Phytotherapy in the Management of Diabetes and Hypertension: Volume 3 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Phytotherapy in the Management of Diabetes and Hypertension
- Sprache: Englisch
Medicinal plants are a source of potential therapeutic compounds. Phytotherapycan give patients long term benefits with less or no side effects. This is the thirdvolume of the series which features monographs on selected natural productsused to treat diabetes and hypertension. This volume brings 7 chapterscontributed by 22 researchers, that cover updates on the biochemistry ofdiabetes, information on anti-diabetic and antihypertensive properties of oil bearingplants, herbs, fruits and vegetables, medicinal plants from Asia, as well as the medicinal valueof specific plants such as, star apple (Chrysophyllum cainito).In terms of therapeutic agents, two reviews in this volume focus on terpenoidsand glucagon-like peptide – 1 are also included.Each review covers different plant species or medicinal agents whereapplicable, providing readers essential information about their role in thetreatment of diabetes and hypertension.Both academic and professional pharmacologists as well as clinicianswill find comprehensive information on a variety of therapeutic agents in thisvolume.
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Veröffentlichungsjahr: 2020
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PREFACE
The volume 1 of the present ebook series “Phytotherapy in the Management of Diabetes and Hypertension” has emphasized the basic Biochemistry of diabetes mellitus and hypertension, and described many aspects of these lifestyle diseases and its control or remediation through a cost effective, safe, easy-going, easy-adaptable method through the age-old practice validated by scientific research. In response to requests from WHO in providing safe and effective herbal medicines for use in national health-care systems and to prepare monographs of used medicinal plants around the world, the volume 2 of this e-book series has been published in 2016 and contained monographs related to antihypertensive and antidiabetic plants. The present volume 3 is dedicated to different aspects including the evaluation of the efficacy and safety of medicinal plants and their derivatives on diabetes and hypertension. The study of the mechanisms of action of medicinal plants is deeply discussed. This volume includes 7 complementary chapters that describe different aspects including the biochemistry of type 2 diabetes, the pathophysiology of diabetes and hypertension, the role of essential oils extracted from medicinal plants in the management of diabetes and hypertension, the mechanistic perspectives of the treatment of diabetes and hypertension, some important phytochemicals with beneficial action on diabetes and hypertension, and detailed monographs concerning some potential medicinal plants used in the treatment of diabetes and hypertension. This volume will be useful to the students, teachers, researchers, scientists, clinicians, herbalists, and even the common people interested to know about the subject.
ACKNOWLEDGMENTS AND GRANTS
The Editor would like to express his thanks to all the authors, the reviewers, and Miss Salma Sarfraz for their special effort during the preparation of this book. This work was supported by the Ministry of National Education, Vocational Training, Higher Education and the Scientific Research (Morocco) and the National Center for Scientific and Technical Research (CNRST) (Morocco) under grant N° PPR/2015/35.
List of Contributors
Biochemistry of Type 2 Diabetes Mellitus
Ekambaram Sanmuga Priya*,Perumal Senthamil Selvan,Erusappan ThamizharasiAbstract
Diabetes mellitus, a metabolic disorder, characterized by chronic hyperglycemia results from defects in insulin secretion, insulin action, or both. Insulin is an anabolic peptide hormone that possesses pleiotropic activity. It can hinder with multiple physiological processes by either upregulating or downregulating various metabolic intracellular pathways. The complex insulin signaling system makes it vital in a variety of biological responses. This chapter describes the biochemistry of type 2 diabetes mellitus, as well as the features underlying its pathophysiology.
