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Review

The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain

Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(11), 2493; https://doi.org/10.3390/ijms18112493
Submission received: 30 October 2017 / Revised: 17 November 2017 / Accepted: 20 November 2017 / Published: 22 November 2017
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

Abstract

:
Alzheimer’s disease (AD), characterized by the aggregation of amyloid-β (Aβ) protein and neuroinflammation, is the most common neurodegenerative disease globally. Previous studies have reported that some AD patients show impaired glucose utilization in brain, leading to cognitive decline. Recently, diabetes-induced dementia has been called “type 3 diabetes”, based on features in common with those of type 2 diabetes and the progression of AD. Impaired glucose uptake and insulin resistance in the brain are important issues in type 3 diabetes, because these problems ultimately aggravate memory dysfunction in the brain. Glucagon-like peptide 1 (GLP-1) has been known to act as a critical controller of the glucose metabolism. Several studies have demonstrated that GLP-1 alleviates learning and memory dysfunction by enhancing the regulation of glucose in the AD brain. However, the specific actions of GLP-1 in the AD brain are not fully understood. Here, we review evidences related to the role of GLP-1 in type 3 diabetes.

1. Introduction

Alzheimer’s disease (AD) as an age-related neurodegenerative disorder is not well understood in terms of etiology, even though it was first described over 100 years ago [1]. AD is characterized by extracellular accumulation of aggregated amyloid-β (Aβ) protein, intracellular accumulation of hyper-phosphorylated tau protein, neuroinflammation, and a reduction in cerebral glucose consumption [2]. Recent studies have demonstrated that AD has a pathophysiological relationship with type 2 diabetes mellitus (T2DM), in that both involve impairment of insulin signaling and glucose metabolism [3]. Epidemiological studies have indicated that T2DM increases the risk of AD [4,5]. The brain has been known to regulate body energy and control food intake and body weight [6,7]. Additionally, the brain consumes glucose at a high rate, and uses it for propagation of action potentials and maintenance of the membrane potentials required for neuronal transmission [8,9]. AD patients show decreased glucose utilization in brain areas that are directly related to cognitive functions, including the hippocampus and cerebral cortex [10]. According to several studies, the deregulation of glucose metabolism in AD can be controlled by the administration of a hormone known as a potent regulator of glucose homeostasis [11] and of food intake [12], glucagon-like peptide 1 (GLP-1) [13]. The fact that administration of this peptide improves cognitive decline in patients with AD, as well as in AD mouse model [14,15] suggests that deregulation of glucose in the brain is a crucial issue in the onset and progression of AD [4,5,16,17,18]. Here, we review recent evidence concerning the role of GLP-1 in diabetes-induced dementia. We highlight the importance of GLP-1 in the onset and progression of diabetic AD, sometimes referred to as type 3 diabetes.

2. Diabetes Induced Dementia as the Type 3 Diabetes

Recent studies have demonstrated that patients with T2DM and metabolic syndrome have elevated risk for vascular dementia and AD [19,20]. Other studies have reported aberrant cerebral insulin homeostasis, which is called insulin resistance, in AD patients [21,22]. In the CNS, insulin is synthesized in neurons such as pyramidal and granule cells in the cerebral cortex and hippocampus [23,24]. Pancreatic insulin transported in small amounts across the blood–brain barrier (BBB) could also influence brain function [25,26]. Insulin growth factor-1 (IGF-1) and its receptor (IGF-1R) can be observed in the brain and have been related to the control of neurogenesis and synaptogenesis [27,28]. Deregulation of brain insulin signaling and IGF-1 signaling affects insulin resistance, energy metabolism, and lipid metabolism and results in pathological changes in the central nervous system (CNS) [29,30,31,32]. According to several studies, insulin and IGF-1 resistance can be detected in the brains of AD patients [29], but the relationship between insulin resistance and brain dysfunction remains unclear [33]. Recently, the relationship between brain insulin/IGF-1 signaling impairment and AD has been dubbed type 3 diabetes [34]. Further study of the mechanisms involved in the onset and progression of type 3 diabetes is necessary to improve our understanding of its pathology type 3 diabetes.

