Weight problems are defined as a not unusual chronic sickness of excessive frame fat and has grown to be a global epidemic that is no longer the handiest gift within industrialized international but also in many growing and even underdeveloped nations. At gift, the prevalence of weight problems (described as body mass index [BMI] ≥ 30 kg/m2) is within the range of 15 – 30% in the growing populations in Europe, North America, and many Arabic international locations, with an unequivocal trend for in addition, increases [1]. This circumstance will increase the risk of growing diffusion of negative results to human health ranging from metabolic disturbances, type 2 diabetes mellitus (T2DM), and cardiovascular headaches to problems with locomotor machines and many types of cancer [2]. In addition, weight problems impair the subjective nice of life in affected human beings and can reduce existence expectancy [3]. Although there is a very specific relationship between excessive frame weight and the risk of diabetes, obesity may additionally result in many other disturbances that can aggravate the diabetic state.                                                                                                                                               

Definition of weight troubles and the frame fats distribution Pattern The evaluation and sophistication of weight problems are commonly based on the BMI. This easy anthropometric index may be calculated from frame weight and height, is unbiased to the frame peak, and correlates fairly well with frame fat mass (r = 0.4–0. 7). 

The cutting-edge classification of body weight is steady, with the area health agency (WHO) obtainable in Table 14.1. and 14.2 A BMI greater than 30 kg/m2 is considered a crucial formal criterion for the definition of obesity, which is subdivided into three categories based on the severity of immoderate frame fat

The body mass index (BMI) ranged from 25 to 29. 9 kg/m2 represents the elegance of overweight or pre-obesity, which calls for additional standards to evaluate the concomitant fitness risks. In Western countries, 30–50% of the population is overweight not best the amount of excess body fat mass, however, also the anatomic location of the frame fat mass determines the danger of metabolic and cardiovascular complications. This is specifically critical for the class of mildly overweight, or even in the top everyday range of BMI. At a defined BMI, fat distribution patterns can vary significantly. This has been impressively shown in the use of computed tomography (CT) or magnetic resonance imaging (MRI) scans, which might be the best imaging technique to provide a direct evaluation of the size of intra-abdominal visceral adipose tissue realistically, For Practical mean waist circumference measured midway between the decreased rib margin and the top iliac crest, and was used as an easy anthropometric measure to assess the fat distribution pattern. This variable has been used in many move-sectional and longitudinal studies; therefore, the threshold tiers tested in desk 14.2 are now based primarily on human information units concerning associated health dangers. Waist circumference is closely correlated with BMI, but cannot discriminate between subcutaneous and intra-abdominal fat depots. Weight problems are the maximum potent Risk factor for kind 2diabetes A large body of clinical information demonstrates a close relationship between body fat mass and the risk of diabetes. It is noteworthy that during the evaluation of other weight problems-associated metabolic disturbances, the diabetes risk already increased within the upper normal range of BMI. This has been shown for each man and woman. within the potential Nurses ‘health examination, women in the higher ordinary variety with a BMI of 23.0–24.9 

kg/m2had a 4-to 5-fold extended danger of developing diabetes over a 14-year statement period as compared with girls with a BMI of < 22>

Figure 14.1: Contribution of five body mass index (BMI) categories to the overall prevalence of diabetes.

