondrial preparations coming from the STZ early diabetic rat model, an effect potentially linked to INI improvement in mitoBKCa channel activity and channel β2 subunit expression.
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Affiliation(s)
- Nihad Torabi
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Noursadeghi
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Shayanfar
- Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Nazari
- Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Fahanik-Babaei
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Saghiri
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Evin, Tehran, Iran
| | - Afsaneh Eliassi
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abstract
Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.
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Affiliation(s)
- Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada
- Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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Frazier HN, Ghoweri AO, Sudkamp E, Johnson ES, Anderson KL, Fox G, Vatthanaphone K, Xia M, Lin RL, Hargis-Staggs KE, Porter NM, Pauly JR, Blalock EM, Thibault O. Long-Term Intranasal Insulin Aspart: A Profile of Gene Expression, Memory, and Insulin Receptors in Aged F344 Rats. J Gerontol A Biol Sci Med Sci 2021; 75:1021-1030. [PMID: 31180116 DOI: 10.1093/gerona/glz105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin's efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.
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Affiliation(s)
| | | | - Emily Sudkamp
- The College of Pharmacy, University of Kentucky, Lexington, Kentucky
| | | | | | - Grant Fox
- Department of Pharmacology and Nutritional Sciences
| | | | - Mengfan Xia
- Department of Pharmacology and Nutritional Sciences
| | | | | | | | - James R Pauly
- The College of Pharmacy, University of Kentucky, Lexington, Kentucky
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Patel B, New LE, Griffiths JC, Deuchars J, Filippi BM. Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain. Mol Metab 2020; 43:101123. [PMID: 33227495 PMCID: PMC7753200 DOI: 10.1016/j.molmet.2020.101123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES The dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour and body weight. Three-days of high-fat diet (HFD) in rats are sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. We investigated the effects that altered Drp1 activity in the DVC has on feeding behaviour. Additionally, we aimed to uncover the molecular events and the neuronal cell populations associated with DVC insulin sensing and resistance. METHODS Eight-week-old male Sprague Dawley rats received DVC stereotactic surgery for brain infusion to facilitate the localised administration of insulin or viruses to express mutated forms of Drp1 or to knockdown inducible nitric oxide synthase (iNOS) in the NTS of the DVC. High-Fat diet feeding was used to cause insulin resistance and obesity. RESULTS We showed that Drp1 activation in the DVC increases weight gain in rats and Drp1 inhibition in HFD-fed rats reduced food intake, weight gain and adipose tissue. Rats expressing active Drp1 in the DVC had higher levels of iNOS and knockdown of DVC iNOS in HFD-fed rats led to a reduction of food intake, weight gain and adipose tissue. Finally, inhibiting mitochondrial fission in DVC astrocytes was sufficient to protect rats from HFD-dependent insulin resistance, hyperphagia, weight gain and fat deposition. CONCLUSION We uncovered new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.
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Affiliation(s)
- Bianca Patel
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom
| | - Lauryn E New
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom
| | - Joanne C Griffiths
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom
| | - Jim Deuchars
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom
| | - Beatrice M Filippi
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom.
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Kullmann S, Kleinridders A, Small DM, Fritsche A, Häring HU, Preissl H, Heni M. Central nervous pathways of insulin action in the control of metabolism and food intake. Lancet Diabetes Endocrinol 2020; 8:524-534. [PMID: 32445739 DOI: 10.1016/s2213-8587(20)30113-3] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 01/22/2020] [Accepted: 03/20/2020] [Indexed: 12/18/2022]
Abstract
Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.