3. Glucagon-Like Peptide 1 (GLP1)

GLP-1 is an endogenous incretin hormone of 30-amino acids, produced by enteroendocrine L-cells, that influences food ingestion [35,36], enhances glucose-induced insulin secretion from pancreatic islets [37], and can act as a neuropeptide when released in the brain [38]. GLP-1 receptors (GLP-1R) exist widely throughout the brain, in areas including the hypothalamus, thalamus, hippocampus, cortex, and brainstem nucleus [39,40,41]. GLP-1 and other GLP-1 analogues can cross the BBB [42,43]. Because GLP-1 and its receptors exist in both the CNS and peripheral tissues, the effect of GLP-1 on energy metabolism is mediated by both the CNS and the peripheral nervous system (PNS) [11,44,45]. Moreover, GLP-1 is synthesized by neurons within the nucleus of the solitary tract [46,47]. These neurons have long projections to hypothalamic, thalamic, and cortical brain areas [48]. GLP-1 contributes to glycemic homeostasis and GLP1R agonists such as exendin-4, liraglutide, and lixisenatide have been approved to treat T2DM [49,50]. Furthermore, GLP-1 increases the spontaneous activity of neurons in the hippocampal CA1 region and promotes excitatory synaptic transmission in the hippocampus [51]. GLP-1 receptor knockout mice show decreased memory retention in the Morris water maze task, and the administration of GLP-1 agonists leads to improvement in learning and memory [52]. Here, given that GLP-1 could regulate glucose metabolism and potentially be used for treatment of T2DM [44,49], we focused on the role of GLP-1 in type 3 diabetes, highlighting the therapeutic importance of GLP-1 in diabetes-induced dementia.

4. The Effect of GLP-1 in Type 3 Diabetes: GLP-1 Attenuates Neuroinflammation and Improves Neurogenesis and Insulin Sensitivity in AD

One study suggested that GLP-1 mimetic drugs have neuroprotective, neurotrophic, and anti-inflammatory effects, which play a role in retardation of AD progression [14]. Another study demonstrated that liraglutide, a GLP-1 receptor agonist, can alleviate spatial memory dysfunction and neuroinflammation that leads to cognitive impairment [53]. GLP1 has been shown to act as a growth factor in the brain and promote neurite growth [54]. GLP-1 receptor activators stimulate the differentiation of neuronal stem cells in a manner similar to nerve growth factor, so it may inhibit brain atrophy in AD patients [55]. Additionally, GLP1 receptor agonists such as liraglutide and exendin-4 attenuate endogenous levels of amyloid beta in the brain and prevent amyloid plaque accumulation in the AD brain [42,53]. Furthermore, stimulating glucose metabolism in AD patients through the administration of GLP-1 markedly improves cognitive dysfunction in the AD brain [56,57]. In APP/PS1 mice (a mouse model of AD) brain, liraglutide and GLP-1 increase long-term potention (LTP) [42,58] and increase synaptic plasticity [41,55,59]. Moreover, GLP-1 has been found to improve insulin sensitivity [60,61] and control energy metabolism [62,63]. Recent studies reported that GLP-1 could attenuate brain insulin resistance by decreasing c-Jun N-terminal kinase (JNK) signaling and increasing the expression of the B-cell lymphoma 2 gene (Bcl2) in the T2DM mouse [64]. One study demonstrated that liraglutide treatment in an AD mouse model triggers the activation of microglia in the brain [42]. Neurogenesis, the generation of new neurons from neuronal progenitor stem cells [65,66], occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampal [67,68]. According to previous results, adult neurogenesis is linked to memory function and the facilitation of LTP [69,70]. In the AD brain, a decrease in neurogenesis is commonly observed and aggravates the disease pathology [41,71]. Several studies found that GLP-1 receptor agonists increase the proliferation of neural progenitor cells [41] and increase neurogenesis in the dentate gyrus of the hippocampus [43]. Earlier studies reported the impaired proliferation of neural stem cell in the AD mouse model [66,72] and that GLP-1 and analogues of GLP-1 can promote neural stem cell proliferation in the brain [73,74]. GLP-1 receptor activates neurogenesis in hippocampus through mitogen activated protein kinases (MAPK) [75], leading to enhancement of learning and memory [75,76,77]. Collectively, GLP-1 could attenuate neuroinflammation and enhance neurogenesis and insulin resistance in diabetes-induced dementia, also known as type 3 diabetes.

