26. Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated...

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1440 CNS & Neurological Disorders - Drug Targets, 2014, 13, 1440-1457

Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated Neurological Disorders

Nazir M. Khan1, Ausaf Ahmad2, Rajesh K. Tiwari2, Mohammad A. Kamal3,4, Gohar Mushtaq5 and Ghulam M. Ashraf *,3

1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110025, India 2AMITY Institute of Biotechnology, AMITY University Uttar Pradesh, Lucknow-226010, Uttar Pradesh, India 3King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia 4Enzymoic, 7 Peterlee Pl, Hebersham, NSW 2770, Australia 5Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia

Abstract: The increasing worldwide prevalence of type 2 diabetes mellitus (T2DM) and associated neurological disorders (NDs), such as Alzheimer disease and Parkinson’s disease, have raised concerns about increasing health care and financial burden. Due to the overwhelming growth rate of T2DM and its strong association with NDs, there is an ever-growing and an urgent need to improve the diagnosis and management of the disease. Major hurdles in the management of T2DM comprise of striving for glycemic targets, polypharmacy, patient adherence and clinical inertia. The challenges occurring in the treatment of T2DM are mainly attributed to the complex heterogeneous nature of the disease and its close association with a wide variety of neurological, metabolic and cardiovascular disorders. To overcome these challenges, authors propose to focus on the treatment strategies that employ shared pathogenesis and common molecular denominators involved in the aetiology of T2DM and associated NDs. Impaired insulin signalling (as a result of perturbed redox status), insulin resistance and mitochondrial dysfunction are key molecular events that may lead to the pathogenesis of T2DM and associated NDs. However, effective management of these therapeutic strategies requires holistic experimental evidence from animal as well as clinical human studies. Therefore, a shift in the treatment paradigm from single point glycemic control to shared pathogenesis control would be an ideal approach to combat the alarming progression of diabetes and associated NDs. Therapeutic interventions focused on shared molecular pathogenesis, along with effective glycemic control, may provide protection from associated NDs.

Keywords: Insulin signalling, neurological disorders, non-pharmacological intervention, pharmacological intervention, type 2 diabetes mellitus.

1. OVERVIEW

It has been estimated that approximately 8.5% of the world population currently lives with diabetes mellitus and more than 90% of those people suffer from type 2 diabetes mellitus (T2DM), which is the most common form of diabetes [1]. International Diabetes Federation has estimated that 382 million people had diabetes in the year 2013 and this number has been estimated to reach 592 million by the year 2035 [2]. The American Diabetes Association has projected that increase in the incidence of T2DM will see a concomitant increase in the risk for developing neurological disorders (NDs) [3]. The World Health Organization (WHO) has described diabetes mellitus as a “metabolic disorder of multiple aetiology characterised by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism

*Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Tel: +966552679568; Fax: +966- 26952076; E-mails: [email protected], [email protected]

resulting from defects in insulin secretion, insulin action, or both” [4, 5]. The prevalence of T2DM continues to increase at an alarming rate around the world. The root cause of current pandemic is mainly attributed to modern globalisation, sedentary lifestyle and a sudden increase in unbalanced dietary habits. T2DM is a heterogeneous metabolic disorder. Several epidemiological studies have established a potential link of T2DM with numerous neurodegenerative disorders including dementia and peripheral neuropathy [6]. In a longitudinal prospective cohort study, it was estimated that a diabetic individual has 65% increased risk of developing Alzheimer’s disease (AD) [7]. In addition, patients with T2DM were found to have 36% increased risk of developing Parkinson’s disease (PD) [3, 6, 8]. Due to the devastating nature of T2DM and its high association with NDs, there is an ever-growing and urgent need to improve the diagnosis and management of the disease. Although the pathophysiology and prognosis of T2DM is well studied, its treatment has remained challenging, with only half of the patients achieving the recommended glycemic levels. In the recent past, revolution

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Management of T2DM and Associated Neurological Disorders CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 1441

occurred in diabetes management from simple insulin therapy to the development of an impressive number of potential therapeutic approaches. However, regardless of remarkable progress in treatment strategies, the number of diabetic individuals and related neurological complications continue be on the rise at an alarming rate, thereby posing serious challenges to the health care professionals. Hence, future treatment strategies should focus on addressing multiple clinical endpoints associated with multifactorial nature of T2DM.

2. MOLECULAR PATHOGENESIS OF T2DM AND ASSOCIATED NDs

The challenges occurring in the treatment of T2DM arise mainly due to heterogeneous nature of the disease and its close association with a wide variety of neurological, metabolic and cardiovascular disorders. Therefore, to overcome these challenges, we hypothesize that the treatment strategy should focus more on the complex molecular network underlying basic pathogenesis and shared molecular pathways being implicated in these diseases. The common molecular denominators that are involved in the aetiology of T2DM and associated NDs (including AD, PD and other types of dementia), should be a major point of interest during the management of these diseases. Hence, a shift in the treatment paradigm from a single point glycemic control to shared molecular pathways control may prove beneficial while dealing with all concomitant NDs occurring during the progression of T2DM. Here, we shall be describing here the molecular pathways and shared molecular pathogenesis that are being implicated in T2DM and associated NDs.

2.1. Insulin Signalling Pathways in T2DM

In a healthy human, glucose homeostasis is kept under control (normal range of glucose goes from 80 to 120 mg/dl) by normal insulin signalling pathway. In diabetic individuals, inappropriate insulin response due to pancreatic β-cells dysfunction results in hyperglycemia [4, 5]. Insulin, a key hormone secreted by the pancreatic β -cells, regulates glucose metabolism and plays a major role in the aetiology of T2DM [9]. Insulin resistance is a characteristic feature of T2DM, resulting in impaired insulin response to insulin-dependent cells like skeletal muscles and liver. The various defects in insulin action such as decreased glucose transport and phosphorylation, reduced glycogen synthesis, impaired glycolysis, and aberrant glucose oxidation lead to the development of insulin resistance [10]. Insulin affects glucose uptake in the peripheral tissues by binding to the α -subunit of insulin receptor (IR), a cell surface protein belonging to the receptor protein tyrosine kinase family. This binding leads to phosphorylation of the β-subunit, which results in the activation of insulin receptor tyrosine kinase, hence providing docking sites for adaptor proteins such as insulin receptor substrate (IRS) proteins [11, 12]. At present, four members of the IRS family are known to be involved in insulin signaling, with IRS-1/2 being the most important for glucose transport [13, 14]. Docking of IRS-1 induces the activation of downstream pathways such as the phosphatidyl-inositol 3-kinase (PI3K) and the mitogen activation protein kinase (MAPK) cascade [11, 12] (Fig. 1). The activated PI3K in turn activates protein kinase B (Akt) and stimulates the glucose transport via glucose transporter type 4 translocation to the membrane. Activation of PI3K by phosphorylated IRS-1 also leads to activation of glycogen

Fig. (1). Insulin signalling in T2DM: In T2DM, insulin signalling via insulin receptor substrate1/2-PI3K-Akt pathways is impaired which results in deregulated glucose transport through GLUT-4 (glucose transporter 4) leading to development of insulin resistance and hyperglycemia.