National Health and Nutrition Examination Survey (NHANES) samples of 1976 – 1980 and 1999 – 2004 were compared. Reproduced from Gregg et al. [7], with permission from Elsevier. In addition to the level and duration of obesity, the risk of developing diabetes is strongly influenced by fat distribution patterns. In an early study in humans, an abdominal pattern of fat distribution was found to be an independent risk factor for T2DM [8]. Subsequent studies confirmed this observation in several age groups and ethnic populations. Particularly at low degrees of overweight, and even in the upper normal range, the fat distribution pattern strongly predicts the risk for diabetes and metabolic syndrome. Therefore, waist circumference should be routinely assessed when estimating the risk of diabetes, even in normal-weight subjects. In the clinical setting, it is striking that the majority of subjects with diabetes, particularly those of middle age, show visible preferential truncal accumulation of excess body fat. It is also interesting to note that similar observations were made regarding the association between BMI and cardiovascular disease. Among overweight and obese subjects, only those with an abdominal type of fat distribution are at increased risk of coronary heart disease, as recently documented in the INTERHEART study [9]. Genetic predisposition for weight problems and type 2 diabetes.  It is well known from the circle of relatives, adoption, and dual research that obesity such as T2DM has a sturdy genetic foundation. inside the traditional adoption take look using Stunkard et al. [10], there has been no resemblance between the BMI of adopted Danish youngsters and the BMI of the adopting parents, but there has been an extensive correlation between the BMI of the biological dad and mom, especially to the BMI class of the biological mother. In a twin look at weight problems, concordance feels special tiers of overweight were twice as high for monozygotic twins than for dizygotic twins. This high heritability for BMI became visible at the age of 20 years and, to a comparable extent, at a 25-year follow-up, suggesting that body fatness is beneath widespread genetic manipulation [11]. There may also be a close correlation between monozygotic twins reared apart, additionally indicating excessive heritability of the BMI trait. In the latest look at 5092 twins residing in the London vicinity, the authors predicted the heritability of BMI and waist circumference as 0-77, further helping the robust impact of the genetic additives regardless of the pressure of the obesogenic surroundings [12]. during the last decade, numerous monogenic problems that results in obesity in humans. These genetic disorders are most effectively located in rare instances, but usually in children and youth with early-onset  obesity. At gift, a spread of homozygous and compound heterozygous mutations have been described inside the leptin–Milano sure signaling pathway, some of them with practical effects resulting in human obesity. functional mutations in the melanoma curtain - 4 - receptor gene are considered the maximum frequent motive of monogenic obesity in children with a frequency of 2-4% of all overweight cases. it’s miles hanging that those defects affect genes that might be involved in the Central Management of food intake [13]. Recent genome-wide affiliation (GWA) research in massive cohorts with BMI as a phenotype pronounced common genetic versions on diverse chromosomes. these polymorphisms predispose to obesity on the populace level and also are largely related to important pathways of meal consumption {14-16}. consequently, human weight problems might also represent a heritable neuro behavioral ailment this is quite sensitive to environmental situations, especially an electricity-dense Palatable ingredients which can be abundantly available in many societies. despite those splendid advances in our know-how of the genetic factors related to obesity, the impact size of the maximum of the novel “weight problems genes “is alternatively modest. The most effective folks that are homozygous for the high-risk allele of the FTO gene weigh 3 kg more than individuals with two low-hazard alleles. The gene encodes 2 - oxoglutarate - dependent nucleic acid demethylase, which is mainly expressed in the brain and arcuate nucleus of the hypothalamus [17]. Among the almost 20 gene variants found in GWA studies so far, variants near the FTO and the MC4R gene appear to have the strongest effect on the size of body weight. All other recently discovered gene polymorphisms affect body weight by less than 1 kg. Thus, it is apparent from recent work that obesity represents a rather heterogeneous disorder in terms of genetic background and susceptibility to  etiological and environmental factors. Additionally, the risk of developing comorbidities, including T2DM, may strongly depend on an individual’s genetic predisposition to such diseases. In the case of T2DM, the lifetime risk of developing this disease is about 30% of the white North American population and are similar to those of other ethnic groups [18]. It is currently assumed that only those obese subjects who exhibit a genetic failure of the pancreas to compensate for insulin resistance, which is a characteristic consequence of obesity, will develop T2DM [19]; even among severely obese subjects (BMI ≥ 40 kg/m2) Only 30 – 40% will years developed diabetes throughout life. Thus, the development of T2DM requires the presence of “diabetes genes “which probably limit β - cell function. Developmental programming of obesity and diabetes. A new component that may play a major role in the development of obesity and T2DM is the modification of gene expression by Epigenetic mechanisms during fetal development. Although this is still a poorly defined phenomenon and it is rather unclear which mechanisms may underlie this association, there is some clue that epigenetics may also operate in this context. Observational studies have suggested that infants of mothers with gestational diabetes are at an increased risk of developing childhood obesity [20]. In another study, siblings born after the mother had developed gestational Diabetes (i.e., exposure to diabetes in utero) has a much greater risk of T2DM in young adulthood than those not exposed to diabetes in utero (odds ratio 3.7; P = 0.02) [21]. Another interesting clinical observation is that excessive weight gain during pregnancy, independent of the initial BMI, may also increase the risk of early development of obesity in offspring [22,23]. It has been speculated that both hyperglycemia and chronic over nutrition during pregnancy may cause fetal hyperinsulinemia, hypercholesterolemia, and hyperleptinemia. These hormonal Changes may result in persistent mal programming of hypothalamic centers controlling energy homeostasis and metabolism, thereby increasing the lifetime risk for obesity and T2DM, and possibly the risk for other adverse long-term health consequences [24]. The mechanisms mediating these effects are largely elusive, However, it is speculated that Epigenetic processes such as DNA methylation, histone modification, and changes in the microRNA pattern are involved. Animal experiments suggest that this imprinting process mainly affects the central neuroendocrine pathways, which may modify appetite regulation. Pathophysiology of obesity Irrespective of the strong genetic influence on body weight, there is no doubt that the evolving worldwide epidemic of obesity is primarily a consequence of substantial changes in the environment and lifestyle. It is rather new to mankind that food is abundant in many countries, and that physical activity is no longer a prerequisite for survival. These dramatic changes in the environment and subsequent lifestyle changes have occurred within a few decades, a period probably too short to result in adaptations of the genetic background and biological systems to optimize survival. To date, the relative contributions of various environmental factors to the obesity epidemic are difficult to quantify in detail, and considerable differences exist between populations. Humans, like other mammals, are characterized by tight control of energy homeostasis, which allows a stable body weight to be maintained. This set point of body weight can vary substantially among individuals and may also vary across a lifetime.                                                                                                               

A complex regulatory system controls energy homeostasis, which involves central pathways and peripheral components such as the size of adipose tissue, which is sensed by the brain via the secretion of leptin. In addition, gut hormones, signals from the gastrointestinal nervous system, and nutrient signals to the brain induces induce a complex central integration according to the dietary intake and nutrient requirements of the organism. Central pathways are the orexigenic leptin – melano cortin link and the orexigenic NPY – AgRP pathway. Many other factors, such as insulin, modify these signaling processes and thereby influence energy balance [25]. This complex and potent homeostatic system also serves to defend body weight against a critical energy deficiency, but also chronic over nutrition. Several adaptive systems are known to restore initial body weight under fluctuations in energy intake and expenditure. This may explain why obese individuals exhibit a strong tendency to regain weight after intentional dietary weight reduction. The same tendency to return to the initial body weight was observed after experimental overfeeding. The role of energy homeostasis in the development of obesity has been elaborated in previous studies using indirect calorimetry to investigate the contribution of the resting metabolic rate (RMR) to the risk of obesity. In a study by Pima Indians, RMR was found to be a familial trait that varied considerably across families [26]. In prospective studies in American Indians, a reduced rate of energy expenditure assessed in a respiratory chamber predicted body weight gain over a 2 - year follows - period. This finding was confirmed in another study over a 4 - year - follow - up period in the same paper, indicating that a low rate of energy expenditure may contribute to the aggregation of obesity in families [27]. At present, the genetic components responsible for these differences in energy metabolism are still unknown.                                 