5. Conclusions

Summing up, we suggest that GLP-1 is a good candidate for improving cognitive dysfunction in diabetes-induced dementia. First, GLP-1 could attenuate the inflammatory responses in brain caused by amyloid beta (Aβ)-induced oxidative stress. GLP-1 could regulate the activation of microglia and protect neurons against oxidative stress. Second, GLP-1 could promote neurogenesis in AD brain. This means that GLP-1 could stimulate the generation of new neurons to replace damaged neurons in the AD brain. Finally, GLP-1 can alleviate insulin resistance in the AD brain, suggesting that impaired glucose metabolism and insulin resistance leads to severe memory dysfunction. To conclude, our study highlights that manipulation of GLP-1 may be an effective therapy for improving AD-like pathology in diabetes-induced dementia, also known as type 3 diabetes.

Acknowledgments

This study was supported by the Brain Research Program through the National Research Foundation of Korea funded by a grant from 2016R1D1A1B03930394.

Author Contributions

Juhyun Song contributed to writing the preliminary draft of this manuscript and revised the manuscript. Choon Sang Bae contributed to writing the draft and revising manuscript as a whole.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Querfurth, H.W.; LaFerla, F.M. Alzheimer’s disease. N. Engl. J. Med. 2010, 362, 329–344. [Google Scholar] [CrossRef] [PubMed]
  2. LaFerla, F.M.; Green, K.N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012, 2, a006320. [Google Scholar] [CrossRef] [PubMed]
  3. Akter, K.; Lanza, E.A.; Martin, S.A.; Myronyuk, N.; Rua, M.; Raffa, R.B. Diabetes mellitus and Alzheimer’s disease: Shared pathology and treatment? Br. J. Clin. Pharmacol. 2011, 71, 365–376. [Google Scholar] [CrossRef] [PubMed]
  4. Baglietto-Vargas, D.; Shi, J.; Yaeger, D.M.; Ager, R.; LaFerla, F.M. Diabetes and Alzheimer’s disease crosstalk. Neurosci. Biobehav. Rev. 2016, 64, 272–287. [Google Scholar] [CrossRef] [PubMed]
  5. Mamelak, M. Energy and the Alzheimer brain. Neurosci. Biobehav. Rev. 2017, 75, 297–313. [Google Scholar] [CrossRef] [PubMed]
  6. Roh, E.; Song, D.K.; Kim, M.S. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp. Mol. Med. 2016, 48, e216. [Google Scholar] [CrossRef] [PubMed]
  7. Roh, E.; Kim, M.S. Brain Regulation of Energy Metabolism. Endocrinol. Metab. 2016, 31, 519–524. [Google Scholar] [CrossRef] [PubMed]
  8. Attwell, D.; Laughlin, S.B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 2001, 21, 1133–1145. [Google Scholar] [CrossRef] [PubMed]
  9. Magistretti, P.J.; Pellerin, L. Metabolic coupling during activation. A cellular view. Adv. Exp. Med. Biol. 1997, 413, 161–166. [Google Scholar] [PubMed]
  10. Doraiswamy, P.M.; Sperling, R.A.; Coleman, R.E.; Johnson, K.A.; Reiman, E.M.; Davis, M.D.; Grundman, M.; Sabbagh, M.N.; Sadowsky, C.H.; Fleisher, A.S.; et al. Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: A multicenter study. Neurology 2012, 79, 1636–1644. [Google Scholar] [CrossRef] [PubMed]
  11. Holst, J.J. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007, 87, 1409–1439. [Google Scholar] [CrossRef] [PubMed]
  12. Barrera, J.G.; Jones, K.R.; Herman, J.P.; D’Alessio, D.A.; Woods, S.C.; Seeley, R.J. Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J. Neurosci. 2011, 31, 3904–3913. [Google Scholar] [CrossRef] [PubMed]
  13. Sherwood, V. WNT signaling: An emerging mediator of cancer cell metabolism? Mol. Cell. Biol. 2015, 35, 2–10. [Google Scholar] [CrossRef] [PubMed]