Insulin

Insulin Receptor

IRS1/2

MAPK PI3K PDK-1 AKT

GLUT-4Glucose

Insulin Resistance

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1442 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 8 Khan et al.

synthase [15]. In addition to insulin signalling via PI3K, insulin can activate MAPK, which leads to the phosphorylation of transcription factors that promote cell growth, proliferation and differentiation [13, 16] (Fig. 1). In T2DM subjects, insulin signalling through MAPK pathway remains functional whereas IRS-1/PI3K pathways are impaired, resulting in excessive stimulation of MAPK pathway that is involved in inflammation, cell proliferation and atherogenesis [15].

2.2. Insulin Signalling Pathways in NDs

Existing data suggest that insulin resistance, hyperinsulinemia and T2DM are associated with elevated levels of several pro-inflammatory mediators that increase

the risk of NDs like AD, PD and dementia [17-21]. A recent study has shown that T2DM and PD share remarkably similar dysregulated pathways that lead to the development of these age-related chronic diseases [6]. Although, T2DM and PD are dissimilar in terms of clinical characteristics, they both share common molecular pathways in their pathogenesis. PD individuals are characterized by the presence of intracytoplasmic Lewy bodies consisting of aggregated filamentous α-synuclein and the loss of dopaminergic neurons in the brain. A recent study showed that insulin signaling is impaired in more than 60% of the PD patients who were found to be glucose intolerant [22]. The common molecular pathways leading to the aetiology and progression of both the diseases, as shown in Table 1 and Fig. (2), include mitochondrial dysfunction,

Table 1. Mechanism of action of current treatment therapy for T2DM.

S. No. Drug Mechanism of Action

1 Metformin Reduces insulin resistance and hepatic glucose output; increases peripheral glucose utilisation and glucose turnover between intestine and liver

2 Sulphonyl Urea Directly increases insulin secretion by stimulating pancreatic β-cells and binding to sulphonyl urea receptor1 on β-cells

3 Glinides Directly increase insulin secretion by binding to benzamido site on sulphonyl urea receptor-1

4 Thaizolindines Increase insulin action and adipogenesis; stimulate PPAR-γ; alter glucose-fatty acid cycle

5 Insulin Decreases lipolysis and hepatic glucose output; increases peripheral glucose uptake, storage, and utilisation

6 DPPIV inhibitor Increases insulin secretion and decreases hepatic glucose output and insulin resistance

7 Incretin Increases insulin secretion; decreases glucagon secretion; resistant to degradation by DPP4; potentiates nutrient induced insulin secretion

Fig. (2). Common molecular pathways and physiological process leading to development of T2DM and PD: The mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, glucose intolerance and autophagy lead to insulin resistance, a common molecular denominator for development of T2DM and PD.

Mitochondrial Dysfunction • ROS production• Lipid peroxidation

ER Stress

p p

• Protein aggregation• Unfolded Protein Response

Glucose Intolerance • Hyperglycemia• Loss of Insulin receptor reactivity

Inflammation

Autophagy

• Pro-inflammatory cytokines

• Inclusion bodiesl ip gy • α-synuclein

Insulin resistanceInsulin resistanceInsulin resistanceInsulin resistance

Parkinson Disease

Type2Diabetes

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endoplasmic reticulum (ER) stress, inflammatory response, insulin resistance, impaired glucose tolerance, autophagy and ubiquitin-proteasome mediated degradation pathways [6]. In addition, the transcription factors being implicated in both diseases include peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and hepatocyte nuclear factor 4 alpha that were known to regulate several metabolic genes involved in gluconeogenesis, lipid metabolism and fatty acid metabolism [23]. PGC-1α has been suggested in both T2DM and neurodegeneration to play a key role in mitochondrial biogenesis and gluconeogenesis [6]. AD, the most common cause of dementia among the elderly, is characterised by the aggregation of tau proteins that form neurofibrillary tangles (NFTs) in the brain [24, 25]. Using genomic, epigenomic, transcriptomic and proteomic as well as the gut microbiome and enzymoinformatic approaches, several recent studies have established a molecular linkage between T2DM and AD [26-43]. AD results from age-associated, progressive, chronic neurodegeneration and deficient insulin signalling pathways [44]. In T2DM patients, the defective insulin signalling leads to the impairment of IRS-1/PI3K pathways (Fig. 1). 3-phosphoinositide-dependent protein kinase-1 (PDK1), that is downstream of PI3K signalling, is activated by phosphorylation at Ser241 site by PI3K. The activated PDK1 then activates Akt by phosphorylating it at Thr308. The

downstream of Akt is GSK-3 (Glycogen synthase kinase-3), the activity of which is inhibited by phosphorylation at Ser21 of GSK-3α (Glycogen synthase kinase-3 alpha) or Ser9 of GSK-3β (Glycogen synthase kinase-3 beta) by Akt, leading to glycogen synthesis (Fig. 3). GSK-3β is a major tau kinase that causes the phosphorylation of tau proteins, a characteristic feature of AD (Fig. 3). Further, insulin has been shown to modulate the levels of Aβ peptide by promoting the release of intracellular Aβ through a mechanism that involves insulin degrading enzyme [45, 46]. Hyperinsulinemia leads to increased central insulin levels that compete with insulin degrading enzyme and results in decreased degradation of Aβ. This leads to an upregulation of Cyclin-dependent kinase 5 (CDK) activity, hence causing hyperphosphorylation of tau proteins and promoting the tangle formation, resulting in the development of AD [47] (Fig. 3). Therefore, defective insulin signalling leads to an increased tau phosphorylation through the activation of GSK-3 and CDK-5, thereby resulting in development of AD.

2.3. Shared Molecular Pathogenesis Leading to T2DM and NDs

As discussed above, impaired insulin signalling is central to the pathogenesis of T2DM and the associated NDs including PD and AD (Figs. 1-3). It has been shown that

Fig. (3). Insulin signalling in AD: In AD, defective insulin signalling leads to impaired GSK3β function which results in phosphorylation of tau protein, a hallmark pathological state of AD. In addition, insulin degrading enzyme causes tau phosphorylation through activation of β-amyloid peptide degradation and CDK5 activation.

