**1. Introduction**

### **1.1 Diabetes mellitus**

Diabetes mellitus (DM) is often incident endocrine disorder in many countries [1]. The International Diabetes Federation reported that 6 million people die directly from diabetes every year, and additional 318 million people are suffering with DM. This number is predicted to reach 642 million by 2040 [2] and 693 million by 2045 [3]. DM is a heterogeneous group of chronic disease characterized by a relative or absolute lack of insulin resulting in hyperglycemia [4]. It causes a variety of complications as cardiovascular disease, renal failure, neuropathy, and retinopathy [5]. Chronic hyperglycemia mostly deteriorates the vascular tree and promotes the development of micro- and macrovascular disease [6]. It was reported that hyperglycemia accelerates the development of DM complications through some mechanisms such as increased aldose reductase-related polyol pathway flux, formation of advanced glycation end products (AGEs), increased hexosamine pathway flux, activation of protein kinase C isoforms, and rising generation of reactive oxygen species [7]. Metabolic imbalance in the peripheral nervous system that is activated in the diabetic milieu of hyperglycemia, impaired insulin signaling, and dyslipidemia are the key parameters in the development of diabetic neuropathy [8]. The determining points involve multiple mechanisms of glucose toxicity

including polyol pathway activity, hexosamine pathway, nonenzymatic glycations of proteins, and altered protein kinase C activity [9]. Activation of these pathways can eventually flow into inflammatory and oxidative stress in neurons and adjacent microvascular system [10].

DM is divided into two main forms—type 1 and type 2 [4]. Type 1 diabetes mellitus (T1DM) or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease and is a result of β cells' death, because a foreign protein is incorporated into islet β cells. In response, lymphocytes attack the foreign protein and unwillingly destroy β cells as collateral damage. It causes an absolute insulin deficiency [11]. It is uncertain what activates the autoimmune response, but some environmental factors as toxins, viral infections, and psychosocial inputs are thought to play a plumbless role [12].

Historically, the usual ratio for T1DM to T2DM has been 1:20. Now it is changing because of expressive increase in the incidence of T2DM in children and young people [11].

### **1.2 Diabetes mellitus type 2**

Type 2 diabetes mellitus (T2DM) or non-insulin-dependent diabetes mellitus (NIDDM) is a syndrome of β cells' dysfunction including relative insulin deficiency associated with insulin resistance [11] and compensatory increases in insulin secretion [13]. It is associated with incorrect sensing of glucose signals by the β cells. T2DM is linked to a stage of insulin resistance. Insulin secreted by the β cells and bound to liver, muscle, and fat cells is subnormally efficacious in carrying out its metabolic action [11]. Generally, T2DM is characterized by the incapability of the pancreatic β cells to secrete appropriate quantities of insulin in order to offset hyperglycemia arising from peripheral insulin resistance and increases hepatic glucose output [14]. It is a multifactorial and complex disorder [13] that is estimated to affect more than 100 million people worldwide [15]. About 80% of all people with diabetes suffer from T2DM [16]. Insulin resistance alone is insufficient to cause diabetes. A progression to overt diabetes required β cells' failure as well [16–18]. Insulin resistance is associated with decrease in insulin receptors in target tissues (muscle, fat, or liver) and insulin receptor kinase activity that causes decrease in glucose transporter 4 (GLUT 4) translocation due to impaired signaling [19]. The onset of T2DM is preceded by an expressive increase in the plasma levels of free fatty acids (FFA) and by sixfold rise in triglyceride (TG) concentration in the pancreatic islets [20]. Chronic exposure to high glucose level and rising FFA concentration is detrimental to β cell function. This situation results in weak glucose-induced insulin secretion and rising level of apoptosis [21].

In spite of the increasing number of T2DM, little is known about the prevention of the disease and its complications at early stages [22]. In this stage insulin-sensitive tissue such as adipose tissue and skeletal muscle become insulin resistant. This causes the development of impaired glucose tolerance, and it can occur over a few years [23].

The pathogenesis of T2DM is complex and is primarily related to gene variation, external and internal environmental factors, abnormal protein modifications, oxidative stress, epigenetic effects, and energy metabolism disorders [24]. It was revealed that also the gut microbiota has been recognized as a key contributor to T2DM, and T2DM is linked to dysbiosis of the intestinal microbiota [25].