INTRODUCTION
Diabetes mellitus (DM), a metabolic disorder, characterized by chronic hyperglycemia results from defects in insulin secretion, insulin action, or both. Diabetes mellitus is classically characterized into two types viz.Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). T1DM, which is also known as insulin dependent diabetes mellitus (IDDM), is caused due to deficiency of insulin secretion from β cells of the pancreas. T2DM, which is also known as non-insulin dependent diabetes mellitus (NIDDM), is associated with diminished sensitivity of insulin in target tissues. This reduced sensitivity to insulin is a characteristic of insulin resistance. The reduced insulin levels or the resistance to insulin reduced the uptake of glucose by most of the tissues of the body except the brain [1]. This leads to an increase in blood glucose concentration along with a decrease in utilization of glucose by cells which results in an increase in the utilization of fats and proteins. The clinical features of patients with T1DM and T2DM are shown in Table 1.
EPIDEMIOLOGY OF T2DM
The number of people with T2DM is progressively increasing. According to the World Health Organisation (WHO), there were 422 million adults with diabetes worldwide in 2014. The prevalence in adults increased from 4.7% in 1980 to 8.5% in 2014, with a higher increase in low and middle-income countries compared to high-income ones [2]. Further, the International Diabetes Federation (IDF) estimates to have 374 million people at an increased risk of developing T2DM. Without any intervention to slow down this rise in T2DM, there will be at least 700 million people with diabetes by 2045. The demographics of T2DM and the percentage of the population by geographical location are illustrated in Fig. (1). The lower rate of diagnosis of diabetes and the difficult access to diabetes care in low- and middle-income countries lead to 90% of all diabetes-related premature deaths and, 87% of all diabetes-related deaths [3]. Consequently, high blood glucose causes almost 4 million deaths each year [2]. The demographic and geographic outline of diabetes worldwide is shown in Fig. (1).
ETIOLOGY OF T2DM
T2DM, the more prevalent form of diabetes, is a heterogeneous disorder triggered by a multitude of genetic factors related to diminished insulin secretion, insulin resistance and related factors, such as obesity, overeating, sedentary lifestyle, stress and aging [4]. This multifactorial disease involves numerous genes as well as environmental factors [5]. There is an acute need for insulin by the body in T2DM to avoid the ketoacidosis. Predominately it is not an autoimmune disorder. Also, there is no identification of the susceptible genes that may account for a predisposition to T2DM in most patients. This can be accounted to the heterogeneity of the genes accountable for the susceptibility to T2DM.
Fig. (1)) Demographic and geographic outline of diabetes.SOME MAJOR CAUSES OF DEVELOPING INSULIN RESISTANCE INCLUDE
Obesity, especially accumulation of adipose tissue surrounding the viscera.Mutations in insulin receptor genes.Mutations of the peroxisome proliferator activator receptor-γ (PPAR-γ) genes.Mutations that cause genetic obesity, e.g., melanocortin receptor mutations.Higher glucocorticoids, e.g., Cushing’s syndrome or steroid therapy.Higher growth hormone (acromegaly).Pregnancy leading to gestational diabetes.Polycystic ovary disease (PCOD).Hypertension, i.e. (≥140/90 mmHg)HDL cholesterol level(<35 mg/dL (0.90 mmol/L) or triglyceride level >250 mg/dL (2.82 mmol/L) or both).Acquired or genetic lipodystrophy associated with accumulation of lipids in liver.Hemochromatosis.Female delivering a baby weighing >9 lb or prior diagnosis of Gestational Diabetes Mellitus [1, 6].PATHOPHYSIOLOGY OF T2DM
T2DM is characterized by chronic hyperglycemia, which results from a multifactorial interaction between genetic predisposition and environmental factors [7, 8]. T2DM is the more common form of diabetes that accounts for at least 90% of all cases of diabetes mellitus [9]. The rise in prevalence is projected to be much greater in developing (69%) than in developed countries (20%) [10]. Several important pathophysiological studies have highlighted a clear understanding of insulin secretion and resistance in the course of disease onset and progression.