Insulin

Insulin Receptor

IRS1/2

PI3K

PDK1

AKT

GSK3β

Glycogen Synthesis Tau-phosphorylation

Alzheimer Disease

Insulin Degrading enzyme

Aβ-peptide degradation

Cyclin dependent kinase

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peripheral insulin abnormalities increase the risk of memory loss and neurodegenerative disorders such as AD [47]. The biological basis for the involvement of defective insulin signalling in T2DM and associated NDs lies in the fact that insulin plays a major role in the regulation of multiple molecular pathways including glucose homeostasis, energy homeostasis, neuronal maintenance, neurogenesis, and neurotransmitter regulation. What is the molecular basis of impaired insulin signalling in such diverse but related diseases? Recent evidence suggests that genetic polymorphisms in the genes affecting feeding behaviour and metabolism can result in an increased storage of nutrients that may disturb insulin secretion and action [48]. In addition, environmental factors such as inappropriate quality and excess quantity of nutrients, insufficient physical activity, sedentary lifestyle, low grade inflammation, and oxidative stress, in combination with the genetic factors, may potentially increase insulin resistance and impaired insulin function [49]. Now the question arises whether there is any unifying mechanism that leads to impaired insulin function and the development of T2DM and associated NDs. Oxidative stress has been implicated as a major contributor to the onset and progression of T2DM and related NDs including PD and AD [50]. Oxidative stress is the pathogenic outcome of an imbalanced ratio of reactive oxygen species (ROS) produced and eliminated by the cell’s

antioxidant capacity [51]. In a healthy condition, a delicate balance exists between ROS generation and elimination which is maintained by different complex mechanisms. Malfunction of any of these mechanisms leads to changes in cellular redox homeostasis which may alter the pathophysiological state of various diseases involving oxidative stress [52]. Oxidative stress has been shown to activate a series of stress pathways involving a family of serine/threonine kinases, which in turn have a negative effect on insulin signalling. Hyperglycemia, a hallmark feature of T2DM can cause an increase in oxidative stress due to enhanced membrane lipid peroxidation, increased polyol pathway flux, elevated levels of intracellular advanced glycation end products, activation of protein kinase C, or overproduction of superoxide by the mitochondrial electron transport chain [53-55] (Fig. 4). The increased oxidative stress causes impairment of the insulin signalling pathway that leads to the development of T2DM pathophysiology. The mitochondrial dysfunction has been reported in several PD patients as a result of decreased expression of mitochondrial complex I and impaired function of various mitochondrial genes like SNCA, PARKIN, LRRK2, PINK1 and DJ-1, consequently causing mitochondrial oxidative stress [6, 56]. This plays a pivotal role in the pathogenesis of neurodegeneration and results in the development of PD [57].

Fig. (4). Oxidative stress as a common denominator for impaired insulin signalling: Oxidative stress is result of hyperglycemia, a hallmark feature of T2DM which leads to generation of insulin resistance through activation of inflammatory processes, mitochondrial dysfunction and impaired insulin signalling, resulting into development of T2DM and PD. Oxidative stress causes tangles and plaque formation in brain resulting in AD pathogenesis.

Oxidative Stress

Oxidative Stress

Hyperglycemia

Lipid peroxidation

Superoxide formationPolyol pathway flux

Advance glycation end product

Insulin

IR

IRS1/2

PI3K

PKCSerine/threonine kinase

p qTangles and

plaque yMitochondrial

dysfunction pInflammatory

response

Insulin Resistance

AlzheimerDisease

Parkinson Disease

Type 2 Diabetes

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Furthermore, it has been shown that oxidative stress plays a major role in the pathogenesis of AD where cellular changes through redox-active transition metals and mitochondrial oxidation lead to appearance of the NFTs and senile plaques, the hallmark pathologies of AD [58, 59]. The oxidative conversion of protein side-chains or adduct formation of bifunctional sugar- or lipid-derived products can result in abnormal protein cross-linking. Oxidative changes in nucleic acids, lipids and mitochondrial proteins amplify ROS production that triggers the cells to generate antibodies, tau-phosphorylation and NFTs, resulting in the pathogenesis of AD [60]. Hence, the common molecular denominator for impaired insulin signalling is the development of oxidative stress which forms the major basis for the development of T2DM and associated NDs.

3. APPROACHES AND CHALLENGES FOR THE TREATMENT OF T2DM

T2DM is a multifaceted and progressive disease that requires advanced treatment over time. The basis of a successful therapy relies on deep understanding of the complexity of pathogenesis of the disease and the need for a careful assessment of risk-to-benefit ratio for each type of treatment. The key to any effective T2DM treatment is to intensively control the glucose levels and to delay or prevent the development and progression of serious complications [61]. The major culprit in T2DM pathogenesis is impaired insulin signalling which is also closely linked to neurodegenerative diseases like AD and PD. Therefore, managing insulin signalling is of utmost importance to clinicians.

3.1. Treatment Strategy for T2DM

Major factors responsible for the development of T2DM are impaired insulin secretion resulting from declining β-cell function, decreased glucose uptake by the peripheral tissues, increased hepatic glucose production, in addition to the augmented gluconeogenesis [62-64]. Insulin secretion increases initially in the T2DM subjects as the pancreas attempts to compensate for the elevated plasma glucose concentration for which the insulin-dependent cells (liver and muscle) are unable to respond effectively, eventually leading to the development of insulin resistance [4]. When pancreatic β-cells function decreases significantly with regard to insulin secretion, the resulting insulin resistance contributes to T2DM aetiology [65, 66]. Currently, several therapeutic interventions are available that target the pathophysiological and molecular pathways involved in the aetiology and prognosis of T2DM.

3.1.1. Non-Pharmacological Interventions

T2DM is a progressive disease that results from insulin resistance, IFG (impaired fasting glucose), and IGT (impaired glucose tolerance). The conversion of IGT/IFG to T2DM may take long time if lifestyle management is proper. Sedentary lifestyle is considered as an important risk factor for T2DM [66]. In addition, obesity, central adiposity and age serve as important but modifiable risk factors and contribute to the pathogenesis of T2DM [66]. Hence, initial treatment of T2DM generally begins with non-

pharmacological interventions such as diet, lifestyle and exercise. A randomized clinical trial named “Look AHEAD” (Action for Health in Diabetes) has shown that one year of intensive lifestyle modification resulted in significant improvement in glycemic control, thus highlighting the importance of exercise in the management of T2DM [67]. Routine exercise produces positive results in T2DM patients by improving insulin sensitivity and glucose disposal in the skeletal muscles, expression of nitric oxide synthase in the endothelial cells as well as maintaining proper body fitness [66-69]. A healthy lifestyle corresponds to an optimum dietary intake that includes less than 7% saturated fat and provides adequate energy restriction and sufficient dietary fiber reduction [70, 71]. The diet should include 50-55% carbohydrate, 30% fat, 15-20% protein as well as fiber. The energy requirement of an individual depends on his/her body weight and is calculated by body weight (in pounds) multiplied by 10 plus 30-100% (depending upon extent of exercise) to get energy requirement in Kilojoules.