Environmental Factors promoting obesity and Type 2 Diabetes. It is now established that a complex gene-environment interaction determines the individual risk to develop obesity (Table 14.3). Even in societies with an abundance of affordable, highly palatable food, there is a high variation in body weight across populations, ranging from lean individuals to extremely obese individuals. Many other factors such as physical activity, education, and socioeconomic status may also act as strong modifiers of body weight. After two to three decades of modern lifestyle, the trend towards obesity appears to reach a plateau, as suggested by recent data from the USA and other western countries. This observation also supports the concept that genetic and biological factors contribute substantially to susceptibility to obesity.

Despite the genetic predisposition, it is widely accepted that the current worldwide epidemic of obesity is largely a consequence of dramatic changes in lifestyle and environment that have emerged over the past 30–50 years. A dramatic change in eating habits and food selection took place, whereas physical activity decreased remarkably because of technological development concerning transportation and workplaces. Although dietary abundance and sedentary lifestyles have multiple origins, both may equally contribute to a chronic positive energy balance, which may result in energy storage in the adipose tissue. A rather novel phenomenon is the expansion of fast-food culture characterized by high-fat, low-starch foods, together with a high intake of sugar-sweetened beverages. In addition to having high energy density, fast-food menus have large portion sizes. This combination has led to the assumption that frequent fast-food consumption is linked to body weight gain and the maintenance of overweight and obesity in the population. Despite this popular explanation, there is limited evidence of this association in scientific literature. Nevertheless, a recent systematic review of six cross-sectional and seven prospective cohort studies concluded that sufficient evidence exists, at least in the adult population [28]. In addition, the high intake of sugar-sweetened beverages is another part of the global fast-food culture. Another systematic review concluded that a high intake of Calorically sweetened beverages can be regarded as a determinant of obesity, although there was no evidence that this association is mediated by increased energy intake, suggesting that alternative biological explanations should also be explored [29]. Given the expansive growth of the fast-food industry in many countries, this is a critical issue that may require more intense public discussion on the health consequences of this policy. According to a recent survey, people from the USA obtain one-third of their daily caloric intake from restaurant meals again, and one-third of customers of chain restaurants in New York purchase meals containing more than 1000 calories [30]. Thus, there is a growing need to develop new public health policies to limit fast-food consumption and facilitate healthier food selection.                                                                                      Another aspect in the context of high fast-food consumption, which may further explain the elevated risk of obesity, is the energy density of modern foods. There is convincing evidence that the energy density of foods is a key determinant of caloric intake. From an evolutionary point of view, the human regulatory system for energy intake has adapted to starchy foods with low caloric content, which requires large volumes to obtain sufficient energy. Today, most fast foods have a high energy density, which may favor passive overconsumption of calories. A recent study showed that the average energy density of fast-food menus is approximately 1100 kJ/100 g, which is 65% higher than that of the average British diet (approximately 670 kJ/100 g) and more than twice the energy density of recommended healthy diets (approximately 525 kJ/100 g). It is 145% higher than in traditional African diets (approximately 450 kJ/100 g), which represents the levels against which human Weight-regulatory mechanisms have evolved. The authors concluded that the high energy density of many fast foods challenges human appetite control systems under conditions for which they were never developed [31]. Another determinant of the obesity epidemic may be the persistent trend over the last few decades toward increasing portion sizes. A study from the USA demonstrated that the average portion size for many food items increased markedly between 1977 and 1998, with the greatest increase in food consumed at fast food restaurants and at home [32]. Similar trends have also been documented in other countries. Experimental human studies have established that both increasing the portion size and the energy density of food an associated with an increase in caloric intake and, in the long run, may promote weight gain and obesity [33]. Finally, socioeconomic status is a strong determinant of obesity and T2DM. In most countries, there is a gradient between education, household income, and obesity prevalence. Low socioeconomic status is associated with an unfavorable lifestyle including poor nutrition, low leisure-time physical activity, and low health consciousness. This gradient is usually greater in females than in males. Thus, the association between low household income and obesity may be mediated by the low cost of energy-dense foods, whereas prudent healthy diets based on lean meats, fish, vegetables, and fruit may be less affordable for those with lower socioeconomic status [34]. Pathophysiologic links between Obesity and type 2 diabetes T2DM is characterized by an impaired insulin action or a defective secretion of insulin or both. Both defects are thought to be required for the manifestation of the disease and are present many years before the clinical onset of the disease. To date, the mechanisms by which obesity increases the risk of developing T2DM are only partially understood, and the evolving picture is becoming increasingly complex. The main adverse effect of obesity is the action of insulin, particularly in the liver, muscle, and adipose tissue; however, obesity also affects insulin secretion. Substantial advances have been made in recent years in our understanding of how excessive fat mass, but also chronic over nutrition may cause metabolic disturbances resulting in overt T2DM in patients with a genetic predisposition for the disease. Lipids and insulin resistance the earliest hypothesis to explain the relationship between obesity and T2DM is the “glucose–fatty acid cycle “, which is based on the observation of competition between glucose and fatty acid oxidation in the heart muscle was introduced by Randle et al. [35]. The increased supply of non-esterified fatty acids from expanded adipose tissue depots compete with glucose utilization, particularly in the muscle, which represents the organ that oxidizes the largest proportion of glucose. The proposed mechanism involves the inhibition of the glycolytic enzyme’s pyruvate dehydrogenase, phosphofructokinase, and hexokinase. Consequently, the rate of glucose oxidation is reduced, and glucose concentrations increase. The concomitant increased fatty acid turnover is accompanied by an increased release of glycerol from adipose tissue, which is re-utilized for hepatic glucose production, further Augmenting the imbalance in glucose metabolism. Increased hepatic glucose output is another early disturbance contributing to glucose intolerance.  In addition, elevated free fatty acid levels can directly impair insulin activity. Recent studies have suggested that obese subjects and those with T2DM have high intramyocellular lipid accumulation, which is an important feature of the insulin-resistant state. Exposure of skeletal muscle to excessive lipid supply may lead to intramuscular accumulation of neutral fatty acids as well as lipid-derived metabolites such as ceramide, diacylglycerol, and fatty acyl-coenzyme A (CoA). This lipid accumulation is associated with coincident disturbances in insulin action mediated by activation of a serine-threonine kinase cascade leading to serine-threonine phosphorylation of insulin receptor substrate 1 (IRS - 1) and IRS - 2 which may cause an impairment of insulin signaling including an impaired activation for phosphoinositol - 3 kinase and other downstream elements [36]. This condition is exacerbated by chronic over nutrition with high dietary fat intake. Thus, the increased availability of fatty acids may be the single most critical factor in disturbance of insulin action in obesity. 