In T2DM, the first step is impaired insulin-stimulated glucose transport in skeletal muscles. The pancreatic β-cells increase the secretion of insulin to compensate for this impaired glucose transport which results into hyperinsulinemia. Thus, peripheral insulin resistance, along with the impaired insulin secretion in late-stage T2DM leads to hyperglycemia Fig. (2). At the end stage of T2DM, the inability to inhibit hepatic gluconeogenesis with endogenous insulin is accompanied by a decline of pancreatic β-cell function. The progression towards the severity of T2DM results when the over-secretion of insulin by the β-cell fails to compensate for insulin resistance. The obese euglycemic people have 30% reduced insulin sensitivity compared to lean euglycemic subjects therefore obese euglycemic people show increased insulin secretion to maintain the normal glucose tolerance. This phenomenon is known as “euglycemic hyperinsulinemia”. Over the course of time, the obese euglycemic people develop further reduction in insulin sensitivity, which is no longer associated with compensatory hyperinsulinemia. This results in an increased blood glucose concentration termed as “hyperglycemic hyperinsulinemia” [11].
Two different hypotheses are proposed for adipose tissue dysfunction [12]:
The Lipid Burden Hypothesis PPAR-γ expression, that determines the ability to store triacylglycerol (TAG) is reduced in the adipose tissue of obese individuals. At the same time, the levels of PPAR- γ are elevated in their liver and muscles, which is ectopic. simultaneously, all the tissues like adipose, liver, and muscle tissues becomes less insulin sensitive.The Role Of Inflammation (The Inflammatory Hypothesis) In obese individuals, the adipocytes release monocyte chemoattractant protein-1 (MCP-1) due to the overloading of TAG. This MCP-1 attracts macrophages which in-turn release TNF-α and other cytokines, hampering with the insulin signaling.Fig. (2)) Pathophysiology of T2DM.The mechanism of insulin resistance in muscles and liver revolves around the role of the mitochondria. Dysfunction of adipose tissue causes fatty acid accumulation in the liver. In addition, excessive nutrition causes increase in malonyl-CoA in the liver, that inhibits carnitine palmitoyl transferase 1 (CPT1). This, in turn, inhibits fatty acid oxidation. Ultimately, the storage of triglycerides (TRIGs) increases in the lack of fatty acid oxidation. Due to CPT1 inhibition, the fatty acid metabolism also leads to the production of diacylglycerol (DAG) and ceramide. DAG triggers stress-induced kinases, and results in reduced insulin signaling. In the muscles, fatty acid accumulation causes an increase in beta oxidation and decreases the rate of citric acid cycle. The products of incomplete fat oxidation (acylcarnitines and reactive oxygen species) stimulate stress-induced kinases and reduce the insulin signaling [12].
Various studies on subjects with T2DM point to an increased gluconeogenesis, that occurs in spite hyperinsulinaemia, signifying hepatic insulin resistance as the main cause of fasting hyperglycemia [13]. The visceral obesity causes accumulation of fat in liver and muscles which leads to impaired insulin-mediated glucose uptake due to intracellular damage to insulin signaling [14].
The biochemistry of these adipose, muscle, and liver tissue dysfunction will be discussed in depth in this chapter.
GENETIC FACTORS ASSOCIATED WITH T2DM
A sedentary lifestyle coupled with a high calorie consumption is a major causative factor in the development of T2DM. However, a genetic predisposition also plays a contributing role in the development. Using the genome-wide linkage methods, various genes have been identified for polymorphisms correlated to T2DM [15].