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Affiliation(s)
- Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, and Nephrology, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
| | - André Kleinridders
- German Center for Diabetes Research, Neuherberg, Germany; Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Dana M Small
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Psychiatry, Yale University, New Haven, CT, USA; Modern Diet and Physiology Research Centre, Yale University, New Haven, CT, USA
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, and Nephrology, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, and Nephrology, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Pharmacy and Biochemistry, Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, and Nephrology, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
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Carey M, Lontchi-Yimagou E, Mitchell W, Reda S, Zhang K, Kehlenbrink S, Koppaka S, Maginley SR, Aleksic S, Bhansali S, Huffman DM, Hawkins M. Central K ATP Channels Modulate Glucose Effectiveness in Humans and Rodents. Diabetes 2020; 69:1140-1148. [PMID: 32217610 PMCID: PMC7243288 DOI: 10.2337/db19-1256] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 03/20/2020] [Indexed: 12/23/2022]
Abstract
Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.
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Affiliation(s)
- Michelle Carey
- Albert Einstein College of Medicine, Bronx, NY
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
| | | | | | - Sarah Reda
- Albert Einstein College of Medicine, Bronx, NY
| | - Kehao Zhang
- Albert Einstein College of Medicine, Bronx, NY
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Interaction of glucose sensing and leptin action in the brain. Mol Metab 2020; 39:101011. [PMID: 32416314 PMCID: PMC7267726 DOI: 10.1016/j.molmet.2020.101011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/27/2020] [Accepted: 05/05/2020] [Indexed: 01/10/2023] Open
Abstract
Background In response to energy abundant or deprived conditions, nutrients and hormones activate hypothalamic pathways to maintain energy and glucose homeostasis. The underlying CNS mechanisms, however, remain elusive in rodents and humans. Scope of review Here, we first discuss brain glucose sensing mechanisms in the presence of a rise or fall of plasma glucose levels, and highlight defects in hypothalamic glucose sensing disrupt in vivo glucose homeostasis in high-fat fed, obese, and/or diabetic conditions. Second, we discuss brain leptin signalling pathways that impact glucose homeostasis in glucose-deprived and excessed conditions, and propose that leptin enhances hypothalamic glucose sensing and restores glucose homeostasis in short-term high-fat fed and/or uncontrolled diabetic conditions. Major conclusions In conclusion, we believe basic studies that investigate the interaction of glucose sensing and leptin action in the brain will address the translational impact of hypothalamic glucose sensing in diabetes and obesity.
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Brain insulin sensitivity is linked to adiposity and body fat distribution. Nat Commun 2020; 11:1841. [PMID: 32296068 PMCID: PMC7160151 DOI: 10.1038/s41467-020-15686-y] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 03/23/2020] [Indexed: 01/09/2023] Open
Abstract
Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance. Brain insulin action regulates eating behavior and whole-body energy fluxes, however the impact of brain insulin resistance on long-term weight and body fat composition is unknown. Here, the authors show that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution.
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Mulyani WRW, Sanjiwani MID, Sandra, Prabawa IPY, Lestari AAW, Wihandani DM, Suastika K, Saraswati MR, Bhargah A, Manuaba IBAP. Chaperone-Based Therapeutic Target Innovation: Heat Shock Protein 70 (HSP70) for Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2020; 13:559-568. [PMID: 32161482 PMCID: PMC7051252 DOI: 10.2147/dmso.s232133] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 12/06/2019] [Indexed: 12/24/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is still a global health problem. Current T2DM treatments are limited to curing the symptoms and have not been able to restore insulin sensitivity in insulin-sensitive tissues that have become resistant. In the past decade, some studies have shown the significant role of a chaperone family, heat shock protein 70 (HSP70), in insulin resistance pathogenesis that leads to T2DM. HSP70 is a cytoprotective molecular chaperone that functions in protein folding and degradation. In general, studies have shown that decreased concentration of HSP70 is able to induce inflammation process through JNK activation, inhibit fatty acid oxidation by mitochondria through mitophagy decrease and mitochondrial biogenesis, as well as activate SREBP-1c, one of the lipogenic gene transcription factors in ER stress. The overall molecular pathways are potentially leading to insulin resistance and T2DM. Increased expression of HSP70 in brain tissues is able to improve insulin sensitivity and glycemic control specifically. HSP70 modulation-targeting strategies (including long-term physical exercise, hot tub therapy (HTT), and administration of alfalfa-derived HSP70 (aHSP70)) in subjects with insulin resistance are proven to have therapeutic and preventive potency that are promising in T2DM management.
