Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis

2021 ◽  
Vol 18 ◽  
Author(s):  
Xuemin Peng ◽  
Xiaoli Shi ◽  
Jiaojiao Huang ◽  
Shujun Zhang ◽  
Yongli Yan ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Insulin Signaling ◽  
High Glucose ◽  
Neuronal Cell ◽  
Insulin Synthesis ◽  
Brain Insulin ◽  
Glucagon Like Peptide 1 ◽  
Gsk 3Β ◽  
The Brain

Background and Objective: Type 2 diabetes(T2D) patients are more prone to develop Alzheimer’s disease (AD). We have previously shown that Glucagon-like peptide-1 receptor agon- ist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating in- sulin signaling, and peripheral injected Ex-4 increases insulin levels in the T2D brain. This study aims to further clarify whether the elevated insulin in the brain is produced by nerve cells under the action of Ex-4. Methods: The neuronal cell line-HT22 was treated with Ex-4 under high glucose or normal cultiva- tion, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-re- lated genes were examined. The db/db mice were treated with a peripheral injection of Ex-4 and/or intracerebroventricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis-relat- ed genes and the behavior tests were carried on. Finally, plasma glucose, cerebrospinal fluid (CSF) glucose, CSF insulin, phosphorylation of tau, phosphorylation of AKT and GSK-3β of db/db mice were detected. Results : We found that Ex-4 promoted the expression of insulin synthesis-related genes and in- duced an obvious increase of insulin-positive HT-22 neuronal cells in a high glucose environment. Peripheral injection of Ex-4 improved the cognitive function of db/db mice and increased brain in- sulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphory- lation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive func- tion of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain in- sulin levels dropped to an extremely low level, and the phosphorylation level of tau increased signi- ficantly. Conclusion: This study demonstrated that Ex-4 improved cognition function by promoting brain in- sulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyper- phosphorylation.

scholarly journals Regulation of brain insulin signaling: A new function for tau

2017 ◽  
Vol 214 (8) ◽  
pp. 2171-2173 ◽  
Author(s):  
Maud Gratuze ◽  
Emmanuel Planel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Insulin Signaling ◽  
Loss Of Function ◽  
Brain Insulin ◽  
The Brain

In this issue of JEM, Marciniak et al. (https://doi.org/10.1084/jem.20161731) identify a putative novel function of tau protein as a regulator of insulin signaling in the brain. They find that tau deletion impairs hippocampal response to insulin through IRS-1 and PTEN dysregulation and suggest that, in Alzheimer’s disease, impairment of brain insulin signaling might occur via tau loss of function.

Evidence for paracrine/autocrine regulation of GLP-1-producing cells

2013 ◽  
Vol 305 (10) ◽  
pp. C1041-C1049 ◽  
Author(s):  
Camilla Kappe ◽  
Qimin Zhang ◽  
Jens J. Holst ◽  
Thomas Nyström ◽  
Åke Sjöholm
Keyword(s):  
Cell Viability ◽  
Insulin Signaling ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Novel Drugs ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9–39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

scholarly journals Alternate day fasting impacts the brain insulin-signaling pathway of young adult male C57BL/6 mice

2011 ◽  
Vol 117 (1) ◽  
pp. 154-163 ◽  
Author(s):  
Jianghua Lu ◽  
Lezi E ◽  
WenFang Wang ◽  
Jennifer Frontera ◽  
Hao Zhu ◽  
...  
Keyword(s):  
Young Adult ◽  
Signaling Pathway ◽  
Adult Male ◽  
Insulin Signaling ◽  
Insulin Signaling Pathway ◽  
Young Adult Male ◽  
Brain Insulin ◽  
Alternate Day Fasting ◽  
The Brain

scholarly journals Resveratrol, Metabolic Dysregulation, and Alzheimer’s Disease: Considerations for Neurogenerative Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4628
Author(s):  
Alex J. T. Yang ◽  
Ahmed Bagit ◽  
Rebecca E. K. MacPherson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Metabolic Disorders ◽  
Synaptic Function ◽  
Metabolic Dysregulation ◽  
Beta Peptide ◽  
The Brain ◽  
Metabolic Impairments