Figure 14.2 Hyperbolic relation between β - cell function and insulin sensitivity. IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus. Reproduced from Stumvoll M, Goldstein BJ, van Haeften TW.

Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365 :1333 – 1346, with permission from Elsevier. Lipids and β- cell function Obesity is characterized by elevated insulin secretion and decreased hepatic insulin clearance. Human studies have suggested that β-cell volume is increased by approximately 50% in healthy obese subjects, probably because of hypertrophy of existing β-cells. Insulin release and insulin sensitivity are closely reciprocally related in a nonlinear manner (Figure 14.2 ). Failure of this feedback system results in a progressive decline in β-cell function and underlies the development of T2DM. In addition to glucose, long-chain fatty acids may also exert a stimulatory effect on insulin secretion from pancreatic β-cells via the generation of fatty acyl CoA and activation of protein kinase C [36]. Another effect of fatty acids on insulin secretion is via binding to the G - protein-coupled receptor GPR 40 on the β - cell membrane, which may result in a subsequent increase in intracellular calcium levels and secretory granule exocytosis [37]. Although fatty acids are critical for normal insulin secretion, chronic exposure of β - cells to excessive fatty acids is associated with marked impairment of glucose-stimulated insulin secretion and a decrease in insulin biosynthesis [38]. Another mechanism by which elevated fatty acids may impair insulin secretion in response to glucose is via increased expression of uncoupling protein 2 (UCP - 2) in β-cells. UCP-2 was upregulated under glucolipotoxic conditions, and mitochondrial superoxide was identified as a post-translational negative regulator of UCP-2 activity in islets [39]. Glucose sensing in pancreatic β-cells requires intact oxidative mitochondrial metabolism to generate ATP. The resulting high ADP ratio is a prerequisite for normal insulin secretion. Studies in humans have suggested the occurrence of insulin resistance. additionally, get up from defects in mitochondrial fatty acid oxidation This may result in extended intracellular fatty acid metabolite production (fatty acid CoA and diacylglycerol). It changed into lately shown that younger insulin-resistant offspring of dad and mom with T2DM have functions of impaired mitochondrial function [40]. furthermore; it changed pronounced that overweight people have smaller mitochondria with decreased bio energetic potential than lean controls [41]. even though research in this subject matter is nevertheless restrained, there is growing evidence that a faulty mitochondrial characteristic could a distinguish the function of disturbances in both insulin secretion and motion [42]. 

Figure 14.3 Secretory products from adipose tissue and functional relationship. Reproduced from 

Lafontan M. Fat cells: afferent and efferent messages define new approaches to treat obesity. 

Annu Rev Pharmacol Toxicol2005; 45 :119 – 146, with permission from Annual Reviews Adipose tissue as a secretory organ Another hypothesis that could explain the association between obesity and T2DM is that adipose tissue is a secretory organ that produces and releases an expansion of factors that could contribute to the development of insulin resistance and different fitness risks (Figure 14.3; Table 14.4). Among these factors, the maximum information was collected for the mediator position of tumor necrosis factor α (TNF-α). TNF-α is a multifunctional cytokine primarily expressed in adipose tissue [43]. It was subsequently proven that TNF-α exerts an expansion of catabolic effects in adipose tissue. similarly to TNF - α, it changed into pronounced that its receptor subtypes are overexpressed in adipose tissue from obese subjects [44–46]. The upregulated TNF - α device induces multiple negative results at the nearby organ stage, such as inhibition of glucose uptake due to an impairment of insulin signaling and suppression of GLUT 4 expression, a discount of lipoprotein lipase expression and interest, and a boom in Lipolysis [47]. Moreover, TNF-α activates the NF-κB pathway in adipose tissue, which results in an elevated expression of many proinflammatory proteins, including interleukin 6 (IL - 6), IL - 8, and monocyte chemotactic protein 1 (MCP - 1) among others. Finally, TNF - α been shown to reduce the expression of adiponectin, a protein abundantly expressed in fat cells, and experts direct antidiabetic and anti-atherosclerotic movements. A key mechanism by way of which TNF - α causes insulin resistance can be that this cytokine stimulates the phosphorylation of IRS - 1 at the serine residue 307, which inhibits the transduction of the insulin signal to the downstream elements [48]. Using an in vitro co-culture of f the life version of human adipocytes and muscle cells, it has been confirmed that other fat cell secretory products, in addition to TNF-α, are involved in the development of muscle insulin resistance [49]. Thus, it is likely that the negative effect on muscle insulin action is caused by a combination of Adipokines. Although there is currently little information on the nature and complex interplay of such painful aortic and anti-inflammatory factors, a few relevant players have been identified. One such element may be MCP-1 [50]. Other potential candidates with a prediabetic action may include plasminogen activator inhibitor 1 (PAI - 1), as well as lipid metabolites such as ceramide. Retinol-binding protein 4 (RBP - 4) has also been shown to contribute to insulin resistance via reduced PI 3 kinase signaling and enhanced hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. An interesting observation in this context is that adiponectin may antagonize the insulin resistance-promoting activity of protein-inflammatory cytokines released from adipose tissue in an autocrine fashion [51].                                                         

