**5. The role of obesity and inflammatory markers in insulin resistance and T2DM**

**4. Insulin resistance**

66 Treatment of Type 2 Diabetes

the risk of developing T2DM by a factor of 3 [26].

which could precede the overt T2DM by 10 to 20years [28].

receptor [30].

Patients with T2DM have high whole body glucose production and glucogenesis but low glycogenolysis compared with normal subjects. In patients with IR, there is impairment of glucose transport and insulin signaling in target tissues with release of inflammatory markers from the adipose tissue [23, 24]. The glucose, FFA, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1) are mediators sending signals to the βcells to respond to IR. The maintenance of normal glucose and lipid metabolism is by the reciprocal relation of IR to IS and insulin secretion. Hyperbolic relation is the best description of the curvilinear relation between IS and secretion. This relation is impaired with failure of these signals to act on β-cells to secret insulin ends with subsequent development of dysgly‐ cemia (Impaired Fasting glucose- IFG, impaired Glucose tolerance –IGT and DM) [25].

Obesity is the most common cause of IR and T2DM. Simply being overweight (BMI >25) raises

The main components of IR are dysglycemia, dyslipidemia, obesity, hypertension and hyperinsulinemia. Therefore, it is the key feature of metabolic syndrome (MS) and vascular complications (cardiovascular and stroke). IR components once are acquired, those with genetic predisposition will develop the full picture of the disorder suggesting the final phenotypic expression involves both genetic and acquired influences. The most important environmental factor in IR is central obesity which is mainly caused by intake of high fat, and refined carbohydrate without physical activity. These are exacerbated by genetic predisposi‐ tion but IR could be reduced with minimizing dietary intake and regular exercise [27].

The three potential mechanisms of the controlling glucose metabolism in the skeletal muscles are the glycogen synthase, the hexokinase and the major insulin-stimulated glucose trans‐ porter GLUT4. Therefore, defects in glycogen synthesis in the skeletal muscles playing a major role in the pathogenesis of IR [28]. The decrease in the ability of normal responding skeletal muscles to circulating insulin levels or concentrations is main principle of development of IR

T2DM is characterized by increased hepatic glucose output, increased peripheral resistance to insulin action (due to receptor and postreceptor defects) and impaired insulin secretion.

Two major variants of insulin receptor abnormalities associated with acanthosis nigricans, hyperinsulinemia and marked hyperandrogenism. The classic type A IR syndrome, which is due to genetic defect in the insulin-signaling system such as mutation in the insulin receptor gene [29] and type B IR syndrome, which results from autoantibodies to the insulin

Many factors could enhance IR include, obesity, inflammation and inflammatory markers,

defects in genes and drugs. These will be demonstrated further in this chapter.

Obesity has a substantial negative effect on life expectancy and longevity. It reduces the length of life in severely obese people by an estimation of 5 to 20 years. This negative effect should be addressed in the health public policy [31]. Obesity, IR, and T2DM are growing health concerns, and the incidence and the prevalence of these diseases are increasing worldwide [32, 33]. Obesity will cause a decline in life expectancy for the first time in recent history due to numerous co-morbid disorders [31] and it is a risk factor for many human diseases [34]. Obesity is associated with an increased risk of developing IR and T2DM [34, 35]. The primary defects in obese individuals are the dysfunction of adipocyte and adipose tissue [34].

IR in obese subjects is determined by the release of high amounts of non-esterified FA, glycerol, hormones, pro-inflammatory cytokines and many other factors from adipose or fat tissue. This is followed by dysfunction of pancreatic β- cells and failure to secret insulin to control blood glucose levels. These metabolic and inflammatory changes are critical in defining the risk and the development of T2DM. [35]. There is a clear hyperbolic relationship between IS and insulin secretion by the β-cells of the pancreas. This demonstrates the concept of a feedback loop governs the interaction between the β-cells function and IS tissues. This helpful in explain that patients or subjects with IR have significant increase in insulin response compared with low responses in IS group [11, 36].

IR is a characteristic feature of T2DM and obesity, and the majority of patients with T2DM are obese. Obesity has a major impact to cause IR in subjects without DM. IR is the primary defect in obese elderly and middle aged patients with T2DM despite, adequate circulating insulin. But, in the second group the impairment of insulin release and the alteration of hepatic glucose output are other defects contributing to the development of the disease [37, 38, 39]. The intraabdominal fat is a major determinant of IR among other distributed fat in the body while the dysfunction of the β- cells is correlated with reduction of β-cells mass and subsequently reduction in IS. The genetic and the molecular basis of these pathological abnormalities are there. But, not fully understood. As mentioned, the progressive declining or failure of the βcells function and IS are associated with development of T2DM. Prior to the onset of T2DM, there are stages from normal glucose concentration to dysglycemia (IFG, IGT) emphasizing in number of ethnic group the OGTT response is a major determinant of β-cells function [25, 36]. The elevations in plasma FFA concentrations in obese subjects and in patients with T2DM inhibit insulin stimulated peripheral glucose uptake (fat and skeletal muscle) and glycogen synthesis [40, 41].