Alzheimer’s disease (AD) has traditionally been discussed as a disease where serious cognitive decline is a result of Aβ-plaque accumulation, tau tangle formation, and neurodegeneration. Recently, it has been shown that metabolic dysregulation observed with insulin resistance and type-2 diabetes actively contributes to the progression of AD. One of the pathologies linking metabolic disease to AD is the release of inflammatory cytokines that contribute to the development of brain neuroinflammation and mitochondrial dysfunction, ultimately resulting in amyloid-beta peptide production and accumulation. Improving these metabolic impairments has been shown to be effective at reducing AD progression and improving cognitive function. The polyphenol resveratrol (RSV) improves peripheral metabolic disorders and may provide similar benefits centrally in the brain. RSV reduces inflammatory cytokine release, improves mitochondrial energetic function, and improves Aβ-peptide clearance by activating SIRT1 and AMPK. RSV has also been linked to improved cognitive function; however, the mechanisms of action are less defined. However, there is evidence to suggest that chronic RSV-driven AMPK activation may be detrimental to synaptic function and growth, which would directly impact cognition. This review will discuss the benefits and adverse effects of RSV on the brain, highlighting the major signaling pathways and some of the gaps surrounding the use of RSV as a treatment for AD.

scholarly journals Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions

2021 ◽  
Author(s):  
Igor Pomytkin ◽  
Vsevolod Pinelis
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Metabolic Stress ◽  
Glutamate Excitotoxicity ◽  
Receptor Signal ◽  
Brain Insulin Resistance ◽  
Substrate Proteins ◽  
The Brain

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

scholarly journals mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease

2016 ◽  
Vol 13 (2) ◽  
pp. 152-167 ◽  
Author(s):  
Andrés Norambuena ◽  
Horst Wallrabe ◽  
Lloyd McMahon ◽  
Antonia Silva ◽  
Eric Swanson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Neuronal Cell ◽  
Cell Cycle Reentry ◽  
Brain Insulin

scholarly journals Brain Insulin Receptor Causes Activity-Dependent Current Suppression in the Olfactory Bulb Through Multiple Phosphorylation of Kv1.3

2000 ◽  
Vol 83 (4) ◽  
pp. 2332-2348 ◽  
Author(s):  
D. A. Fadool ◽  
K. Tucker ◽  
J. J. Phillips ◽  
J. A. Simmen
Keyword(s):  
Olfactory Bulb ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Outward Current ◽  
Patch Clamp Recording ◽  
Insulin Levels ◽  
Brain Insulin ◽  
Elisa Testing ◽  
Activity Dependent ◽  
The Brain

Insulin and insulin receptor (IR) kinase are found in abundance in discrete brain regions yet insulin signaling in the CNS is not understood. Because it is known that the highest brain insulin-binding affinities, insulin-receptor density, and IR kinase activity are localized to the olfactory bulb, we sought to explore the downstream substrates for IR kinase in this region of the brain to better elucidate the function of insulin signaling in the CNS. First, we demonstrate that IR is postnatally and developmentally expressed in specific lamina of the highly plastic olfactory bulb (OB). ELISA testing confirms that insulin is present in the developing and adult OB. Plasma insulin levels are elevated above that found in the OB, which perhaps suggests a differential insulin pool. Olfactory bulb insulin levels appear not to be static, however, but are elevated as much as 15-fold after a 72-h fasting period. Bath application of insulin to cultured OB neurons acutely induces outward current suppression as studied by the use of traditional whole-cell and single-channel patch-clamp recording techniques. Modulation of OB neurons is restricted to current magnitude; IR kinase activation does not modulate current kinetics of inactivation or deactivation. Transient transfection of human embryonic kidney cells with cloned Kv1.3 ion channel, which carries a large proportion of the outward current in these neurons, revealed that current suppression was the result of multiple tyrosine phosphorylation of Kv1.3 channel. Y to F single-point mutations in the channel or deletion of the kinase domain in IR blocks insulin-induced modulation and phosphorylation of Kv1.3. Neuromodulation of Kv1.3 current in OB neurons is activity dependent and is eliminated after 20 days of odor/sensory deprivation induced by unilateral naris occlusion at postnatal day 1. IR kinase but not Kv1.3 expression is downregulated in the OB ipsilateral to the occlusion, as demonstrated in cryosections of right (control) and left (sensory-deprived) OB immunolabeled with antibodies directed against these proteins, respectively. Collectively, these data support the hypothesis that the hormone insulin acts as a multiply functioning molecule in the brain: IR signaling in the CNS could act as a traditional growth factor during development, be altered during energy metabolism, and simultaneously function to modulate electrical activity via phosphorylation of voltage-gated ion channels.

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