Insulin Resistance as a Risk Factor in Visceral and Neurological Disorders

Akhlaq A. Farooqui

• Publisher: Academic Press
• Year: 2020
• ISBN:
  9780128201848
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Insulin Resistance as a Risk Factor in Visceral and Neurological Disorders provides an overview on the risk factors for insulin resistance in visceral and neurological disorders. The book focuses on molecular mechanisms and signal transduction processes associated with the links. The comprehensive information in this monograph will not only help in the early detection of insulin resistance related visceral and neurological disorders, but also promote the discovery of new drugs which may block or delay onset in elderly patients. Understanding these processes is important not only for patients, caregivers and health professionals, but also for health policymakers who must plan for national resources.

• Presents the first comprehensive book dedicated to insulin resistance as a risk factor for neurological disorders
• Focuses on the molecular mechanisms and signal transduction processes associated with insulin resistance
• Discusses insulin resistance to heart disease, obesity, diabetes, stroke, Alzheimer's, Parkinson's, dementia and depression

Chapter 1

Insulin resistance and obesity

Abstract

Insulin resistance is a pathological condition involving a failed response to normal levels of insulin. It is defined by reduction of its capacity of insulin to stimulate glucose utilization, either due to insulin deficiency or by impairment in its secretion and/or utilization. The molecular mechanisms contributing to insulin resistance are not fully understood. However, many studies have indicated that insulin resistance is not only controlled by genes, but also by the accumulation of lipids (saturated free fatty acids, diacylglycerol, and triacylglycerol) and lipid mediators such as long-chain acyl-CoAs, acylcarnitines, uric acid (2,6,8-trioxy-purine), isoprostane, and ceramide. The development of a stable and diverse gut microbiota is essential to various host physiologic functions such as immunoregulation, pathogen prevention, energy harvest, and metabolism.

Keywords

Type 2 diabetes; metabolic syndrome; insulin resistance; microbiota; obesity; lipid mediators

Introduction

Insulin is an anabolic hormone (51 amino acid containing peptide with mol mass of 5800 kDa), which is synthesized and secreted by β-cells of the islets of Langerhans located in the pancreas and its serum concentration increases in a direct proportion to the glucose concentration. Insulin is coded on the short arm of chromosome 11 and synthesized in the β-cells of the pancreatic islets of Langerhans as its precursor, proinsulin (Wilcox, 2005). Removal of the signal peptide forms proinsulin results in the synthesis of insulin. Insulin plays an important role in carbohydrate and lipid metabolism in the body by modulating the uptake of glucose and its storage as glycogen in the liver, muscles, and fat cells (Duckworth et al., 1997). Insulin also plays an important role in maintenance of mitochondrial function, promotes a microcirculation, and induces the cell proliferation (Ye, 2007). In the brain, neural cells produce small amount of insulin (Banks, 2004). However, most insulin’s action in the brain is probably due to the circulating peripheral insulin, which crosses the blood–brain barrier (BBB) and produces its neurochemical actions (Banks, 2004).

BBB is not simply a physical barrier but a regulatory interface between the brain and immune system. The BBB both affects and is affected by the immune system and connects at many levels with the brain. The permeability of peripheral insulin to the brain across BBB vary considerably among different regions of brain. It is shown that insulin crosses the BBB two to eight times faster in the olfactory bulb than other brain regions (Banks et al., 2012). Insulin not only regulates glucose and lipid metabolism in the brain, but also modulates neurotransmission and synaptic activities (Zhao and Alkon, 2001; Zhao et al., 2004) such as long-term potentiation (LTP) (Nisticò et al., 2011), as well as promoting long-term depression (LTD) (Labouèbe et al., 2013). In addition, brain insulin regulates dendritic sprouting, neuronal stem cell activation, cell growth, repair, synaptic maintenance, and neuroprotection (Fig. 1.1) (Craft and Watson, 2004; Van Dam and Aleman, 2004; Kleinridders et al., 2014). Insulin enhances cognitive abilities via activation of insulin receptors (IRs) in the hippocampal region of brain. Insulin also stimulates translocation of glucose transporter type 4 (GLUT4) to hippocampal plasma membranes thereby enhancing the glucose uptake in the time-dependent manner (Ren et al., 2014). Insulin is stored in synaptic vesicles at nerve endings in rat brain and is released on depolarization conditions (Blázquez et al., 2014). Insulin also potentiates the brain transport of molecules such as leptin (Kastin and Akerstrom, 2001) and amino acids (Tagliamonte et al., 1976). Insulin signaling in the brain is associated with neuronal survival, neurotransmission, and modulation of synaptic activities (Zhao and Alkon, 2001). In addition, insulin is also involved in the regulation of synaptic plasticity and modulation of LTP (Nisticò et al., 2011), as well as promoting LTD (Labouèbe et al., 2013). These processes are involved in learning and memory. Insulin also potentiates the brain transport of molecules such as leptin (Kastin and Akerstrom, 2001) and amino acids (Tagliamonte et al., 1976). In streptozotocin-treated mice, insulin increases cerebral microvessels expression of occludin, claudin-5, and ZO-1 (Sun et al., 2015). In specific types of hypothalamic neurons, insulin decreases the expression of orexigenic neuropeptides such as neuropeptide Y (NYP) or agouti-related peptide (AgRP) thereby promoting the decrease in food intake (Fick and Belsham, 2010; Kleinridders et al., 2014; Posey et al., 2009). Insulin also inhibits food intake by promoting expression of anorexigenic neuropeptides such as pro-opiomelanocorticotropin (POMC). Insulin is also involved in regulation of hedonic behavior and nonhomeostatic control of intake of food and other substances via reward processing. Insulin also supports neuronal protein synthesis and cytoskeletal protein expression (Schuling Kemp et al., 2000), neurite outgrowth (Dickson, 2003; Song et al., 2003), migration, and differentiation in the absence of other growth factors, and nascent synapse formation (Schuling Kemp et al., 2000). Besides inhibiting AgRP synthesis, insulin induces the hyperpolarization of the AgRP-expressing arcuate neurons reduces the firing rate of these neurons. Finally, insulin also modulates receptor for advanced glycation end products (RAGE) expression. Levels of soluble RAGE are inversely correlated with plasma insulin concentration during an oral glucose tolerance test in healthy human subjects (Forbes et al., 2014). In isolated brain microvessels from streptozotocin-injected mice, insulin reduces the concentration of RAGE compared to diabetic mice (Sun et al., 2015) supporting the view that insulin modulates RAGE.