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Affiliation(s)
| | | | - Sandra
- Faculty of Medicine, Universitas Udayana, Bali, Indonesia
| | - I Putu Yuda Prabawa
- Department of Clinical Pathology, Faculty of Medicine, Universitas Udayana, Sanglah General Hospital, Bali, Indonesia
| | - Anak Agung Wiradewi Lestari
- Department of Clinical Pathology, Faculty of Medicine, Universitas Udayana, Sanglah General Hospital, Bali, Indonesia
| | - Desak Made Wihandani
- Department of Biochemistry, Faculty of Medicine, Universitas Udayana, Bali, Indonesia
| | - Ketut Suastika
- Department of Internal Medicine, Faculty of Medicine, Universitas Udayana, Sanglah General Hospital, Bali, Indonesia
| | - Made Ratna Saraswati
- Department of Internal Medicine, Faculty of Medicine, Universitas Udayana, Sanglah General Hospital, Bali, Indonesia
| | - Agha Bhargah
- Faculty of Medicine, Universitas Udayana, Bali, Indonesia.,Cardiology Department, Faculty of Medicine, Universitas Udayana-Sanglah General Hospital, Bali, Indonesia
| | - Ida Bagus Amertha Putra Manuaba
- International Ph.D Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Medical and Health Education Unit, Faculty of Medicine, Universitas Udayana, Bali, Indonesia
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Shpakov AO, Derkach KV, Surkova EV, Bespalov AI. [Perspectives of application of intranasally administered insulin for correction of metabolic and hormonal disorders in diabetes mellitus and metabolic syndrome]. ACTA ACUST UNITED AC 2019; 65:389-395. [PMID: 32202743 DOI: 10.14341/probl9960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 11/08/2018] [Indexed: 11/06/2022]
Abstract
In recent years, the possibility of using intranasally administered insulin to treat Alzheimers disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.
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Affiliation(s)
- A O Shpakov
- Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences
| | - K V Derkach
- Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences
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Li N, Yan QT, Jing Q, Pan RY, Wang HJ, Jiang B, Li XJ, Wang Y, Dong JH, Wang XJ, Zhang MJ, Meng QG, Li XZ, Liu ZJ, Gao ZQ, Qu MH. Duodenal-Jejunal Bypass Ameliorates Type 2 Diabetes Mellitus by Activating Insulin Signaling and Improving Glucose Utilization in the Brain. Obes Surg 2019; 30:279-289. [DOI: 10.1007/s11695-019-04153-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Microbiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model. Sci Rep 2019; 9:12609. [PMID: 31471539 PMCID: PMC6717200 DOI: 10.1038/s41598-019-48090-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 07/18/2019] [Indexed: 12/26/2022] Open
Abstract
An elevated number of women of reproductive age are overweight, predisposing their offspring to metabolic and neuropsychiatric disorders. Gut microbiota is influenced by maternal factors, and has been implicated in the pathogenesis of neurodegenerative diseases. Our aim was to explore the effects of maternal high-fat feeding on the relationship linking gut microbiota and cognitive development in the offspring. Murine offspring born to dams undergoing normal diet (NDm) and high-fat diet (HFDm) were studied at 1 or 6 months of age to assess cognitive function by Y-maze test, cerebral glucose metabolism and insulin sensitivity by Positron Emission Tomography, brain density by Computed Tomography, microbiota profile (colon, caecum) and inferred metabolic pathways (KEGG analysis) by 16S ribosomal RNA sequencing. From 3 weeks post-weaning, mice born to HFDm developed hyperphagia and overweight, showing reduction in memory and exploratory behaviour, and brain insulin resistance in adulthood. We identified a panel of bacteria characterizing offspring born to HFD dams from early life, and correlating with dysfunction in memory and exploratory behaviour in adults (including Proteobacteria phylum, Parabacteroides and unclassified Rikenellaceae genera). Microbiota-derived metabolic pathways involved in fatty acid, essential aminoacid and vitamin processing, sulphur metabolism, glutaminergic activation and Alzheimer’s disease were differently present in the HFDm and NDm offspring groups. Our results document tight relationships between gut dysbiosis and memory and behavioural impairment in relation to maternal HFD. Persistent bacterial signatures induced by maternal HFD during infancy can influence cognition during adulthood, opening the possibility of microbiota-targeted strategies to contrast cognitive decline.