CAPN10 CAPN10 which codes for the cysteine protease calpain 10, was considered to be the first T2DM susceptibility gene that was identified through a genome-wide scan and positional cloning. The CAPN10 gene is situated on chromosome 2q37.3 and distances 1 kb, composed of 15 exons encoding a 672 amino acid protein. The genetic variants in CAPN10 may modify insulin secretion or insulin action and the production of glucose by the liver. The significant role of CAPN10 in the survival of pancreatic β-cells was revealed in the recent studies.Hepatocyte Nuclear Factor 4-Α (HNF-4A) HNF4A is a gene that acts as a switch to turn on and off other genes in the body. Variations in the HNF4A gene could lead to T2DM by reducing the amount of insulin secreted by the pancreas. The HNF4A gene is present on chromosome 20, a region that is related to T2DM. The HNF4A gene, located at 20q12–q13.1, is encoded in 12 exons. Single nucleotide polymorphisms (SNPs) in the HNF4A gene impact pancreatic β-cell function that leads to changes in the insulin secretion and also results in the progression of maturity onset diabetes of the young 1 (MODY1).PPAR-gamma It is a transcription factor which binds to another transcription factor known as retinoid X receptor (RXR) on activation. These two transcription factors were found to interact and bind with specific PPAR response elements available in the target genes and regulate their expression. PPAR-γ is a key regulator of adipocyte differentiation and it stimulates the differentiation of fibroblasts as well as other undifferentiated cells into mature fat cells. Increasing evidence suggests that the mutations of PPAR-γ gene are linked to insulin resistance.(TCF7L2) The transcription factor 7 like-2, is a T-cell specific HMG-box and also one of the four TCF proteins that are involved in the signaling pathways originating from the Wnt family of secreted growth factors. TCF7L2 gene contains the SNPs for two highly linked polymorphisms with T2DM.β CELL DYSFUNCTION AND INSULIN RESISTANCE
The dynamics of β cell dysfunction and insulin resistance are illustrated in Fig. (3) [16]. The failure of pancreatic β-cells to function efficiently is the main cause for the manifestation of hyperglycemia in T2DM [16]. In genetically predisposed individuals, the augmented demand between insulin synthesis and secretion ultimately results in β-cell dysfunction [17, 18]. Studies suggest that the ‘stressed’ β-cells may kindle local inflammation and alter the balance between α- and β- cell mass and function within the Islets of Langerhans. Insulin tends to exert negative paracrine action on α-cells and limits the secretion of glucagon [19]. Consequently, the lack of insulin results in higher levels of glucagon, which cause a rise in the blood glucose concentration via hepatic gluconeogenesis.
Fig. (3)) Dynamics of βcell dysfunction and insulin resistance in T2DM: The relationship between βcell dysfunction and insulin resistance largely depends on metabolic state and it is dynamic. Insulin resistance could be triggered by high fat diet and obesity independently. Both βcell physiology and compensation has been impaired through insulin resistance, thereby it induces b cell demise and dysfunction. The use of novel therapeutic treatments both βcell physiology and compensation can be preserved. Thus, to avoid βcell dysfunction, βcell physiology must be maintained through βcell preservation.Insulin resistance is compounded by β-cell dysfunction, which characterizes T2DM. β-cell dysfunction and insulin resistance can be activated by the onset of hyperglycemia which leads to the progression of T2DM. Further, β-cell failure is caused by proinflammatory-mediated cytokines, ER stress, oxidative stress, obesity, inflammation, and free fatty acids (FFA) [16].
ROLE OF INCRETINS
The central role of gut hormones or incretins which are involved in regulation of insulin secretion has been characterized in the past two to three decades. Two incretins, i.e. glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), influence the secretion of insulin. GLP-1 secreted by L cells which are located in the ileum and colon. GIP is secreted by enteroendocrine K cells located in the duodenum and proximal jejunum [20]. These polypeptides are secreted after food ingestion and/or caloric liquid and assist in increasing insulin secretion as well as reduce glucagon secretion. Decreased secretion of GLP-1 is associated with T2DM [21], insulin resistance [22] and obesity [23].
INSULIN RESISTANCE MECHANISMS
The term “insulin resistance” is characterized by a poor biological response to either administered or secreted insulin. Insulin resistance is indicative of T2DM, which is a condition where the cells become irresponsive to insulin. Insulin resistance occurs mainly in insulin-sensitive tissues such as liver, muscles, and fat cells. The causes of insulin resistance are multifactorial and include genetic causes, lipotoxicity, inflammation, negative regulation by hyperglycemia, serine threonine phosphorylation, defects in glucose transport system, mitochondrial dysfunction and ROS generation, ER stress etc.