3.1.2. Pharmacological Interventions

Important lifestyle interventions like healthy food, physical exercise and weight reduction are the first recommended treatment strategies for T2DM. Among the pharmacological interventions, there are anti-hyperglycemic agents such as metformin which is the first line of drug to improve blood glucose control. Even after the usage of metformin, if less than 7% HbA1c levels are not achieved within 2-3 months, then the second stage of glycem-hypoglycemic agents such as sulfonylureas, glinides, thiazolidines or insulin injections are recommended (Fig. 5). Glycem-hypoglycemic agents reduce the plasma glucose level by increasing insulin secretion, reducing insulin resistance and/or delaying glucose absorption in the gut [72-74]. Metformin and thiazolidinediones are potent insulin sensitizers at the hepatic level that inhibit the increased rate of hepatic gluconeogenesis responsible for the elevated rate of hepatic glucose production in patients with T2DM (Table 2) [63, 64, 75, 76]. Thiazolidinediones are potent insulin sensitizers in the muscles, in contrast to metformin which is a weak insulin sensitizer [15]. The thiazolidinediones are excellent insulin sensitizers, exerting a potent anti-lipolytic effect on the adipose tissues, where they have been shown to improve β -cells function [63]. Glucagon-like peptide-1 receptor (GLP-1R) agonist and dipeptidyl peptidase (DPP-4) inhibitors are tier 2 therapy for T2DM and they are known to preserve β -cells function. Recently, incretin based therapies like exenatide and liraglutide have been used in the treatment of T2DM with a successful glycemic control. In many cases, however, anti-hyperglycemic or glycem-Hypoglycemic treatment regimen is not usually enough to achieve adequate blood glucose control and, therefore, insulin therapy is intensified [72, 77, 78]. Nonetheless, insulin therapy has a number of risks associated with it such as hypoglycemia, weight gain, and increased risk of colorectal cancer [79]. With the advancement in anti-hyperglycemic agents, it is clear that combination therapy targeting fundamental pathways is a viable and rational approach for managing T2DM. The weight gain associated with thiazolidinediones can be prevented by combining therapy with exenatide. Furthermore, pathophysio-

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logy based algorithm with early triple-combination therapy consisting of thiazolidinediones, metformin and exenatide, may provide durable results.

3.2. Challenges During Treatment of T2DM

T2DM is a complex metabolic disorder, with its pathophysiology being highly heterogeneous, that necessitates the need for treatment strategies focusing on multiple dimensions of the disease. With the advantage of well-

studied molecular mechanisms of T2DM pathogenesis, several targeted approaches for the treatment are available. However, these treatment strategies often produce unsatisfactory results and have been challenged with the problem of poor glycemic control. Despite major efforts for improving glycemic control, the levels of HbA1c remain problematic in T2DM individuals. International Diabetes Federation report noted that HbA1c levels in T2DM patients were found to be well above the target of 7% in different parts of the world [80]. Inspite of having seven different classes of drugs and more than 30 alternative medicines, why

Fig. (5). Therapeutic approaches available for T2DM. Among available seven therapies for T2DM, metformin serves as first of line of therapy whereas other hypogylcemic agents are used as second line of therapy for T2DM.

Table 2. Plant/herbs as potential therapeutic solutions for the treatment of T2DM and associated NDs and their possible mode of action.

Disease Plant/Herbs Mode of Action

Type 2 Diabetes

Whole grain intake Hypoglycemic and insulin sensitizing properties

Dairy food Hypoglycemic and Hypolipidemic properties

Fish oil Hypoglycemic and Hypolipidemic properties

Turmeric Antioxidant, anti-inflammatory and insulin sensitizing properties

Garlic Hypoglycemic properties

Onion Hypoglycemic and hypocholesterolemic properties

Fenugreek Antioxidant, anti-inflammatory and insulin sensitizing properties

Guava glycemHypoglycemic properties

Pomegranate Hypoglycemic properties

Jackfruit Hypoglycemic and hypolipidemic properties

Neurological disorders

Ocimum sanctum Activation of hypothalamic-pituitary-adrenal-axis

Bacopa monneira Modulation of mitochondrial dysfunction

Evolvulus alsinoides Modulation of oxidative stress

Withania somnifera Modulation of mitochondrial dysfunction

Metformin

SulfonylUrea

Glinides

Thiazolidine

Insulin

DPPIV Inhibitor

Incretin

T2D Therapy

First line of therapy

Second line of therapy

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does HbA1c control remain so elusive? The management of T2DM patients presents a number of challenges to clinicians which include poor glycemic control, presence of comorbidities, potential for polypharmacy, non-adherence to medications, and micro-vascular and macro-vascular complications (Fig. 6). All these challenges contribute to difficulties in optimising outcomes of T2DM subjects. Patient adherence to medication is one of the greatest obstacles for the clinicians in treating T2DM patients [81]. Typically, multidrug regimens are necessary for T2DM patients to manage hyperglycemia [82]. The adherence rates for oral anti-diabetic therapies have been shown to decrease by 5-25% with the addition of one to three medication doses because of the complex prescription patterns and increased frequency of dosing [83, 84]. It has been reported that the mean adherence rates for a drug taken once daily are approximately 80%, and the adherence rates decrease by 4-14% for every increase in dosage frequency up to 4 doses per day [84]. It has been demonstrated that non-adherence is higher among patients with diabetes than those with other common conditions [82]. A prospective study has shown that 15-39% of patients are non-adherent to oral anti-diabetic drugs [85]. Furthermore, Grant et al. (2000) have reported that there is a marked increase in the usage of multiple oral diabetic medications (polypharmacy) as a part of medical management of T2DM. The number of visits listing at least five prescriptions increased from 18.2 to 29.9% during the period from 1991 to 2000 [86, 87]. The large number of medications prescribed without sufficient explanation provided by the physicians to their patient’s results in