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Semisynthetic bile acids: a new therapeutic option for metabolic syndrome. Pharmacol Res 2019; 146:104333. [PMID: 31254667 DOI: 10.1016/j.phrs.2019.104333] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 05/14/2019] [Accepted: 06/25/2019] [Indexed: 12/11/2022]
Abstract
Bile acids are endogenous emulsifiers synthesized from cholesterol having a peculiar amphiphilic structure. Appreciation of their beneficial effects on human health, recognized since ancient times, has expanded enormously since the discovery of their role as signaling molecules. Activation of farnesoid X receptor (FXR) and Takeda G-protein receptor-5 (TGR5) signaling pathways by bile acids, regulating glucose, lipid and energy metabolism, have become attractive avenue for metabolic syndrome treatment. Therefore, extensive effort has been directed into the research and synthesis of bile acid derivatives with improved pharmacokinetic properties and high potency and selectivity for these receptors. Minor modifications in the structure of bile acids and their derivatives may result in fine-tuning modulation of their biological functions, and most importantly, in an evasion of undesired effect. A great number of semisynthetic bile acid analogues have been designed and put in preclinical and clinical settings. Obeticholic acid (INT-747) has achieved the biggest clinical success so far being in use for the treatment of primary biliary cholangitis. This review summarizes and critically evaluates the key chemical modifications of bile acids resulting in development of novel semisynthetic derivatives as well as the current status of their preclinical and clinical evaluation in the treatment of metabolic syndrome, an aspect that is so far lacking in the scientific literature. Taking into account the balance between therapeutic benefits and potential adverse effects associated with specific structure and mechanism of action, recommendations for future studies are proposed.
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Stahel P, Lee SJ, Sud SK, Floh A, Dash S. Intranasal glucagon acutely increases energy expenditure without inducing hyperglycaemia in overweight/obese adults. Diabetes Obes Metab 2019; 21:1357-1364. [PMID: 30740846 DOI: 10.1111/dom.13661] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIM To assess the acute effects of 0.7 mg intranasal glucagon (ING) vs intranasal placebo (INP) on food intake and resting energy expenditure (REE). METHODS A single-blind, crossover study was conducted in 19 overweight/obese adults (15 men, 4 women). REE was assessed by indirect calorimetry over 90 minutes, after which appetite was assessed using a visual analogue scale, and ad libitum caloric intake was assessed. Plasma samples were obtained at baseline and at 15-minute intervals post-treatment up to 90 minutes. RESULTS ING increased total REE (INP 61.5 ± 1.2 kcal vs ING 69.4 ± 1.2 kcal; P = 0.027). There were no between-treatment differences in blood glucose, food intake and appetite. There were no adverse effects. CONCLUSION ING acutely increases REE without increasing plasma glucose. Longer term studies with multiple daily dosing will establish whether this affects body weight.