Adipocytes are also able to release products with anti-inflammatory properties, including adiponectin, IL - 1 receptor antagonist, and IL-10. By far, the most interesting component is adiponectin, which is the most abundantly expressed protein in the adipose tissue. Several clinical studies have shown that circulating adiponectin levels are inversely associated with BMI and that low concentrations predict the development of T2DM [52,53]. Adiponectin is known to exert various antidiabetic and anti-atherosclerotic effects (e.g., adiponectin stimulates fatty acid oxidation in an AMP-activated protein kinase-dependent manner) [54]. 

Signaling pathways of Inflammation in disposed of tissue Current research has shown that the inflammatory response in human obesity is mediated via activation of the c-Jun N-terminal kinase (JNK) and IKK β–NF-κB pathways. Both pathways are simultaneously stimulated by cytokines such as TNF-α and IL - 6, but also by lipids. It has been convincingly demonstrated in experimental studies that genetic or chemical inhibition of these pathways can reduce inflammation and improve insulin resistance (for review, see [55] ) (Figure 14.4 ). In obesity, JNK activity is elevated not only in adipose tissue, but also in the liver and muscle. Loss of JNK1 prevents the development of insulin resistance and diabetes in both genetic and dietary mouse models of obesity [56}IKKβ can act on insulin signaling through at least two pathways. First, it can directly phosphorylate IRS - 1 on serine residues, and second, it can phosphorylate the inhibitor of NF-κB (I κ B), thus activating NK - κ B, a transcription factor that stimulates the production of many pro-inflammatory mediators, including TNF-α and IL - 6 [57]. Mice heterozygous for IKK β are partially protected against insulin resistance caused by lipid infusion, high-fat diet, or genetic obesity [58]. Both the JNK and IKK β–NF-κB pathways are activated via pattern recognition receptors that function as membrane receptors for a variety of external signals. It is interesting to note that endogenous lipids and lipid conjugates were found to activate toll-like receptors (TLRs) in obese individuals. It was recently reported that saturated fatty acids bind and activate TLR - 4 in adipocytes, suggesting a direct link between exogenous nutrients that are redundant in the obese state and inflammation [59]. Mice with a loss-of-function mutation in TLR-4 were found to be protected from diet-induced obesity and insulin resistance. These mice also showed reduced NF-κB and JNK activity under a high-fat diet compared with wild-type control mice [60]. In a similar model, markedly lower circulating levels of MCP - 1 were measured. TLR - 4 deficiency, however, did not attenuate the induction of TNF-α and IL - 6 expression [61]. It is noteworthy that most proteins released from adipose tissue are not produced by fat cells but rather

Figure 14.4 Potential cellular mechanisms for inflammation and development of insulin resistance. AP - 1, activator protein 1; ER, endoplasmic reticulum; IKK, I κ kinase; IL, interleukin; IRS, insulin receptor substrate; JNK, c - Jun N - terminal kinase; NF - κ B, nuclear transcription factor κ B; PKC, protein kinase C; ROS, reactive oxygen species; TLR, toll - like receptor; TNFR, tumor necrosis factor receptor; TZD, thiazolidinedione. Reproduced from Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116 :1793 – 801, with permission from the American Society for Clinical Investigation

by pre-adipocytes and invading immune cells, such as activated macrophages. Leptin and adiponectin are true Adipokines that are almost exclusively produced by adipocytes; TNF-α, IL - 6, IL - 8, MCP - 1 visfatin, PAI-1, and others are especially expressed in pre-adipocytes, macrophages resident in adipose tissue, and likely different cells. The relative contributions of the numerous mobile components in adipose tissue to the secretion of those merchandise stays unknown and can range substantially in keeping with depot and version. Most of these regionally secreted elements seem to participate in the induction and renovation of the subacute inflammatory nation related to obesity. It is also vital to say that invading macrophages release elements that appreciably augment adipocyte inflammation and insulin resistance [62]. Another interesting observation in this context is that pre adipocytes and macrophages share many common capabilities. However, the regulation and biological features of secretory merchandise are poorly understood. In addition to the direct results of fatty acids and their intracellular merchandise, other elements may additionally contribute to the continual inflammatory kingdom in adipose tissue. It has recently been proven that fat cell size is a crucial determinant of the production of painful amatory and anti-inflammatory factors. Enlarged hypertrophic fat cells are characterized by a shift towards a proinflammatory state [63], thereby promoting insulin resistance. This is in agreement with medical information showing that fat cell hypertrophy is related to an increased threat of growing T2DM [64]. Obesity and endoplasmic reticulum stress A recent observation suggests that obesity and chronic over nutrition overload the functional capacity of the endoplasmic reticulum (ER) and that the resulting ER stress contributes to the activation of the inflammatory signaling pathways, including the JNK pathway. In both high-fat diet-induced and genetic obesity models, obesity was shown to cause ER stress via inositol - requiring kinase - 1 α (IRE - 1 α), which plays a crucial role in insulin receptor signaling as a mediator of JNK activation [65]. In a mouse model of type 2 diabetes, systemic overexpression of 150 - kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER, improved insulin intolerance, and enhanced glucose uptake indicating that this chaperone has an important role in insulin sensitivity and is a potential target for the treatment of T2DM [66]                                                                                                                                          Obesity and  oxidative stress A study from Japan demonstrated that fat accumulation is associated with systemic oxidative stress in humans and mice [67]. There was selective production of reactive oxygen species (ROS) in the adipose tissue of obese mice, accompanied by an increased expression of NADPH oxidase and decreased expression of anti-oxidative enzymes. The authors also showed that fatty acids increased oxidative stress in cultured adipocytes via NADPH oxidase activation, which was followed by the dysregulated production of Adipokines such as adiponectin, PAI - 1, IL - 6, and MCP-1. In addition, treatment with an NADPH oxidase inhibitor reduced ROS production, restored the dysregulation of Adipokines in adipose tissue, and improved diabetes, dyslipidemia, and hepatic steatosis, indicating that the redox status of adipose tissue is a critical factor in the development of metabolic syndrome.                                                                                                                   