Various causes of insulin resistance, their molecular mechanism and biochemical effects are discussed below:
Obesity Intra-abdominal adiposity is mainly associated with insulin resistance and to different metabolic variables that include plasma glucose levels, insulin, total plasma cholesterol, triglyceride levels, and decreased plasma HDL cholesterol [24-26]. Although the link between intra-abdominal fat and abnormal metabolism is not well understood, several hypotheses have been derived. The accumulation of abdominal adipose tissue is resistant to the antilipolytic effects of insulin [27] which include changes in lipoprotein lipase activity. Further, it also causes an increased lipase activity and movement of fatty acids to the circulation where the portal circulation receives the highest fatty acid load. Additionally, the high levels of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) present in the mesenteric fat leads to a higher conversion rate of inactive cortisone to active cortisol which causes increased local production of cortisol. This could trigger adipocytes to cause increased lipolysis and to modify the production of adipokines, that may directly control glucose metabolism.
Adipocyte Secretions Adipocytes control the uptake and release of FFAs. They not only take part in the glycerol FFA cycle and release leptin and other hormones responsible for energy status of the body but also release different cytokines containing hormonal, paracrine and autocrine actions [28]. The adipocyte can also be negatively affected by intake of excess nutrients, that leads to adverse events in the body. Due to an increase in the surface area of the adipocytes in obesity, there is an altered expression of leptin, IL-8, IL-6, MCP-1, and granulocyte colony-stimulating factor (GM-CSF). Cytokines attract proinflammatory macrophages (M1 type), that release TNF- α which has local and systemic inflammatory effects.
Mammalian Target Of Rapamycin (mTOR) mTOR is a part of the serine/threonine protein kinase complex, TORC. It integrates signaling from insulin and other growth factor receptors thereby regulating various cell processes including growth, autophagy, apoptosis, transcription and translation. Activation of TORC1 propagates anabolic signals through several downstream targets including inhibition of 4E-BP and S6K. This results in the stimulation of ribosomal translation, initiation of lipogenesis via the stimulation of sterol regulatory element–binding protein 1 (SREBP1), and upsurge in nucleotide synthesis by promoting flux through the pentose phosphate pathway [29]. S6K can also phosphorylate IRS1 at serine and prevent its activity resulting in downregulation of insulin signaling [30].
The association between obesity, adipocyte secretions, and mTOR signaling is explained in Fig. (4a).
Endoplasmic Reticulum (ER) Stress The major functions of ER is post-translational modification of proteins which includes protein folding, maturation, quality control and their transfer to other cellular compartments. When excess levels of unfolded or misfolded proteins accumulate in ER, the overall protein synthesis slows down, whereas the synthesis of chaperones and other proteins increases. This in turn increases the fidelity of protein processing. The ER membrane–associated proteins complexed to the ER protein BiP/GRP78 include eukaryotic initiation factor 2α (eIF2α), a kinase, known as PKR-like endoplasmic reticulum kinase (PERK), RNA-dependent protein kinase like PKR, the inositol-requiring enzyme 1 (IRE1) and the activating transcription factor 6 (ATF6). An Increase in unfolded proteins leads to dissociation of these proteins from BiP/GRP78. eIF2α gets phosphorylated by PERK resulting in inhibition of most of the protein synthesis and reduction in load on ER. IRE1 is also phosphorylated which triggers the cleavage of X-box binding protein 1 (XBP1), leading to the formation of a mRNA which gets translated into active transcription factor. In combination with ATF6α, XBP1 causes activation of transcription corresponding to the production of chaperones and other proteins involved in ER biogenesis, phospholipid synthesis, ER-associated protein degradation (ERAD) and secretion [31].