#### **1.3 Obesity in type 2 diabetes**

Onset and development of T2DM is commonly incurred by several factors, which are combined with lifestyle, obesity, genetic defects, virus infection, and

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*Zucker Diabetic Fatty Rats for Research in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.88161*

of impaired glucose tolerance and T2DM [27].

hunger-satiety mechanisms [33].

**2. Zucker diabetic fatty rats**

drugs [16]. Obesity is defined as a pathological excess of body fat that results from a permanent positive energy balance [26]. Persistent positive energy balance is pertinent to increased storage of triglycerides. This expands the adipose depots and increases the proportion of hypertrophied adipocytes [27]. Under condition of obesity, the lipid storage capacity of adipocytes is overcome, resulting in adipocyte-derived fatty acids and cytokines leaking into the circulation [28]. Damaging lipid species accumulates in ectopic tissue causing local inflammation and provides lipotoxicity [29]. Lipotoxicity determines an important link between obesity, insulin resistance, and T2DM. It interprets the harmful cellular effects of chronically increased concentrations of fatty acids and excess lipid accumulation in tissues other than adipose tissue. Excess adiposity is considered to promote the onset and severity of insulin resistance, contributing to emergence and progression

Obesity-induced insulin resistance accelerates pancreatic islet exhaustion and thus the onset of T2DM [13]. Generally, obesity is a major risk factor for developing T2DM [30]. High-fat diet applied in animal's model that has inclination to DM results in obesity, hyperinsulinemia, and altered glucose homeostasis due to insufficient compensation by the islets [31]. Whereupon it is required in human population suffering T2DM to follow diet regimes and restriction of energy in the food so to maintain glucose concentration in acceptable level. In this case the diet has more considerable impact on diabetic primary complications than genetic predisposition [32]. Genetic disposition to obesity is probably commonly due to the small impingements of a wide selection of genes such as those encoding the beta3adrenoceptor, PPARγ and its co-activator-1, fat mass and obesity-associated gene, and adiponectin and a selection of genes that could potentially influence behavior and hypothalamic

Currently, therapeutic strategies for T2DM are limited. They involve insulin and four main classes of oral antidiabetic agents in order to stimulate pancreatic insulin secretion. However, these agents suffer from generally inadequate efficacy and various adverse effects. So there is the possibility to try new therapeutic agents or treatments, most of them are under preclinical and early clinical stages [34].

An animal model for biomedical investigation is one in which normative biology, behavior, and pathological process can be studied and in which the phenomenon in one or more respects resembles the same phenomenon in humans [35]. Research in diabetes on humans is not possible or only partially possible. Hence, animal model of DM is very useful and advantageous [36]. Animal disease models are essential tools for studying the pathophysiology of DM enabling therapeutic interventions to be developed [37]. It is true that the present therapeutic approaches to treat DM and obesity, which are saving many lives every day, were invented, validated, and optimized on animal models [38]. When studying T2DM the use of an animal model with a homogenous genetic background is advised [39]. Most of the available models are based on rodents [36]. Rodents are most commonly utilized due to their small size, short generation interval, and easy availability [39] and because of economic consideration [36]. Being mammals, the physiology of rats is similar to humans than nonmammalian species [40]. Nevertheless, nonrodent models of diabetes are needed as a valuable supplement to rodents for both practical and physiological reasons with respect to humans [36]. Many animal models for DM research are obese, reflecting the human condition where obesity is closely related to T2DM development [41]. Animals exhibiting a syndrome of insulin resistance

#### *Zucker Diabetic Fatty Rats for Research in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.88161*

*Animal Models in Medicine and Biology*

microvascular system [10].

play a plumbless role [12].

**1.2 Diabetes mellitus type 2**

secretion and rising level of apoptosis [21].

**1.3 Obesity in type 2 diabetes**

people [11].

including polyol pathway activity, hexosamine pathway, nonenzymatic glycations of proteins, and altered protein kinase C activity [9]. Activation of these pathways can eventually flow into inflammatory and oxidative stress in neurons and adjacent

DM is divided into two main forms—type 1 and type 2 [4]. Type 1 diabetes mellitus (T1DM) or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease and is a result of β cells' death, because a foreign protein is incorporated into islet β cells. In response, lymphocytes attack the foreign protein and unwillingly destroy β cells as collateral damage. It causes an absolute insulin deficiency [11]. It is uncertain what activates the autoimmune response, but some environmental factors as toxins, viral infections, and psychosocial inputs are thought to