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Affiliation(s)
- Priska Stahel
- Departments of Medicine and Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - So Jeong Lee
- Departments of Medicine and Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Shawn K Sud
- Departments of Medicine and Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Alejandro Floh
- Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Satya Dash
- Departments of Medicine and Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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Agarwal SM, Kowalchuk C, Castellani L, Costa-Dookhan KA, Caravaggio F, Asgariroozbehani R, Chintoh A, Graff-Guerrero A, Hahn M. Brain insulin action: Implications for the treatment of schizophrenia. Neuropharmacology 2019; 168:107655. [PMID: 31152767 DOI: 10.1016/j.neuropharm.2019.05.032] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/22/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022]
Abstract
Insulin action in the central nervous system is a major regulator of energy balance and cognitive processes. The development of central insulin resistance is associated with alterations in dopaminergic reward systems and homeostatic signals affecting food intake, glucose metabolism, body weight and cognitive performance. Emerging evidence has highlighted a role for antipsychotics (APs) to modulate central insulin-mediated pathways. Although APs remain the cornerstone treatment for schizophrenia they are associated with severe metabolic complications and fail to address premorbid cognitive deficits, which characterize the disorder of schizophrenia. In this review, we first explore how the hypothesized association between schizophrenia and CNS insulin dysregulation aligns with the use of APs. We then investigate the proposed relationship between CNS insulin action and AP-mediated effects on metabolic homeostasis, and different domains of psychopathology, including cognition. We briefly discuss a potential role of CNS insulin signaling to explain the hypothesized, but somewhat controversial association between therapeutic efficacy and metabolic side effects of APs. Finally, we propose how this knowledge might inform novel treatment strategies to target difficult to treat domains of schizophrenia. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
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Affiliation(s)
- Sri Mahavir Agarwal
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Chantel Kowalchuk
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Kenya A Costa-Dookhan
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Fernando Caravaggio
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | | | - Araba Chintoh
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Ariel Graff-Guerrero
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Margaret Hahn
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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Edwin Thanarajah S, Hoffstall V, Rigoux L, Hanssen R, Brüning JC, Tittgemeyer M. The role of insulin sensitivity and intranasally applied insulin on olfactory perception. Sci Rep 2019; 9:7222. [PMID: 31076634 PMCID: PMC6510903 DOI: 10.1038/s41598-019-43693-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 04/30/2019] [Indexed: 01/24/2023] Open
Abstract
Olfactory perception determines food selection behavior depending on energy homeostasis and nutritional status. The mechanisms, however, by which metabolic signals in turn regulate olfactory perception remain largely unclear. Given the evidence for direct insulin action on olfactory neurons, we tested olfactory performance (olfactory threshold, olfactory discrimination) in 36 subjects of normal- and overweight after administration of three different insulin doses (40 I.U., 100 I.U., 160 I.U.) or corresponding placebo volume in a within-subject design. Poor peripheral insulin sensitivity as quantified by HOMA-IR in baseline condition and increases in systemic insulin levels reactive to intranasal administration predicted poor olfactory performance. In contrast, intranasal insulin enhanced odor perception with a dose-dependent improvement of olfactory threshold. These findings indicate a new diametric impact of insulin on olfactory perception depending on peripheral or central availability.
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Affiliation(s)
- Sharmili Edwin Thanarajah
- Max-Planck-Institute for Metabolism Research, Cologne, Germany.
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany.