  14. Holscher, C. Central effects of GLP-1: New opportunities for treatments of neurodegenerative diseases. J. Endocrinol. 2014, 221, T31–T41. [Google Scholar] [CrossRef] [PubMed]
  15. Talbot, K.; Wang, H.Y. The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer’s disease. Alzheimers Dement. 2014, 10, S12–S25. [Google Scholar] [CrossRef] [PubMed]
  16. Peng, S.; Eidelberg, D.; Ma, Y. Brain network markers of abnormal cerebral glucose metabolism and blood flow in Parkinson’s disease. Neurosci. Bull. 2014, 30, 823–837. [Google Scholar] [CrossRef] [PubMed]
  17. Berti, V.; Mosconi, L.; Pupi, A. Brain: Normal variations and benign findings in fluorodeoxyglucose-PET/computed tomography imaging. PET Clin. 2014, 9, 129–140. [Google Scholar] [CrossRef] [PubMed]
  18. Carpenter, K.L.; Jalloh, I.; Gallagher, C.N.; Grice, P.; Howe, D.J.; Mason, A.; Timofeev, I.; Helmy, A.; Murphy, M.P.; Menon, D.K.; et al. 13C-labelled microdialysis studies of cerebral metabolism in TBI patients. Eur. J. Pharm. Sci. 2014, 57, 87–97. [Google Scholar] [CrossRef] [PubMed]
  19. Tolppanen, A.M.; Lavikainen, P.; Solomon, A.; Kivipelto, M.; Uusitupa, M.; Soininen, H.; Hartikainen, S. History of medically treated diabetes and risk of Alzheimer disease in a nationwide case-control study. Diabetes Care 2013, 36, 2015–2019. [Google Scholar] [CrossRef] [PubMed]
  20. Biessels, G.J.; Strachan, M.W.; Visseren, F.L.; Kappelle, L.J.; Whitmer, R.A. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: Towards targeted interventions. Lancet Diabetes Endocrinol. 2014, 2, 246–255. [Google Scholar] [CrossRef]
  21. Butterfield, D.A.; Di Domenico, F.; Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain. Biochim. Biophys. Acta 2014, 1842, 1693–1706. [Google Scholar] [CrossRef] [PubMed]
  22. Bedse, G.; Di Domenico, F.; Serviddio, G.; Cassano, T. Aberrant insulin signaling in Alzheimer’s disease: Current knowledge. Front. Neurosci. 2015, 9, 204. [Google Scholar] [CrossRef] [PubMed]
  23. Devaskar, S.U.; Giddings, S.J.; Rajakumar, P.A.; Carnaghi, L.R.; Menon, R.K.; Zahm, D.S. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 1994, 269, 8445–8454. [Google Scholar] [PubMed]
  24. Kuwabara, T.; Kagalwala, M.N.; Onuma, Y.; Ito, Y.; Warashina, M.; Terashima, K.; Sanosaka, T.; Nakashima, K.; Gage, F.H.; Asashima, M. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol. Med. 2011, 3, 742–754. [Google Scholar] [CrossRef] [PubMed]
  25. Banks, W.A.; Owen, J.B.; Erickson, M.A. Insulin in the brain: There and back again. Pharm. Ther. 2012, 136, 82–93. [Google Scholar] [CrossRef] [PubMed]
  26. Le Roith, D.; Hendricks, S.A.; Lesniak, M.A.; Rishi, S.; Becker, K.L.; Havrankova, J.; Rosenzweig, J.L.; Brownstein, M.J.; Roth, J. Insulin in brain and other extrapancreatic tissues of vertebrates and nonvertebrates. Adv. Metab. Disord. 1983, 10, 303–340. [Google Scholar] [PubMed]
  27. Kar, S.; Chabot, J.G.; Quirion, R. Quantitative autoradiographic localization of [125I] insulin-like growth factor I, [125I] insulin-like growth factor II, and [125I] insulin receptor binding sites in developing and adult rat brain. J. Comp. Neurol. 1993, 333, 375–397. [Google Scholar] [CrossRef] [PubMed]
  28. O’Kusky, J.; Ye, P. Neurodevelopmental effects of insulin-like growth factor signaling. Front. Neuroendocrinol. 2012, 33, 230–251. [Google Scholar] [CrossRef] [PubMed]
  29. Talbot, K.; Wang, H.Y.; Kazi, H.; Han, L.Y.; Bakshi, K.P.; Stucky, A.; Fuino, R.L.; Kawaguchi, K.R.; Samoyedny, A.J.; Wilson, R.S.; et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Investig. 2012, 122, 1316–1338. [Google Scholar] [CrossRef] [PubMed]