Fig. (4a)) Association between mTOR, S6 kinase 1, excess nutrient with both obesity and insulin resistance. Nutrient based stimulation of mTOR and S6K decreases IRS tyrosine phosphorylation (pY) and upsurges serine phosphorylation (pS), thereby hindering downstream insulin signalling along with metabolic and transcriptional effects of insulin. On the other hand, AMP kinase–dependent pathways, triggered by exercise, leptin and adiponectin, may counteract the effect of nutrient excess at the level of mTOR and S6K. TSC (tuberous sclerosis complex). Rheb, RAS homolog enriched in brain. Pathways hindering and enabling insulin action are shown in red and blue, respectively.Excessive food consumption and obesity activate the Unfolded Protein Response (UPR) which can be observed in adipose tissue, liver, muscles, pancreatic β-cells and other tissues Fig. (4b). The activation of UPR on excessive food consumption has several effects including activation of Janus kinase (Jak) and nuclear factor-κB (NF-κB)/inhibitor of κB kinase (IKK) pathways which causes a decrease in IRS1 activity, increase in the levels of endogenous inflammatory mediators, changes in SREBP1-mediated transcription, decrease in hepatic gluconeogenesis, cellular dysfunction and apoptosis [32].
Skeletal Muscles The skeletal muscles are the primary site of glucose clearance after food intake. In case of obesity, insulin resistance in skeletal muscles is manifests prior to irregularities in adipose tissue and liver which can be attributed to the limited nutrient storage capacity of skeletal muscles. An abnormal increase in FFAs points towards the progression of condition from impaired glucose tolerance (IGT) to diabetes [33].It is important to highlight that the FFAs might not be distinctly elevated in the periphery, due to an efficient uptake by the liver and skeletal muscles.
All these facts make it important to bring to notice that a minimal elevation in FFAs are not a true indicator of FFAs present in the peripheral tissues. Hence, an altered FFA movement into skeletal muscles, which is observed in increased visceral lipolysis, has been implicated in the inhibition of glucose uptake by muscles.
Fig. (4b)) Association of ER stress, Autophagy, Obesity, Inflammation and Metabolism UPR has been implicated in ER stress-induced autophagy, thus connecting autophagy in ER homeostasis. On stress recovery, the actions of autophagy include degradation of misfolded proteins and the elevation of ER turnover. Autophagy is also known to involve in lipid droplet formation in the liver, survival and function of β cell, adipocyte differentiation, muscle mass control and inflammatory responses, all of which are known to be disturbed in obesity.Various other causes of insulin resistance and their mechanisms are mentioned in the Table 2.
PLEIOTROPIC ACTION OF INSULIN
Insulin, an anabolic peptide hormone released by the β-cells of the pancreas, acts through insulin receptors (IRs) and enhances glucose conversion into glycogen and reduces glucose output. It also stimulates glucose uptake in skeletal muscles and fat tissues through translocation of GLUT4 (Fig. 5). IRs are located in the membranes of the cells in target tissues, mainly in the liver and muscles.. Insulin also acts on other cells by pleiotropic effects. Insulin plays a critical role in human metabolism [60]. Although traditional role of insulin is considered as a glucose homeostasis regulating hormone, recent studies suggest that it has a much wider pleiotropic role.
Fig. (5)) Pleiotropic action of insulin. Insulin signaling of the IR influence numerous physiological processes in the organism by up regulating or down regulating many intracellular metabolic pathways.The well characterized metabolic effects of insulin signaling through the IR can be categorized into three metabolic areas which are carbohydrate metabolism, lipid metabolism and, protein metabolism [61].