| | - Vera Hoffstall
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
| | - Lionel Rigoux
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
| | - Ruth Hanssen
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
- Center for Endocrinology, Diabetes and Preventive Medicine (CEPD), University Hospital of Cologne, Cologne, Germany
| | - Jens C Brüning
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
- Cologne Cluster of Excellence in Cellular Stress and Aging associated Disease (CECAD), Cologne, Germany
- Center for Endocrinology, Diabetes and Preventive Medicine (CEPD), University Hospital of Cologne, Cologne, Germany
| | - Marc Tittgemeyer
- Max-Planck-Institute for Metabolism Research, Cologne, Germany
- Cologne Cluster of Excellence in Cellular Stress and Aging associated Disease (CECAD), Cologne, Germany
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Agarwal SM, Caravaggio F, Costa-Dookhan KA, Castellani L, Kowalchuk C, Asgariroozbehani R, Graff-Guerrero A, Hahn M. Brain insulin action in schizophrenia: Something borrowed and something new. Neuropharmacology 2019; 163:107633. [PMID: 31077731 DOI: 10.1016/j.neuropharm.2019.05.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/15/2019] [Accepted: 05/07/2019] [Indexed: 12/24/2022]
Abstract
Insulin signaling in the central nervous system is at the intersection of brain and body interactions, and represents a fundamental link between metabolic and cognitive disorders. Abnormalities in brain insulin action could underlie the development of comorbid schizophrenia and type 2 diabetes. Among its functions, central nervous system insulin is involved in regulation of striatal dopamine levels, peripheral glucose homeostasis, and feeding regulation. In this review, we discuss the role and importance of central nervous system insulin in schizophrenia and diabetes pathogenesis from a historical and mechanistic perspective. We describe central nervous system insulin sites and pathways of action, with special emphasis on glucose metabolism, cognitive functioning, inflammation, and food preferences. Finally, we suggest possible mechanisms that may explain the actions of central nervous system insulin in relation to schizophrenia and diabetes, focusing on glutamate and dopamine signaling, intracellular signal transduction pathways, and brain energetics. Understanding the interplay between central nervous system insulin and schizophrenia is essential to disentangling this comorbid relationship and may provide novel treatment approaches for both neuropsychiatric and metabolic dysfunction. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
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Affiliation(s)
- Sri Mahavir Agarwal
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Fernando Caravaggio
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Kenya A Costa-Dookhan
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Chantel Kowalchuk
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Ariel Graff-Guerrero
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Margaret Hahn
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada.
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Lundqvist MH, Almby K, Abrahamsson N, Eriksson JW. Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes? Front Physiol 2019; 10:457. [PMID: 31133864 PMCID: PMC6524713 DOI: 10.3389/fphys.2019.00457] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/01/2019] [Indexed: 01/08/2023] Open
Abstract
Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.
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Affiliation(s)
| | - Kristina Almby
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Plomgaard P, Hansen JS, Ingerslev B, Clemmesen JO, Secher NH, van Hall G, Fritsche A, Weigert C, Lehmann R, Häring HU, Heni M. Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels. Diabetes Obes Metab 2019; 21:993-1000. [PMID: 30552787 DOI: 10.1111/dom.13615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/11/2018] [Accepted: 12/13/2018] [Indexed: 12/27/2022]
Abstract
AIMS To evaluate the effects of brain insulin on endogenous glucose production in fasting humans, with a focus on hepatic glucose release by performing a randomized, placebo-controlled, blinded, crossover experiment. MATERIALS AND METHODS On two separate days, 2 H2 -glucose was infused to nine healthy lean men, and blood was sampled from the hepatic vein and a radial artery. On day 1, participants received 160 U human insulin through nasal spray, and on day 2 they received placebo spray, together with an intravenous insulin bolus to mimic spillover of nasal insulin to the circulation. Hepatic glucose fluxes and endogenous glucose production were calculated. RESULTS Plasma insulin concentrations were similar on the two study days, and no differences in whole-body endogenous glucose production or hepato-splanchnic glucose turnover were detected. CONCLUSIONS Nasal administration of insulin does not influence whole-body or hepatic glucose production in fasting humans. By contrast, pharmacological delivery of insulin to the brain might modulate insulin effectiveness in glucose-producing tissue when circulating insulin levels are elevated; therefore, the metabolic consequences of brain insulin action appear to be dependent on metabolic prandial status.
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Affiliation(s)
- Peter Plomgaard
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Jakob S Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Bodil Ingerslev
- Centre of Inflammation and Metabolism, and the Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens O Clemmesen
- Department of Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Niels H Secher
- Department of Anaesthesiology, Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Cora Weigert
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Rainer Lehmann
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases, Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany
- German Centre for Diabetes Research (DZD), Neuherberg, Germany
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