  30. Bloemer, J.; Bhattacharya, S.; Amin, R.; Suppiramaniam, V. Impaired insulin signaling and mechanisms of memory loss. Prog. Mol. Biol. Transl. Sci. 2014, 121, 413–449. [Google Scholar] [PubMed]
  31. Faria, J.A.; Kinote, A.; Ignacio-Souza, L.M.; de Araujo, T.M.; Razolli, D.S.; Doneda, D.L.; Paschoal, L.B.; Lellis-Santos, C.; Bertolini, G.L.; Velloso, L.A.; et al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am. J. Physiol. Endocrinol. Metab. 2013, 305, E230–E242. [Google Scholar] [CrossRef] [PubMed]
  32. O’Neill, C. PI3-kinase/Akt/mTOR signaling: Impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp. Gerontol. 2013, 48, 647–653. [Google Scholar] [CrossRef] [PubMed]
  33. Kullmann, S.; Heni, M.; Veit, R.; Scheffler, K.; Machann, J.; Haring, H.U.; Fritsche, A.; Preissl, H. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 2015, 38, 1044–1050. [Google Scholar] [CrossRef] [PubMed]
  34. Zhu, X.; Perry, G.; Smith, M.A. Insulin signaling, diabetes mellitus and risk of Alzheimer disease. J. Alzheimer's Dis. 2005, 7, 81–84. [Google Scholar] [CrossRef]
  35. Stanley, S.; Wynne, K.; McGowan, B.; Bloom, S. Hormonal regulation of food intake. Physiol. Rev. 2005, 85, 1131–1158. [Google Scholar] [CrossRef] [PubMed]
  36. Baggio, L.L.; Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131–2157. [Google Scholar] [CrossRef] [PubMed]
  37. Varndell, I.M.; Bishop, A.E.; Sikri, K.L.; Uttenthal, L.O.; Bloom, S.R.; Polak, J.M. Localization of glucagon-like peptide (GLP) immunoreactants in human gut and pancreas using light and electron microscopic immunocytochemistry. J. Histochem. Cytochem. 1985, 33, 1080–1086. [Google Scholar] [CrossRef] [PubMed]
  38. Holst, J.J.; Burcelin, R.; Nathanson, E. Neuroprotective properties of GLP-1: Theoretical and practical applications. Curr. Med. Res. Opin. 2011, 27, 547–558. [Google Scholar] [CrossRef] [PubMed]
  39. Cork, S.C.; Richards, J.E.; Holt, M.K.; Gribble, F.M.; Reimann, F.; Trapp, S. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol. Metab. 2015, 4, 718–731. [Google Scholar] [CrossRef] [PubMed]
  40. Abbas, T.; Faivre, E.; Holscher, C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer’s disease. Behav. Brain Res. 2009, 205, 265–271. [Google Scholar] [CrossRef] [PubMed]
  41. Hamilton, A.; Patterson, S.; Porter, D.; Gault, V.A.; Holscher, C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J. Neurosci. Res. 2011, 89, 481–489. [Google Scholar] [CrossRef] [PubMed]
  42. McClean, P.L.; Parthsarathy, V.; Faivre, E.; Holscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J. Neurosci. 2011, 31, 6587–6594. [Google Scholar] [CrossRef] [PubMed]
  43. Hunter, K.; Holscher, C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012, 13, 33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Hayes, M.R.; De Jonghe, B.C.; Kanoski, S.E. Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol. Behav. 2010, 100, 503–510. [Google Scholar] [CrossRef] [PubMed]
  45. Williams, D.L.; Baskin, D.G.; Schwartz, M.W. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes 2006, 55, 3387–3393. [Google Scholar] [CrossRef] [PubMed]
  46. Larsen, P.J.; Tang-Christensen, M.; Holst, J.J.; Orskov, C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 1997, 77, 257–270. [Google Scholar] [CrossRef]
  47. Vrang, N.; Larsen, P.J. Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: Role of peripherally secreted and centrally produced peptides. Prog. Neurobiol. 2010, 92, 442–462. [Google Scholar] [CrossRef] [PubMed]