ROLE OF INSULIN IN CARBOHYDRATE METABOLISM
Upregulates the glucose transport rate across the cell membrane as well as increases glycolysis in adipose tissue and muscles.Stimulates the glycogen synthesis rate in adipose tissue, muscles and liver.Decreases the rate of glycogen breakdown in muscles and liver.Inhibits the rate of glycogenolysis and gluconeogenesis in the liver.ROLE OF INSULIN IN LIPID METABOLISM
Stimulates the synthesis of FFAs and triacylglycerol in tissues to a certain extent.Increases the rate of formation of very-low-density lipoprotein (VLDL) as well as cholesterol in the liver.Increases the uptake of triglycerides in adipose tissue with a concomitant reduction in the rate of lipolysis thereby lowering plasma FFA levels.Decreases the rate of fatty acid oxidation in muscle and liver.ROLE OF INSULIN IN PROTEIN METABOLISM
Increases the rate of amino acid transport rate of protein synthesis in adipose tissues, muscles, liver, and other tissues.Decreases the rate of protein degradation in muscles and thereby the rate of formation of urea.BIOCHEMISTRY OF GLUCOSE UPTAKE
In a normal individual, the normal plasma glucose ranges from 4 to 7 mM. These values represent the balance between: (a) transport of glucose into the circulation after its absorption from the intestine or by the conversion of stored glycogen to glucose in the liver and (b) utilization and metabolism of blood glucose by peripheral tissues [61, 62].
Glucose transport into the cells is facilitated by the specialized proteins called glucose transporters (GLUTs).The entry of glucose into the cells is restricted by the number of GLUTs as well as their affinity towards glucose. The basal glucose transporters, GLUT1 and GLUT3, have a higher affinity towards glucose and they are located nearly in all cells. Their Km value for glucose is around 2-5 mM. As this value is less than the average blood glucose concentration (5-7 mM), the glucose uptake remains constant in most of the tissues, irrespective of the amount present in the blood.Muscle and fat cells possess a high-affinity insulin-responsive, third type of glucose transporter called GLUT4, with a Km value of around 5 mM. Insulin is measured as the primary regulator of blood glucose levels as it reduces blood glucose levels by: (a) enhancing the uptake of glucose in the muscles and fat tissues via translocation of intracellular GLUT4 to the plasma membrane; (b) utilizing the fat and glycogen in the muscles, liver and adipose tissues via increased glycogenesis, lipogenesis and protein synthesis and (c) lowering the glucose production and its release by the liver via inhibition glycogenolysis. Insulin signaling also reduces the breakdown of fat (lipolysis) and protein.
INTRODUCTION TO THE INSULIN RECEPTOR (IR)
The IR belongs to the tyrosine kinase receptor super family which forms a heterotetramer of two α-subunits and two β-subunits. IR is similar to insulin-like growth factor-1 receptor (IGF-1R) and the insulin-related receptor. In basal conditions, the α-subunit acts as an allosteric inhibitor of the β-subunit. Stimulation by insulin inhibits the suppression of the β-subunit, followed by tyrosine kinase activity via a conformational change leading to transphosphorylation of tyrosine residues on specific β-subunit [63]. β-subunit has three tyrosine residues, Tyr-1158, -1162 and -1163, based on IR-isoform-B, and these residues are considered important in facilitating insulin signaling, Fig. (6). Among these, Tyr-1158 is the most critical residue as the mutation of Tyr-1158 causes ~80% reduction in tyrosine autophosphorylation and failure in detection of endogenous substrates [64]. Some evidences suggest that insulin, IGF-1, and insulin related receptors can form functional hybrids among each other and an inhibitory mutation that occurs in one of the receptor monomer can inhibit the activity of the other [65]. The tyrosine kinase activity of substrate proteins increases insulin signaling via tyrosine phosphorylation of substrate proteins that form a scaffold for multiple signaling events. The IR stimulates a complex intracellular signaling network via insulin receptor substrate (IRS) proteins and the canonical PI3K and ERK cascades. Insulin signaling in the β-cells and livers is emerging as a crucial determinant in preventing T2DM, through the consolidative role of molecules IRS2 and FOXO (Forkhead family of transcription factors) by preventing β-cell differentiation [66].
INSULIN SIGNALING
With the identification of IR, various substrate proteins of the receptor were also identified in which the first and best characterized substrate was IRS-1. It is 160 kDa docking/effector protein [67, 68]. Currently, there are nine insulin receptor substrate proteins which include IRS1-4, Dok, Gab-1, Cbl, APS, and isoforms of Shc Fig. (6). With respect to insulin response, the IRS proteins on activation, employ other proteins such as PI3K, Nck, Grb2, and CrkII. These together and form a multifunctional signaling center which helps initiate the insulin action. Most of the SH2 proteins such as the p85 subunit of PI3K and Grb2 that bind to IRSs serve as the adapter molecules whereas other kinds of proteins carry out enzymatic functions themselves, e.g., SHP2, a tyrosine phosphatase.
