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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
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.
Keywords: glucagon like peptide 1 (GLP-1); type 3 diabetes; diabetes-induced dementia; Alzheimer’s disease (AD); insulin resistance; Amyloid beta (Aβ) glucagon like peptide 1 (GLP-1); type 3 diabetes; diabetes-induced dementia; Alzheimer’s disease (AD); insulin resistance; Amyloid beta (Aβ)

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.

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