Figure 1.1 Roles of insulin in the brain.

Insulin signaling in the brain

Insulin produces its effects by interacting with the IR, a transmembrane receptor with tyrosine kinase activity. It is made up of two α-subunits and two β-subunits (Fig. 1.2). The α-subunits (120–135 kDa) contain the insulin-binding sites. The α-subunit of IR is predominantly hydrophilic in nature, lacks membrane anchor regions, and contains 15 potential N-glycosylation sites and 37 cysteine residues. The β-subunits (95 kDa) form transmembrane and intracellular parts of the receptor (White, 2003). The intracellular part of the β-subunits contains ATP-binding motifs, autophosphorylation sites, and tyrosine-specific protein kinase activity, which facilitate rapid autophosphorylation upon ligand-binding. This results in the recruitment and tyrosine phosphorylation of adaptor proteins, including insulin receptor substrates (IRSs) such as IRS-1 and IRS-2 (Long et al., 2011). In the brain, IRS-2 signaling plays an important role in brain growth, nutrient sensing, and life span regulation, whereas IRS-1 may be less important for these functions (Taguchi and White, 2008). The metabolic action of insulin is linked with IRS through phosphatidyl-inositol 3 kinase (PtdIns 3K) and Akt pathway (Fig. 1.2). Upon activation, the IR phosphorylates IRS proteins. These proteins represent a critical node of activation in insulin and IGF-1 signaling cascades (Shaw, 2011). In addition to their activation of the Ras–mitogen-activated protein kinase (MAPK) pathway, activated IRS proteins serve as docking sites for the assembly and activation of, among others, PtdIns 3K, which generates the lipid second messenger phosphatidylinositol 1,4,5-trisphosphate (PtdIns 1,4,5-P₃). PtdIns 3K represents another critical node of cross-talk with other signaling pathways, including the c-Jun-N-terminal kinase (JNK) stress signaling pathway (Fig. 1.2). Elevated levels of PIP₃ activate phosphoinositide-dependent protein kinase-1 (PDK1) and Akt. Akt represents yet another critical node of interaction with the mammalian target of rapamycin (mTOR) nutrient signaling pathway. Under physiological conditions, the binding of Akt targets rapamycin (mTOR), and extracellular signal-regulated kinases (ERK). This activation of kinases eventually results in phosphorylation of the IRS leading to inhibition of insulin signaling in a negative feedback regulation (Talbot et al., 2012; Biessels and Reagan, 2015; Pearson-Leary and McNay, 2012; Di Domenico et al., 2017). In neurons, the PtdIns 3K, Akt, glycogen synthase kinase 3β, BCL-2 agonist of cell death, transcription factor fork-head box class O (FOXO), mTOR, and the MAPK pathways are critical for cell survival signaling and are regulated by the activity of the IR (Craft, 2005; McCrimmon et al., 2012). Among these pathways, mTORC1 pathway is a major pathway contributing to cellular energy sensing. This pathway serves as a key energy sensor that controls several important cellula...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• About the author
• Preface
• Acknowledgments
• List of abbreviations
• Chapter 1. Insulin resistance and obesity
• Chapter 2. Insulin resistance, diabetes, and metabolic syndrome
• Chapter 3. Insulin resistance and heart disease
• Chapter 4. Insulin resistance and sleep apnea
• Chapter 5. Insulin resistance and stroke
• Chapter 6. Insulin resistance and Alzheimer’s disease
• Chapter 7. Insulin resistance and Parkinson’s disease
• Chapter 8. Insulin resistance, dementia, and depression
• Chapter 9. Use of phytochemicals for the treatment of insulin resistance–linked visceral and neurological disorders
• Chapter 10. Summery and perspective for future research on insulin resistance and insulin resistance–linked visceral and neurological disorders
• Index