Adipose tissue hypoxia An expansion of adipose tissue mass leads to fat cell hypertrophy and subsequent tissue hypoxia. Recent studies convincingly support the concept that hypoxia does not play a central role in the development of chronic inflammation, macrophage infiltration, impaired adipokine secretion, ER stress, and mitochondrial dysfunction in white adipose tissue in obesity [68,69]. These effects are also accompanied by inhibition of adipogenesis, triglyceride synthesis, and elevated circulating free fatty acid concentrations. Measurement of the interstitial partial oxygen pressure (PO 2) in adipose tissue showed a reduction of up to 70%, leading to oxygen levels of about 2% in obese animals compared with lean controls. This observation was further substantiated by the determination of hypoxia response genes, such as hypoxia-inducible factor 1 α (HIF - 1 α ), vascular endothelial growth factor (VEGF), and heme oxygenase 1 (HO - 1), and others. The low oxygen pressure may also contribute to < on> mitochondrial respiration with a consecutive increase in lactate production. In humans, HIF - 1 α was also shown to be increased in the white adipose tissue of obese patients, and its expression was reduced after surgery-induced weight loss [70]. Hypoxia was also demonstrated to decrease adiponectin expression in adipocytes.                                                                                                                           

The physiological basis of adipose tissue hypoxia may be related to a reduction in adipose tissue blood flow and capillary density, as has been reported in both obese humans and animals. Although the hypoxic state leads to increased production and release of pro-angiogenic factors from adipose tissue, such as VEGF and others, this compensatory mechanism may not be sufficient to maintain PO 2 at a normal level, as the free diffusion of oxygen in the adipose tissue may be limited Accumulation of immune cells Leptin, TNF - α, MCP and other chemo kinesis have an essential role in the recruitment of macrophages to adipose tissue. The secretory profile of both pre adipocytes and adipocytes includes a variety of chemo attractants for immune cells. It was recently reported that the attraction of T - lymphocytes was possibly caused by stromal cell-derived factor 1 (SDF - 1) represents the initial step that subsequently leads to the invasion and activation of circulating monocyte-macrophages, resembling the scheme originally described for atherosclerosis. Such accumulation of immune cells and inflammation of adipose tissue has been shown in obese humans  and appears to be more pronounced in omental then subcutaneous adipose tissue , which would also fit with the concept that the amount of visceral fat is the culprit for the metabolic and cardiovascular complications of obesity                                                                                                    Role of body fat distribution pattern Another important issue in this context is body fat distribution. It has long been known from Early clinical studies have shown that subjects with a more abdominal body fat distribution are at increased risk of developing T2DM and other metabolic and cardiovascular complications; however, the underlying cause has only recently become evident. Intra-abdominal fat cells exhibit differing expression profiles and are lipolitically more active than subcutaneous adipocytes. Moreover, they show a greater metabolically   accumulation of lymphocytes and macrophages, indicating greater proinflammatory activity. Visceral adipose tissue also has much higher blood vessel and nerve density, leading to much greater metabolic activity. Visceral adipose tissue drains into the portal vein; thus, the liver is directly exposed to fatty acids and proteins released from the active fat depot, thereby promoting insulin resistance in the liver. Thus, the inflammatory process is detected not only at the level of adipose tissue but may also affect the liver and possibly other organs. As enlarged visceral fat depots are frequently associated with fat accumulation in the liver, it was hypothesized that secretory products from the visceral adipose tissue may directly cause hepatic insulin resistance. In summary, a variety of data suggests that chronic over nutrition with a high-fat, high-sugar diet and as a consequence an accumulation of body fat is the primary cause of chronic inflammation in obesity and may promote the development of systemic insulin resistance which affects many tissues including the liver, muscle and the brain (Figure 14.5). It should be noted that apart from an unhealthy diet, other lifestyle factors, such as lack of physical activity, may substantially contribute to these pathological processes. 

Figure 14.5: Nutrition and obesity - induced inflammation and development of systemic insulin resistance. Reproduced from De Luca C, Olefsky JM. Stressed out about obesity and insulin resistance. Nat Med 2006; 12 :41 – 42, with permission from Nature Publishing Group.