Historically, the usual ratio for T1DM to T2DM has been 1:20. Now it is changing because of expressive increase in the incidence of T2DM in children and young

Type 2 diabetes mellitus (T2DM) or non-insulin-dependent diabetes mellitus (NIDDM) is a syndrome of β cells' dysfunction including relative insulin deficiency associated with insulin resistance [11] and compensatory increases in insulin secretion [13]. It is associated with incorrect sensing of glucose signals by the β cells. T2DM is linked to a stage of insulin resistance. Insulin secreted by the β cells and bound to liver, muscle, and fat cells is subnormally efficacious in carrying out its metabolic action [11]. Generally, T2DM is characterized by the incapability of the pancreatic β cells to secrete appropriate quantities of insulin in order to offset hyperglycemia arising from peripheral insulin resistance and increases hepatic glucose output [14]. It is a multifactorial and complex disorder [13] that is estimated to affect more than 100 million people worldwide [15]. About 80% of all people with diabetes suffer from T2DM [16]. Insulin resistance alone is insufficient to cause diabetes. A progression to overt diabetes required β cells' failure as well [16–18]. Insulin resistance is associated with decrease in insulin receptors in target tissues (muscle, fat, or liver) and insulin receptor kinase activity that causes decrease in glucose transporter 4 (GLUT 4) translocation due to impaired signaling [19]. The onset of T2DM is preceded by an expressive increase in the plasma levels of free fatty acids (FFA) and by sixfold rise in triglyceride (TG) concentration in the pancreatic islets [20]. Chronic exposure to high glucose level and rising FFA concentration is detrimental to β cell function. This situation results in weak glucose-induced insulin

In spite of the increasing number of T2DM, little is known about the prevention of the disease and its complications at early stages [22]. In this stage insulin-sensitive tissue such as adipose tissue and skeletal muscle become insulin resistant. This causes the development of impaired glucose tolerance, and it can occur over a few years [23]. The pathogenesis of T2DM is complex and is primarily related to gene variation, external and internal environmental factors, abnormal protein modifications, oxidative stress, epigenetic effects, and energy metabolism disorders [24]. It was revealed that also the gut microbiota has been recognized as a key contributor to

T2DM, and T2DM is linked to dysbiosis of the intestinal microbiota [25].

Onset and development of T2DM is commonly incurred by several factors, which are combined with lifestyle, obesity, genetic defects, virus infection, and

**76**

drugs [16]. Obesity is defined as a pathological excess of body fat that results from a permanent positive energy balance [26]. Persistent positive energy balance is pertinent to increased storage of triglycerides. This expands the adipose depots and increases the proportion of hypertrophied adipocytes [27]. Under condition of obesity, the lipid storage capacity of adipocytes is overcome, resulting in adipocyte-derived fatty acids and cytokines leaking into the circulation [28]. Damaging lipid species accumulates in ectopic tissue causing local inflammation and provides lipotoxicity [29]. Lipotoxicity determines an important link between obesity, insulin resistance, and T2DM. It interprets the harmful cellular effects of chronically increased concentrations of fatty acids and excess lipid accumulation in tissues other than adipose tissue. Excess adiposity is considered to promote the onset and severity of insulin resistance, contributing to emergence and progression of impaired glucose tolerance and T2DM [27].

Obesity-induced insulin resistance accelerates pancreatic islet exhaustion and thus the onset of T2DM [13]. Generally, obesity is a major risk factor for developing T2DM [30]. High-fat diet applied in animal's model that has inclination to DM results in obesity, hyperinsulinemia, and altered glucose homeostasis due to insufficient compensation by the islets [31]. Whereupon it is required in human population suffering T2DM to follow diet regimes and restriction of energy in the food so to maintain glucose concentration in acceptable level. In this case the diet has more considerable impact on diabetic primary complications than genetic predisposition [32]. Genetic disposition to obesity is probably commonly due to the small impingements of a wide selection of genes such as those encoding the beta3adrenoceptor, PPARγ and its co-activator-1, fat mass and obesity-associated gene, and adiponectin and a selection of genes that could potentially influence behavior and hypothalamic hunger-satiety mechanisms [33].

Currently, therapeutic strategies for T2DM are limited. They involve insulin and four main classes of oral antidiabetic agents in order to stimulate pancreatic insulin secretion. However, these agents suffer from generally inadequate efficacy and various adverse effects. So there is the possibility to try new therapeutic agents or treatments, most of them are under preclinical and early clinical stages [34].