patients’ refusal and resistance to comply with the regular use of medications. Therefore, multidrug treatment of T2DM is a serious challenge to the clinicians especially with respect to patients’ compliance for medication [87]. Adherence to therapy is not just a problem for patients, but is also a setback for the physicians. The failure of clinicians to initiate or intensify a suitable therapy in patients who are not at the evidence-based therapeutic (e.g., glycemic) goal is termed as clinical inertia [81]. Such a lack of therapeutic appropriateness imposes a major challenge to the patients, although they are an integral part of the T2DM management team. Patients’ lack of diabetic education leads to poor understanding and ineffective care of the disease. The obstacles such as the restraints of the healthcare process, patient adherence and fear, and individual metabolic needs have together contributed to clinical inertia and hindered therapeutic success. Therefore, patients should be empowered via an appropriate training to prevent or treat their hyperglycemia. The presence of co-morbidities is another major challenge faced by physicians during treatment. The cardiovascular disease is the major cause of death among people with T2DM. The Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) showed that approximately 50% of all mortalities in T2DM patients are due to cardiovascular problems [82, 88]. In addition, the United Kingdom Prospective Diabetes Study (UKPDS) suggested that nearly 25% of patients develop micro-albuminuria within 10 years of diagnosis of T2DM [89]. Therefore, renal impairment disease is also a major challenge to clinicians during treatment of T2DM patients.

Fig. (6). Current challenges during treatment of T2DM: Pictorial representation of major challenges faced by clinicians during treatment of T2DM.

T2D Treatment Challenge

Polypharmacy(Multi drug

regimenClinical Inertia (lack of diabetes

education)

Non-adherence to medication

Poor glycemiccontrol

Sedentary life style

Obesogenicculture

Dietary adherence

Co-morbities

Depression

Vascular complication

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Furthermore, the sedentary lifestyle, obesogenic culture, cost, accessibility, social support, health illiteracy, all contribute to poor diabetes control. T2DM has been found to be associated with several NDs. For instance, it was found that depression is frequently noted in T2DM patients which interferes with optimal T2DM treatment. Depression has been shown to be associated with poor self management of T2DM due to lesser physical exercise and dietary adherence among patients with depression. Additionally, depression can create a tendency in T2DM patients to skip their doctor’s appointment which may lead to imbalanced glycemic controls.

3.3. Management of Challenges During the Treatment of T2DM

The management strategies that have been demonstrated to improve T2DM treatment include practice redesign, team-based approaches, care managers, flowsheets, reminders, quality improvement efforts and numerous educational initiatives [81]. The general management of T2DM subjects should focus on educating the patients. The national standard of diabetes management has suggested that patients should be educated about disease process, treatment options, nutritional and exercise plans, knowledge of the prescribed diabetes medicines, blood glucose monitoring, knowledge of acute and chronic complications, psychosocial issues and individual strategies to promote health [90]. For effective management, the Diabetes Prevention Program Research Group has highlighted the concept of right therapy in the right patient at the right time. The major focus should be on a healthy and balanced diet aimed at maintaining normal body weight and avoiding to be overweight. An earlier study had indicated that as little as 10% weight losses can have dramatic effects on the blood glucose levels and even progress in the treatment of T2DM. A healthy lifestyle not only affects the blood glucose levels but also interferes with insulin resistance, the pathogenic basis of T2DM. Further, lifestyle measures have an impact on cardiovascular risk factors, such as blood pressure, lipids and weight. Hence, diabetes self-management education has the potential to improve diabetes care. To overcome the problem of polypharmacy, combination therapy is recommended to T2DM patients which includes combining more than one drug in one pill, which may provide an advantage [87]. Simplifying drug regimens is of utmost importance for T2DM patients. Adherence has been reported to increase from 61% to 86% when patients were given a fixed-dose combination tablet compared with multiple tablets [49]. A recent study showed that the adherence (medication possession ratio) and HbA1c levels improved significantly upon switching to fixed-dose combination therapy in comparison to dual therapy [91]. Fixed-dose combination has the advantage of limiting the number of tablets per day and minimizing the total number of daily doses, thereby promoting adherence [83, 92]. The first line of therapy for T2DM patients is undoubtedly metformin, which is an economical and efficacious oral anti-diabetic drug. However, the second tier of therapeutic interventions is difficult to unify due to the lack of prospective studies. Based on the profile of the

T2DM patients, a choice of second drug can be made as follows: sulfonylureas when a rapid drop in HbA1c is desired, glinides when a secretagogue for postprandial control is needed, and thiazolidinediones when insulin resistance is overwhelming. GLP-1 mimetics may be preferred when weight is a major issue and DPP-4 inhibitors are chosen when an oral beta cell secretagogue is needed. Furthermore, new glucose lowering agents (exenatide and liraglutide) exploiting the incretin concept offer another area of interesting alternatives. A stepped-care approach to drug therapy provides the most rational and cost-efficient approach for management of T2DM. Pharmaco-economic analyses of clinical trials are needed to determine cost-effective treatment strategies for management of T2DM. If combination of two oral agents fails to provide adequate glycemic control, the current approach for the management of T2DM patients is to initiate insulin therapy. Insulin therapy is still the necessary step for all patients when combinations of oral anti-diabetic agent are not sufficient to control hyperglycemia. However, for every 10 units of insulin administered, an average of 1 kg of weight may be gained [93]. Early and sustained glycemic control is important and glucose control should be embedded in a multifactorial approach. Controlling glycemia is just one part of T2DM therapy. Other risk factors such as elevated lipid levels and high blood pressure are also needed to be addressed. Efforts should be made to substantially increase appropriate use of self-monitoring, providing both the patient and the clinicians with considerable information necessary to achieve glycemic goals. It is essential for both the clinicians and the patients to recognize the need for comprehensive care that includes glucose, lipid and blood pressure control to improve the patient outcomes.

4. APPROACHES AND CHALLENGES FOR THE TREATMENT OF NDs

The term “neurological disorder” encompasses various types of brain disorders. However, the present article, focuses primarily on altered metabolism-induced disorders such as T2DM and the associated NDs including PD, AD, dementia and to some extent depression and related neurodegenerative diseases [3, 6-8]. Hence, our approach is centred around the treatment of NDs by focusing on those therapies which are also linked to the treatment of T2DM. This knowledge may impart insights into various interesting queries such as why and how these therapies will prove to be helpful in both T2DM and NDs, whether these therapeutic agents modulate some common molecular pathway which could be the basis of both T2DM and NDs or the therapeutic effect is a mere reflection of normalizing one disorder via a molecular pathway and thereby accommodating other disease also. Perturbations of insulin signaling and glucose metabolism during T2DM lead to increased glycation, toxic lipids, oxidative load, neuronal apoptosis, mitochondrial dysfunction and damage to the blood brain barrier [53, 55, 94-96]. These changes have detrimental effect on brain metabolism and contribute towards neurodegeneration and various NDs. Here we highlight the action of various anti-diabetic drugs in the treatment of some common NDs:

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4.1. Intranasal Insulin

A number of clinical trials have shown that intranasal insulin improves memory in individuals suffering from various forms of dementia and mild cognitive impairments [97, 98]. But these effects have been observed in a differential manner depending upon the presence or absence of APOE-€4 allele [97]. Thus, inspite of promising effects of intranasal insulin in the treatment of neurological impairments, there exists a need to conduct long term clinical trials of exogenous central insulin administration at various doses in large and diverse populations.