Fig. (6)) Schematic diagram of IR indicating the structural landmarks and functional domains.SH2-containing proteins bind to phosphotyrosine motifs and further dock with insulin receptor substrate proteins as well as enzymatic proteins such as PI3K, Fyn (tyrosine kinase), Csk (tyrosine kinase), SH2 domain-containing inositol 5-phosphatases-2 (SHIP-2; phosphotyrosine phosphatase) and other adapter proteins like Grb-2, Crk, APS, and Nck [69]. The adapter proteins also contain SH3 domains along with SH2 domains and bind to proline-rich sequences in other proteins containing consensus sequence PXXP. The adapter proteins interact with receptor substrates via their SH2 domains and employ other proteins that are bound to their SH3 domains. The SH3-bound proteins majorly constitute downstream signaling molecules and catalytic subunits, that contribute in the transduction of the insulin signal. Thus, insulin receptor substrates act as the fork in the insulin signal transduction pathways leading into the mitogenic (Ras/MAP kinase) and metabolic (PI3K) pathways.
MITOGENIC PATHWAY (RAS/MAP KINASE)
Grb-2 is a small SH2 domain containing cytosolic adapter protein which docks with IRSs Fig. (7). Grb-2 also contains an SH3 binding domain that binds with proteins through its interaction with proline-rich sequences, and one of such protein is SOS (mammalian homologue of the Drosophila son-of-sevenless protein), a GDP/GTP exchange factor. After insulin stimulation, Grb-2 binds to IRS via its SH-2 domain, and recruits SOS for the activation of Ras signaling pathway. SOS enables the activation of membrane-bound Ras, which is a 21 kDa small molecular weight GTPase, and it plays an important role in cell growth and oncogenesis. The GTP-bound form of Ras gets complexed with Raf-1 kinase and activates it, thereby initiating a cascade that leads to sequential phosphorylation and activation of MAP kinase, MAP kinase kinase and p90RSK. The IR also facilitates the activation of Ras/MAP kinase pathway via another substrate docking molecule called SHC [40]. In response to insulin, SHC also activates Ras and the MAP kinase pathway by making a complex with Grb-2/SOS. After activation with either IRS or SHC, MAP kinase translocates into the nucleus and phosphorylates transcription factors which facilitate the mitogenic and growth promoting effects of insulin [70]. The phosphorylation of nuclear transcription factors influences DNA binding properties and their ability to regulate gene transcription. For example, p90RSK phosphorylates c-fos and MAP kinase phosphorylates Elk-1and in both cases, the transcriptional factor activity is increased. The MAP kinase cascade stimulates glycogen synthase, p90 S6 kinase in turn activates the glycogen-associated protein phosphatase-1, which in turn dephosphorylates and activates glycogen synthase. This indicates that MAP kin-ase pathway is highly significant and possesses the potential to interact with various metabolic signaling pathways. However, MAP kinase pathway is not essential for the stimulation of glucose transport and thus is considered as being critically associated to the mitogenic effects of insulin. In adipocytes, inhibition of the MAP kinase pathway by dominant negative forms of Ras [71] or inhibitors of MAPKK [72] block the transcriptional effects but do not restrict the insulin stimulation of glucose transport or glycogen synthesis.
METABOLIC PATHWAY (PI3K/AKT)
The phosphorylation of IRS-1 or IRS-2 offers docking sites for the SH2 domains of the regulatory subunit p85 of PI3K that is bound to the catalytic subunit p110 as a heterodimer. The lipid products of PI3K include phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol triphosphate (PIP3) [73-75]. These lipid products induce the activation of protein serine kinase cascades through co-recruitment to the membranes via