  48. Llewellyn-Smith, I.J.; Reimann, F.; Gribble, F.M.; Trapp, S. Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience 2011, 180, 111–121. [Google Scholar] [CrossRef] [PubMed]
  49. Lovshin, J.A.; Drucker, D.J. Incretin-based therapies for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2009, 5, 262–269. [Google Scholar] [CrossRef] [PubMed]
  50. Vella, A.; Shah, P.; Reed, A.S.; Adkins, A.S.; Basu, R.; Rizza, R.A. Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans. Diabetologia 2002, 45, 1410–1415. [Google Scholar] [PubMed]
  51. Oka, J.I.; Goto, N.; Kameyama, T. Glucagon-like peptide-1 modulates neuronal activity in the rat’s hippocampus. Neuroreport 1999, 10, 1643–1646. [Google Scholar] [CrossRef] [PubMed]
  52. Isacson, R.; Nielsen, E.; Dannaeus, K.; Bertilsson, G.; Patrone, C.; Zachrisson, O.; Wikstrom, L. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur. J. Pharm. 2011, 650, 249–255. [Google Scholar] [CrossRef] [PubMed]
  53. McClean, P.L.; Holscher, C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology 2014, 76, 57–67. [Google Scholar] [CrossRef] [PubMed]
  54. Hayes, M.R. Neuronal and intracellular signaling pathways mediating GLP-1 energy balance and glycemic effects. Physiol. Behav. 2012, 106, 413–416. [Google Scholar] [CrossRef] [PubMed]
  55. Salcedo, I.; Tweedie, D.; Li, Y.; Greig, N.H. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: An emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharm. 2012, 166, 1586–1599. [Google Scholar] [CrossRef] [PubMed]
  56. Parthsarathy, V.; Holscher, C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoS ONE 2013, 8, e58784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Craft, S.; Baker, L.D.; Montine, T.J.; Minoshima, S.; Watson, G.S.; Claxton, A.; Arbuckle, M.; Callaghan, M.; Tsai, E.; Plymate, S.R.; et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch. Neurol. 2012, 69, 29–38. [Google Scholar] [CrossRef] [PubMed]
  58. McClean, P.L.; Gault, V.A.; Harriott, P.; Holscher, C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer’s disease. Eur. J. Pharm. 2010, 630, 158–162. [Google Scholar] [CrossRef] [PubMed]
  59. Darsalia, V.; Hua, S.; Larsson, M.; Mallard, C.; Nathanson, D.; Nystrom, T.; Sjoholm, A.; Johansson, M.E.; Patrone, C. Exendin-4 reduces ischemic brain injury in normal and aged type 2 diabetic mice and promotes microglial M2 polarization. PLoS ONE 2014, 9, e103114. [Google Scholar] [CrossRef] [PubMed]
  60. Adamska, E.; Ostrowska, L.; Gorska, M.; Kretowski, A. The role of gastrointestinal hormones in the pathogenesis of obesity and type 2 diabetes. Przeglad Gastroenterol. 2014, 9, 69–76. [Google Scholar] [CrossRef] [PubMed]
  61. Ravassa, S.; Beaumont, J.; Huerta, A.; Barba, J.; Coma-Canella, I.; Gonzalez, A.; Lopez, B.; Diez, J. Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot study. Free Radic. Biol. Med. 2015, 81, 1–12. [Google Scholar] [CrossRef] [PubMed]
  62. Toft-Nielsen, M.B.; Damholt, M.B.; Madsbad, S.; Hilsted, L.M.; Hughes, T.E.; Michelsen, B.K.; Holst, J.J. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 2001, 86, 3717–3723. [Google Scholar] [CrossRef] [PubMed]
  63. Vilsboll, T.; Krarup, T.; Deacon, C.F.; Madsbad, S.; Holst, J.J. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001, 50, 609–613. [Google Scholar] [CrossRef] [PubMed]