4.2. Amelioration of Hippocampal Dysfunction

The hippocampus is one of the key regions in the brain performing various crucial functions such as learning and memory, regulation of circadian glucocorticoid rhythm and inhibition of HPA (hypothalamic-pituitary-adrenal) axis responses to stress [99]. Memory deficits and various forms of degenerative diseases are related to a decrease in cholinergic synaptic terminals in the hippocampus [100, 101]. Persistent stress and sedentary lifestyle lead to hippocampal atrophy and deregulation of HPA axis - a major cause of depression and other neurodegenerative diseases [99, 102, 103]. A number of studies suggest that changes in the hippocampal dopamine levels and concomitant perturbations in acetyl cholinesterase activity are induced by stress [102-104]. The choline acetyltransferase (ChAT) is the rate limiting enzyme of acetyl choline. ChAT is abundantly present in the CA1 area of the hippocampus and it is colocalized with insulin signaling proteins such as insulin receptor subunits, IRS-1, Akt, and GSK3β [105]. Acetylcholinesterase inhibitors, which limit the breakdown of acetyl choline, are the drugs of choice in regulating cholinergic signaling for the treatment of AD [106]. Studies on intracerebral streptozotocin (ic-STZ) induced diabetic rats have shown that administration of peroxisome proliferator-activated receptor (PPAR) agonists results in an increase in insulin receptor sensitivity as well as ChAT expression with improved performance in spatial memory in Morris water maze [107]. This signifies the importance of cholinergic neurotransmission as a potential therapeutic target. Furthermore, modulations in insulin signaling have been strongly linked with hippocampal synaptic plasticity mechanisms such as long-term potentiation (LTP) and long-term depression. Activation of cholinergic receptors augments LTP as a result of increased expression and function of the glutamate receptor subtypes such as N-methyl-D-aspartate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [108]. Synaptic plasticity and insulin signaling is directly associated with GSK3β. The hippocampal LTP is induced by the inhibition of GSK3β [109, 110]. Thus, amelioration of hippocampal dysfunction via regulating cholinergic and glutamatergic neurotransmission, monoamines and LTP through modulation of insulin signaling is an important therapeutic approach towards treating various NDs such as depression, memory deficits, PD, AD and dementia etc.

4.3. Modulation of PPAR Signalling

The ligand activated transcription factors (PPAR-α/β and PPAR-δ/γ) are differentially expressed in various tissues

such as fat, skeletal muscles, liver and brain [111, 112]. In the brain, those ligand activated transcription factors are expressed in microglia, astrocytes, neurons, and oligodendrocytes, although at different levels [113]. They play a significant role in cellular processes such as cell differentiation and metabolism [114, 115]. Metformin, a potent anti-diabetic drug, that is known to alter PPAR-γ coactivator-1α (PGC1α) signalling, has been reported to be involved in mitochondrial biogenesis and a variety of cellular stress conditions [116]. Metformin also reduces tissue inflammation and oxidative stress [117]. Metformin’s exact mechanism of action at the cellular level is not clearly understood. However, a number of studies have suggested that metformin hinders the cAMP-protein kinase A pathway and hepatic glucose synthesis by inhibition of adenylyl cyclase [118]. One study has reported that metformin administered to patients suffering from T2DM and AD resulted in a decrease in cognitive abnormalities as compared to the untreated patients [119]. Metformin decreases Alzheimer’s like neuronal changes in the obese model of mice [120] and also reduces tau phosphorylation [121]. These observations are directly relevant because mitochondrial dysfunction, stress-induced oxidative changes, hepatic glucose alterations and tau phosphorylation are the major contributing factors to NDs like AD, dementia and other neurodegenerative diseases. Not all studies establish metformin as a neuroprotective agent, with one trial showing that T2DM patients have an increased risk of AD when administered with metformin [122]. In certain cases, acute administration of metformin was shown to enhance the brain damage after stroke episode in mice, while chronic exposure indicated that the drug was neuroprotective [123]. The schedule and timing of metformin treatment reported to perturb AMPK activation in a different manner [123]. Thus, the biggest challenge for using metformin for brain diseases is the correct timing in terms of the pathological state as well as proper dosage and management of treatment schedule. A number of studies explore the prospect of using PPAR agonists like rosiglitazone and pioglitazone for the treatment of NDs [124-126]. Recently, it has been reported that PPAR-δ agonist reduces neuronal inflammation, thereby providing protection against neurodegenerative diseases [127-129]. PPAR-γ stabilizes the mitochondria, prevents neuronal apoptosis and ROS generation through up regulation of anti-apoptotic protein bcl-2 [130]. The neuroprotective effect of PPARγ is also related to its involvement with neurotrophins signaling and promoting the nerve growth factor and brain-derived neurotrophic factor levels [131, 132]. A number of studies involving experimental models of animals have demonstrated the effectiveness of PPAR-γ agonists for the treatment of NDs [133-137]. However, in case of human studies, the observations regarding its neuroprotective nature is not consistent. Clinical trials have shown promising results with rosiglitazone in AD patients via an improvement of memory in cases of mild to moderate symptoms [124]. On the other hand, results from a larger group of patients have demonstrated no neurological improvement with rosiglitazone use in patients with AD [138]. The mechanism of action of thiazolidinediones involves PPARs, which act through transcriptional co-activators such as PGC-1α. Thus, the usefulness of thiazolidinediones in the treatment of NDs can be ascribed to a decrease in proinflammatory cytokines

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of activated microglia cells [139]. Furthermore, the direct action of drugs on dopaminergic system and mitochondria cannot be ruled out [140, 141]. Together, these studies suggest that activation of PPARs, particularly PPAR-γ, may be neuroprotective and support neuronal survival.