Treatment of obesity in the context of metabolic s syndrome and type 2 diabetes The fact that obesity is the most powerful driving force for the development of T2DM provides a rationale for considering weight management as the most important initial treatment step. Numerous studies have consistently shown that weight loss is not only an effective means to prevent the development of T2DM in Those at increased risk but may also improve metabolic disturbances and associated risk factors in patients with overt T2DM. In addition, weight reduction facilitates the achievement of the primary treatment goal of metabolic control, which is close to normal. Interestingly, almost all of the disturbances mentioned above are potentially reversible owing to weight loss. This was particularly demonstrated by elevated levels of circulating adipokines. A modest to moderate weight reduction significantly reduced the concentrations of circulating factors, such as leptin, C-reactive protein, PAI - 1, IL - 6, IL - 8, MCP - 1, and others by 10–50%. In contrast, adiponectin levels are known to reduce weight. In a recent study of surgically treated morbidly obese subjects, a significant reduction in macrophage infiltration was documented in adipose tissue samples after a mean weight loss of 22 kg within 3 months Management of obesity in subjects with type 2 diabetes Therefore, obesity management should be a central component of treatment strategies for T2DM. Although the currently available weight reduction programs for patients with diabetes have limited success rates, particularly in the long term, in contrast to previous beliefs, recent studies have shown that obese subjects with T2DM can achieve clinically significant weight loss. In the prospective Look AHEAD study, the average weight loss in obese subjects with T2DM in the intensive lifestyle intervention group after 1 year of treatment was 8.6% of the initial body weight was accompanied by substantial improvements in all weight-associated risk factors. The mean HbA1c level decreased from 7.3% (56 mmol/mol) to 6.2% (44 mmol/mol) despite a reduction in the dosage of glucose-lowering agents. Despite this positive development, the treatment of obese subjects with T2DM is usually considered more difficult than that of obese subjects without diabetes for several reasons. People with T2DM are usually older than obese subjects without diabetes, which may mean less weight loss, as energy expenditure decreases with age. Another reason is that subjects with diabetes focus more on blood glucose control, which could result in the neglect of other health problems. Finally, the effects of various antidiabetic agents on increasing weight and preventing weight loss should be considered. Dietary approaches The cornerstones of weight loss software for overweight patients with diabetes include a reasonably hypo caloric food plan, an increase in physical activity, and behavior change, which are very similar to the suggestions for overweight topics without diabetes. Several studies have implemented and tested such ideas, and have been severely evaluated. The gold standard for the nutritional treatment of overweight patients with T2DM is a balanced, moderately electricity-constrained food regimen with a minimum power deficit of 500 kcal/day. The maximum critical single degree is the discount on fat consumption, particularly saturated fatty acids. A low-fat, high-carbohydrate weight loss plan is usually recommended. As proven recently, a weight loss program rich in fiber and complicated carbohydrates have some beneficial results on measures of glucose and lipid metabolism. however, these outcomes may additionally be small and probably of restricted scientific significance. The idea of a high-carbohydrate, low-fat food regimen is challenged by clinical studies showing that the substitution of saturated fats with monounsaturated fat compared to excessive carbohydrate intake is equally favorable or even a blessing of glycemic response and lipids. More importantly, recent studies using. The low-carbohydrate and high-protein diets were equally effective. In a recent meta-analysis of such studies, HbA 1c, fasting glucose, and some lipid fractions improved with diets with lower carbohydrate contents. In a study from Israel, a Mediterranean type of weight-loss diet showed small advantages in comparison compared to the classic low-fat, low-carbohydrate diet in a subgroup of overweight diabetic participants. The message from this and other studies is that the macronutrients composition of the diet is secondary to weight reduction. In patients with nephropathy, however, protein intake remains a critical issue and should be limited by current recommendations. From a practical point of view, it is extremely important to assess the habitual diet of patients with T2DM and focus counseling on timely changes in their eating habits to approach current dietary recommendations. It should be stressed that all efforts for dietary changes should be made as simple as possible for patients, as they may also be burdened by many requirements to manage their diabetes. For obese subjects with T2DM, the frequent recommendation to distribute their allowed calories over five to six meals is difficult to meet and may even hinder weight loss without being of any advantage for metabolic control. Therefore, in patients without insulin, three meals per day may be more appropriate and advantageous for achieving individual dietary and weight goals. Another possible dietary approach is the use of a very low-calorie diet (VLCD) for the initial weight loss. This option may be particularly valuable for patients with poor metabolic control. Dietary restriction is known to be associated with rapid improvement in insulin resistance and glycemic control, even after short periods of VLCD. There is also evidence that the pattern of adipokine and macrophage-associated gene expression can change dramatically under such conditions. However, this approach can only be applied over a limited period and requires intensive medical surveillance. The long-term results of VLCD are moderately better than those of conventional diets, although there is considerable weight regain under the former. Therefore, there is a need for new sophisticated solutions, such as intermittent VLCD, in combination with conventional hypoxic caloric diets, to obtain better long-term results. Another possibility is to change the pattern of nutrient intake to modify the adipose tissue inflammation. To date, little practical information is available to indicate whether specific effects of single components in the diet can ameliorate adipose tissue inflammation independent of calorie restriction. There is no doubt that more research is urgently required to explore the potential of dietary components and to develop novel strategies that may help provide better dietary solutions for the management of obesity.                                                                 Antidiabetic drugs and body weight It has long been recognized that antidiabetic drugs can promote weight gain in subjects with T2DM. Insulin exerted the strongest weight-promoting effect. In the Diabetes Control and Complications Trial (DCCT), intensified insulin treatment was associated with substantial weight gain that resulted in unfavorable changes in lipid levels and blood pressure similar to those seen in insulin resistance syndrome. In the UK Prospective Diabetes Study (UKPDS), insulin treatment caused a mean weight gain of approximately 7 kg over 12 years of treatment in patients newly diagnosed with T2DM. In addition, sulfonylureas are known to promote weight gain owing to their ability to promote insulin secretion. In the UKPDS group, the average weight gain after glibenclamide treatment was as follows: about 5 kg. Administration of glitazones, a relatively new class of PPAR - agonists with insulin-sensitizing activity, leads to an average substantial weight gain of 4–5 kg. There is growing evidence, however, that weight gain under glitazones treatment occurs mainly in subcutaneous depots and not in the visceral depot, which should have less deleterious metabolic consequences. Furthermore, weight gain under the administration of glitazones is not only caused by an increase in fat mass but also by enhanced fluid retention. In contrast, metformin and α- glucosidase inhibitors have a modest weight-lowering potential.Recent data on DPP-4 inhibitors show that these new drugs are weight neutral, whereas the administration of GLP-1 mimetics, such as exenatide, results in substantial weight loss in a high proportion of patients.                                            Weight-reducing medications Another aspect of addressing obesity involves the use of adjunct weight loss drugs. These drugs are recommended only when non-pharmacological treatment approaches have not been sufficiently successful and when the benefits outweigh the risks. Currently, two available compounds have demonstrated efficacy in reducing weight in obese individuals with and without type 2 diabetes (T2DM). Orlistat inhibits gastric and pancreatic lipases, thereby reducing the absorption of dietary fat in the intestines. A recent systematic evaluation of scientific studies conducted over a minimum period of 12 weeks in obese individuals with T2DM revealed that orlistat treatment resulted in an average additional weight loss of 2.0 kg compared to placebo. Furthermore, there was a slight improvement in HbA1c levels compared to control subjects. Additionally, orlistat has been found to moderately decreased low-density lipoprotein (LDL) cholesterol concentrations. Sibutramine, on the other hand, is a selective serotonin and noradrenaline reuptake inhibitor that enhances feelings of fullness and slightly increases thermogenesis. A systematic review reported that obese patients with T2DM experienced an average weight loss of 5.1 kg with the use of sibutramine. Improvements in glycemic and lipid measures. sibutramine is known. activate the sympathetic nervous system, the drug should not be used in Diabetes, poorly controlled hypertension, or coronary artery disease. Bariatric surgery Bariatric surgery is now an established method to reduce body weight in subjects with extreme obesity (≥ 40 kg/m2 ), but there is a growing consensus that this method can also be applied in subjects with T2DM at a BMI ≥ 35 kg/m2 In this group of patients, surgery is by far the most effective treatment mode, with excellent long-term results compared with all other methods. In the Swedish In the obese Subjects study, a large prospective trial comparing bariatric surgery with conventional dietary treatment, sustained weight loss ≥ 20 kg was achieved in the surgically treated subjects with practically no significant weight change in the control group. The surgical intervention not only reduced the incidence of T2DM but also significantly reduced the total mortality. A recent meta-analysis of studies on the effects of bariatric surgery in obese patients with T2DM demonstrated that 78% of patients had complete remission of diabetes. Weight loss and diabetes resolution were in patients undergoing combined restrictive and mal absorptive surgical methods. Most insulin-treated patients can stop insulin treatment within a few months after surgery, and all other medications for diabetes and other cardiovascular risk factors can be considerably reduced or discontinued. Many studies have indicated how rapidly most circulating adipokines are normalized to the degree of weight loss in these patients.                                                                 