  64. Candeias, E.; Sebastiao, I.; Cardoso, S.; Carvalho, C.; Santos, M.S.; Oliveira, C.R.; Moreira, P.I.; Duarte, A.I. Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats. Mol. Neurobiol. 2017. [Google Scholar] [CrossRef] [PubMed]
  65. Emsley, J.G.; Mitchell, B.D.; Kempermann, G.; Macklis, J.D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 2005, 75, 321–341. [Google Scholar] [CrossRef] [PubMed]
  66. Hamilton, A.; Holscher, C. The effect of ageing on neurogenesis and oxidative stress in the APP(swe)/PS1(deltaE9) mouse model of Alzheimer’s disease. Brain Res. 2012, 1449, 83–93. [Google Scholar] [CrossRef] [PubMed]
  67. Cameron, H.A.; McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 2001, 435, 406–417. [Google Scholar] [CrossRef] [PubMed]
  68. Abrous, D.N.; Koehl, M.; Le Moal, M. Adult neurogenesis: From precursors to network and physiology. Physiol. Rev. 2005, 85, 523–569. [Google Scholar] [CrossRef] [PubMed]
  69. Bruel-Jungerman, E.; Davis, S.; Rampon, C.; Laroche, S. Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J. Neurosci. 2006, 26, 5888–5893. [Google Scholar] [CrossRef] [PubMed]
  70. Van Praag, H.; Shubert, T.; Zhao, C.; Gage, F.H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 2005, 25, 8680–8685. [Google Scholar] [CrossRef] [PubMed]
  71. Harkavyi, A.; Abuirmeileh, A.; Lever, R.; Kingsbury, A.E.; Biggs, C.S.; Whitton, P.S. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J. Neuroinflamm. 2008, 5, 19. [Google Scholar] [CrossRef] [PubMed]
  72. Faure, A.; Verret, L.; Bozon, B.; El Tayara, N.E.T.; Ly, M.; Kober, F.; Dhenain, M.; Rampon, C.; Delatour, B. Impaired neurogenesis, neuronal loss, and brain functional deficits in the APPxPS1-Ki mouse model of Alzheimer’s disease. Neurobiol. Aging 2011, 32, 407–418. [Google Scholar] [CrossRef] [PubMed]
  73. Bertilsson, G.; Patrone, C.; Zachrisson, O.; Andersson, A.; Dannaeus, K.; Heidrich, J.; Kortesmaa, J.; Mercer, A.; Nielsen, E.; Ronnholm, H.; et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J. Neurosci. Res. 2008, 86, 326–338. [Google Scholar] [CrossRef] [PubMed]
  74. Drucker, D.J. Glucagon-like peptides: Regulators of cell proliferation, differentiation, and apoptosis. Mol. Endocrinol. 2003, 17, 161–171. [Google Scholar] [CrossRef] [PubMed]
  75. During, M.J.; Cao, L.; Zuzga, D.S.; Francis, J.S.; Fitzsimons, H.L.; Jiao, X.; Bland, R.J.; Klugmann, M.; Banks, W.A.; Drucker, D.J.; et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 2003, 9, 1173–1179. [Google Scholar] [CrossRef] [PubMed]
  76. Raber, J.; Rola, R.; LeFevour, A.; Morhardt, D.; Curley, J.; Mizumatsu, S.; VandenBerg, S.R.; Fike, J.R. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 2004, 162, 39–47. [Google Scholar] [CrossRef] [PubMed]
  77. Snyder, J.S.; Hong, N.S.; McDonald, R.J.; Wojtowicz, J.M. A role for adult neurogenesis in spatial long-term memory. Neuroscience 2005, 130, 843–852. [Google Scholar] [CrossRef] [PubMed]

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MDPI and ACS Style

Bae, C.S.; Song, J. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. Int. J. Mol. Sci. 2017, 18, 2493. https://doi.org/10.3390/ijms18112493

AMA Style

Bae CS, Song J. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. International Journal of Molecular Sciences. 2017; 18(11):2493. https://doi.org/10.3390/ijms18112493

Chicago/Turabian Style

Bae, Choon Sang, and Juhyun Song. 2017. "The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain" International Journal of Molecular Sciences 18, no. 11: 2493. https://doi.org/10.3390/ijms18112493

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