4.4. Targeting GLP-1R

GLP-1R is abundantly expressed in the brain and functions as a neuroprotective hormone [142, 143]. GLP-1R agonists have demonstrated a strong neuroprotective effect in various animal models of AD [144], PD [57, 145] and other NDs [146]. These benefits of GLP-1 have been observed in terms of behavioral, biochemical, and electrophysiological changes [147-150]. Therefore, there is an increased interest among researchers to evaluate the efficacy of GLP-1R agonists (conventionally used for the setting of T2DM) in patients with neurological abnormalities. The exact mechanism of action of GLP-1R agonists’ treatment still remains to be elucidated. However, several mechanisms have been proposed including reduced neuroinflammation [57], alteration of cell signaling to enhance survival [143], enhancement of hippocampal LTP during memory-impairment [148], reversion of neurodegeneration [147, 150] and increased neurogenesis by promoting the neural stem cell proliferation [149]. GLP-1R agonists may only show assistance in neurological abnormalities when they are linked with some pathological conditions [151]. Nevertheless, sensing the considerable potential of GLP-1R agonists for the treatment of various NDs, a number of clinical trials have been currently set up. Furthermore, an enzyme DPP-4 degrades GLP-1 [152]. However, specific DPP-4 inhibitors like sitagliptin and alogliptin increase the half-life of endogenous GLP-1 and, consequently, lengthen the cellular activation of GLP-1R [152, 153]. DPP-4 inhibitors have shown beneficial effects on learning and memory in animal models of AD [154] as well as reduction of tissue damage during cerebral ischaemia [155] and neuroprotective effects in stroke models in mice [156]. The molecular mechanisms for neuroprotection mediated by GLP-1R agonists and DPP-4 inhibitors may not be overlapping. Hence, in spite of promising results, more detailed studies are required to show achievable benefits of these compounds for the treatment of AD and other NDs.

4.5. Amelioration of Stress-Induced Perturbations

Enhanced modern globalization, physical and psychological stress and explosion of unbalanced dietary habits in the present day life style are the major contributors towards the pathogenesis of T2DM and associated NDs [3, 157]. The autonomic and HPA-axis perturbations during chronic stress augment the metabolic deregulations [102]. Stress-induced changes like oxidative load, neuroinflammation, glycation, toxic lipids, neuronal apoptosis, mitochondrial dysfunction, aberrant insulin signaling, altered glucose and energy homeostasis, restricted neurogenesis, neurotransmitter levels and damage to the blood brain barrier have been implicated as major contributors towards the onset as well as the progression of T2DM and related NDs including PD, AD and depression [53, 54, 94, 95, 102]. Hence, normalizing the stress response

is crucial for the management and treatment of stress-induced metabolic changes and related pathologies like T2DM and NDs. The oxidative burden of cells can be minimized either by using exogenous antioxidants or through facilitation of endogenous antioxidant systems. Rutin, is a flavonoid compound, has been shown to ameliorate stress-induced damage and neuroinflammation in a streptozotocin model of rats [158]. Flavonoids and carotenoids, the ubiquitous antioxidants, have also demonstrated neuroprotective action in different animal models through the modulation of redox state [159, 160]. Lutein is an example of carotenoid that improves cognitive impairments in females when administered with docosahexaenoic [161]. The natural antioxidant curcumin possess anti-inflammatory and amyloid-disaggregating properties in AD transgenic mice [162]. Curcumin also modulates monoamine and HPA-axis response [163]. A recent study has shown the potential of PGC-1α in modulating both T2DM and neurodegeneration due to its key involvement in mitochondrial biogenesis, energy metabolism and mitochondrial antioxidants expression [6]. The progression of dementia has been show to have an inverse correlation with the expression of PGC-1α in human brain [164]. Another study has reported that PPAR-γ activation reduces the plasma corticosterone levels by modulating the autonomic and HPA-axis responses to stress in rats [165]. Chronic administration of rosiglitazone normalizes stress-induced enhancement of corticosterone levels, heart rate, and hypothalamic level of c-Fos protein (a marker of early neuronal activation) [165]. Rosiglitazone has also been reported to reduce corticosterone levels in a mouse model of AD [133]. Although the anti-stress mechanism of PPAR agonists is not well established, but they might work through their influence on glucocorticoid expression, thereby decreasing the stress-induced perturbations [166]. Thus, the therapeutic potential of PPAR agonists both in T2DM and various NDs may be linked to their anti-stress and antioxidant properties.

5. COMMON DENOMINATORS IN THE CHALLENGES DURING TREATMENT OF T2DM AND ASSOCIATED NDs

Management of stress-induced physiological, biochemical, pathological and molecular perturbations is the biggest challenge for the treatment of T2DM and associated NDs. However, shared molecular pathways leading to pathogenesis of both T2DM and associated NDs are common denominators that should be aimed as comprehensive treatment strategy. Impaired insulin signaling as a consequence of perturbed redox state of cell, insulin resistance and mitochondrial dysfunction are important molecular events that lead to the pathogenesis of T2DM and associated NDs. Hence, targeting these shared molecular pathways as a common denominator would be an ideal approach to treat both T2DM and associated NDs simultaneously. To underscore the importance of shared pathogenesis in the treatment of T2D and associated NDs, we constructed a molecular network using bioinformatics approach to examine the functional significance of common molecular denominators. Network analysis can help understand the

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molecular and cellular interactions. We investigated functional interaction among genes and proteins using online interaction databases curated from literature and knowledge based sources to demonstrate the implication of common molecular network. We selected two different web-based network tools: Search Tool for the Retrieval of Interacting Genes (STRING) and Gene Multiple Association Network Integration Algorithm (GeneMANIA) using the genes involved in pathogenesis of T2DM and associated NDs as query gene sets. These tool-sets integrate computational methods to predict gene functions based on a collection of interaction networks and the results can be visualized to represent entities (nodes) and their relationships (arcs). The results as shown in Figs. (7, 8) demonstrate the enrichment of various genes involved in insulin signalling pathways (for example insulin, insulin receptor, insulin receptor substrate and MAPK1/3) as nodes in the interaction network (Figs. 7, 8). These results highlight the importance of insulin signalling as common denominator in pathogenesis of T2DM and associated NDs. The information generated through GeneMANIA shows results for interactive functional associative network according to their gene ontology function. This network occurs not only by integrating functional genomic and proteomic data but also by rewiring new pathways and, hence, would be of tremendous value to understand the complete bandwidth of shared pathogenic processes. Targeting shared molecular networks as a treatment modality would require a holistic view of burden of NDs among T2DM patients and comprehensive understanding of disease diagnosis and prognosis. However, such denominator therapy would be more useful if administered through