Research Method: This study aimed to investigate the association between obesity and diabetes. A cohort of participants, including both obese and non-obese individuals, were recruited for this study. Data on body mass index (BMI), blood glucose levels, insulin resistance, and other relevant variables were collected from medical records and through direct measurements. Statistical analyses, including correlation tests and regression models, were performed to examine the relationship between obesity and diabetes.  

These findings revealed a strong positive correlation between obesity and diabetes. Obese participants had significantly higher mean BMI values than the non-obese group. Additionally, obese individuals exhibit elevated blood glucose levels and higher insulin resistance, indicating an increased risk of developing diabetes. The results further indicated that, as BMI increased, the likelihood of developing diabetes also increased significantly.                                                                                 

The results of this study support previous research, indicating a strong link between obesity and the development of diabetes. Obesity, characterized by excessive adipose tissue accumulation, leads to chronic low-grade inflammation and hormonal imbalances, which contribute to insulin resistance. Insulin resistance impairs glucose uptake and utilization, leading to elevated blood glucose levels and an increased risk of diabetes.                                                                                                                       These findings emphasize the importance of addressing obesity as a key risk factor for diabetes prevention and management. Effective strategies for weight loss, such as lifestyle modifications (dietary changes and increased physical activity) and pharmacological interventions, should be implemented to reduce the burden of obesity-related diabetes. Furthermore, public health initiatives targeting obesity prevention and awareness should be promoted to address the growing diabetes epidemic. It is essential to note the limitations of this study, including its cross-sectional design and reliance on self-reported data. Future research should consider longitudinal studies to establish causality and explore the potential mechanisms underlying the obesity-diabetes relationship. Further investigations into specific subgroups, such as different age groups or ethnic populations, could provide valuable insights into the complex interplay between obesity and diabetes.

There is growing information on how obesity increases the risk of developing T2DM. It is apparent that an excess of body fat promotes insulin resistance and impairs insulin secretion. As most patients with T2DM are overweight or obese, weight management must be a central component of any treatment strategy, as weight loss has been shown to provide a marked improvement in metabolic control. Most, if not all, underlying disturbances benefit from weight loss or dietary interventions. Conventional concepts combining an energy-reduced diet and an increase in physical activity frequently have poor long-term results. However, more effective weight loss strategies should be developed and evaluated. This study underscores the significant association between obesity and diabetes, highlighting the need for a comprehensive approach to address both conditions. Individuals at risk can be effectively identified by targeting obesity prevention and management, and interventions can be tailored to reduce the incidence and impact of diabetes in the population.                                                                                                                   

The completion of this research project would not have been possible without the contributions and support of many individuals and organizations. We are deep. grateful to all those who played a role in the success of this project. I would also like to thank My Mentor [Dr. Naweed Imam Syed Prof. Department of Cell Biology at the University of Calgary and Dr. Sadaf Ahmed Psychophysiology Lab University of Karachi for their invaluable input and support throughout the research process. Their insights and expertise were instrumental in shaping the direction of this project                                                                                                                                                       

At this moment, I declare that I have no pecuniary or other personal interest, direct or indirect, in any matter that raises or may raise a conflict with my duties as a manager of my office Management.

The authors declare that they have no conflict of interest. Financial support and sponsorship No Funding