correct therapeutic window. Although various strategies employing shared molecular pathogenesis have been undertaken such as modulation of redox state, HPA-axis response, neurotransmitter signaling and neuroinflammation etc [99, 157, 167, 168], more studies are needed to decide whether these possible therapies could be used independently or in combination considering the variability in the severity and pathological states of T2DM associated NDs. A previous study has also proposed the importance of common inflammatory signaling pathways in translating basic research into clinical applications [169]. Previous studies have demonstrated that antioxidants and ROS inhibitors show a promising picture in normalizing T2DM and associated NDs. A challenge still exists to evaluate the bioavailability and tissue distribution of these drugs [170]. Intestinal metabolism, absorption and crossing the blood-brain-barrier are some of the important factors which can alter the bioavailability of these drugs, especially the natural antioxidants like curcumin, flavonoids and carotenoids [171]. Furthermore, depending on the concentration and cellular environment, the antioxidant molecules can also behave as pro-oxidants [172]. This disparity in the nature of antioxidant compounds is one the major reasons for their failure in clinical trials [173]. Another challenge faced in the treatment of T2DM associated NDs using antioxidants and/or ROS inhibitor is the appropriate timing. This is even more significant due to the fact that most of these NDs are degenerative diseases with long period of latency. Hence, the failure of various antioxidants in clinical trials may reflect a condition when sufficient damage has already been done.

Fig. (7). Molecular interaction network of genes involved in pathogenesis of T2DM and associated NDs: Network analysis from querying STRING protein network (evidence view) with proteins involved in pathogenesis of T2DM and associated NDs showing enrichment of insulin signalling pathways as molecular interaction node.

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A recent study has demonstrated that the different types of free radicals generated in various regions of brain after exposure to chronic stress may determine modulation of neurotransmitters either through changes in neurotransmitter levels and/or by effects on receptor functioning. Both the monoamine levels and oxidative systems influence each other’s functioning [102, 174]. Thus, more studies are required to understand the neurochemical and antioxidant defense system interactions with the insulin signaling pathway that may possibly be involved in the biological basis of depression and other neurodegenerative conditions [102, 174]. These studies suggest implications for pharmacological interventions targeting simultaneously the central monoamines, cellular antioxidants and insulin signaling as a potential stress management strategy for protecting against stress-induced brain disorders [102, 174]. The various plant products and herbs that can be used as promising target for the treatment of T2DM and associated NDs and their mode of action were explained in Table 2. In the last decade, numerous adaptogenic plants extracts such as Ocimum sanctum, Bacopa monneira, Evolvulus alsinoides, Withania somnifera and/or their constituents have been used to demonstrate their neuroprotective role, mostly through the modulation of monoamine, HPA-axis, neuronal apoptosis, mitochondrial dysfunction and oxidative load [102, 157, 167-169]. One recent study demonstrated that the novel constituents of Ocimum sanctum decrease the activation of HPA-axis via the reduction of circulating corticosterone levels during chronic stress. It is interesting to note that these compounds also reduced the pro-oxidant action of monoamine metabolites and ameliorate the altered redox state and, thus, work by an overall normalization of stress-induced responses [102, 157]. Surprisingly, most of these

studies have not addressed the issue of molecular changes at the level of insulin signaling. Therefore, it is highly relevant and challenging to evaluate the molecular mechanisms of various anti-stress and neuroprotective agents. For proper management of T2DM and associated NDs, the evaluation of anti-oxidant and anti-inflammatory properties of a probable neuroprotective agent might not be sufficient in the present scenario; rather, there should be a holistic approach to link the studies with a focus on the signal transduction changes of molecules such as insulin receptor subunits, IRS-1, Akt and GSK3β which are involved in the pathophysiology of both T2DM and NDs.

CONCLUSION

In the present review, we have provided a detailed discussion of various anti-diabetic drugs in the treatment of some common NDs with a focus on complex molecular network underlying basic pathogenesis and shared molecular pathways being implicated in these diseases. However, for an effective management of these therapeutic possibilities, there are still several issues and challenges that need to be overcome [175]. The most important one is the need for well designed, detailed and holistic research in various animal models of T2DM and associated NDs, supported by placebo-controlled trials in large and diverse populations. The precise diagnosis of certain NDs such as dementia, AD, and PD, along with the knowledge of current physiology and genetic predisposition of related metabolic disorders is important for improved management of therapy. Another important challenge is the bioavailability of various anti-diabetic drugs, especially when it has to cross the blood-brain-barrier for its central effect. Hence, more

Fig. (8). Gene interaction network of genes involved in pathogenesis of T2DM and associated NDs: Network analysis from querying GeneMANIA with genes involved in pathogenesis of T2DM and associated NDs showing enrichment of insulin signalling pathways as interaction node.

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work is needed for improving the penetration of drugs such as metformin, pioglitazone and GLP-1R agonists into the brain [176-178]. It is crucial to enhance the pharmacological properties of these drugs by synthesizing their lipophilic derivatives and analogs. Risk assessment of drugs is another important area to look upon in future. Various risk factors while using anti-diabetic drugs must be considered for the treatment of NDs with and without diabetes. An example in this regard is increased risk of myocardial infarction with the clinical usage of rosiglitazone [179]. A better insight into the molecular mechanisms of GLP-1R agonists and DPP-4 inhibitors is required, particularly to ascertain their crosstalk in terms of their pharmacological action. Finally, in order to project the effectiveness of shared pathogenesis-based therapies, more studies are warranted to confirm the neuroprotective prospects of combinations of anti-diabetic drugs and anti-stress agents.

LIST OF ABBREVIATIONS

AD = Alzheimer’s Disease Akt = Protein Kinase B ChAT = Choline Acetyltransferase CDK5 = Cyclin-Dependent Kinase 5 DPP-4 = Dipeptidyl Peptidase-4 GLP-1 = Glucagon Like Peptide-1 GLP-1R = Glucagon Like Peptide-1 Receptor GSK-3 = Glycogen Synthase Kinase-3 HPA = Hypothalamic-Pituitary-Adrenal IGT = Impaired Glucose Tolerance IRS = Insulin Receptor Substrate LTP = Long-Term Potentiation MAPK = Mitogen Activation Protein Kinase ND = Neurological Disorder PD = Parkinson’s Disease PI3K = Phosphatidyl-Inositol 3-Kinase PPAR = Peroxisome Proliferator-Activated Receptors PGC-1α = Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha ROS = Reactive Oxygen Species T2DM = Type 2 Diabetes Mellitus

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

ACKNOWLEDGEMENTS

The authors are grateful to DSR and KFMRC, King Abdulaziz University (Jeddah, Saudi Arabia) for the facilities provided.

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Received: April 20, 2014 Revised: May 11, 2014 Accepted: May 12, 2014

PMID:25345504

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26. Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated...

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