The impairment of adipose tissue functions in obese subjects caused by interaction of genetic and environmental factors and subsequently leads to obesity medical co-morbidities. How‐ ever, not all obese patients develop the same complications. The adipocyte dysfunctions or impairment occur in form of ectopic fat deposition, adipocyte hypertrophy, hypoxia, changes in the cellular composition with a variety of stresses and inflammatory processes in the fat tissue (release a proinflammatory, atherogenic, and diabetogenic adipokine pattern), increased lipid storage and impaired IS [33]. Obese individuals have large or expanded fat mass and have high or elevated plasma concentration fatty acids [42, 43, 44].

Glucose uptake rather than intracellular glucose metabolism has been implicated as the ratelimiting step for FA-induced IR [45].

In adipose tissue, the glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). In obese human, the glucocorticoids are normal. However, the excess of glucocorticoids produce visceral obesity, IR and DM. In mice, the transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue was exaggerated by high fat diet showed an increase in the level of corticosterone in adipose tissue by increased adipocyte 11beta HSD-1 activity. This could have the same effect in human[46] suggesting that increases in endogenous 11β-HSD1 in the adipose tissue of obese humans and rodents [47,48] contribute to obesity-associated IR, in part due to increased delivery of glucocorticoids to the liver via the portal vein. The c-Jun aminoterminal kinases (JNKs) interfere with insulin action and it is crucial mediator of obesity and IR. In obese mouse, the JNK activity is abnormally elevated and the absence of JNK1 results in decreased adiposity and improved IS. Therefore, it is a potential target for therapeutics [49].

The activation of JNK1 leads to serine phosphorylation of IRS-1 that impairs insulin action [50, 51]. In addition, IKK-β is a mediator of TNF-induced IR [52, 53, 54, 55] demonstrated the TLR4 (Lipopolysaccharide receptor) activation by FFA, plays a critical role in innate immunity and IR in obese human and animals through activation of inflammatory pathways. In mice the lack of TLR4 will protect insulin suppression signaling and reduce insulin mediated changes in systemic glucose metabolism by lipid infusion. This indicates the effect of nutrition as environmental factor on TLR4 and subsequently on IR. The Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. The reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity [53, 54]. This finding may provide an additional link between innate immunity, cellular stress, and IR. The protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat dietinduced obesity. The PTPRT-modulated STAT3 signaling in the regulation of high-fat dietinduced obesity [34]. Figures 3 and 4 with Table 1.



lipid storage and impaired IS [33]. Obese individuals have large or expanded fat mass and

Glucose uptake rather than intracellular glucose metabolism has been implicated as the rate-

In adipose tissue, the glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). In obese human, the glucocorticoids are normal. However, the excess of glucocorticoids produce visceral obesity, IR and DM. In mice, the transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue was exaggerated by high fat diet showed an increase in the level of corticosterone in adipose tissue by increased adipocyte 11beta HSD-1 activity. This could have the same effect in human[46] suggesting that increases in endogenous 11β-HSD1 in the adipose tissue of obese humans and rodents [47,48] contribute to obesity-associated IR, in part due to increased delivery of glucocorticoids to the liver via the portal vein. The c-Jun aminoterminal kinases (JNKs) interfere with insulin action and it is crucial mediator of obesity and IR. In obese mouse, the JNK activity is abnormally elevated and the absence of JNK1 results in decreased adiposity and improved IS. Therefore, it is a potential target for therapeutics [49]. The activation of JNK1 leads to serine phosphorylation of IRS-1 that impairs insulin action [50, 51]. In addition, IKK-β is a mediator of TNF-induced IR [52, 53, 54, 55] demonstrated the TLR4 (Lipopolysaccharide receptor) activation by FFA, plays a critical role in innate immunity and IR in obese human and animals through activation of inflammatory pathways. In mice the lack of TLR4 will protect insulin suppression signaling and reduce insulin mediated changes in systemic glucose metabolism by lipid infusion. This indicates the effect of nutrition as environmental factor on TLR4 and subsequently on IR. The Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. The reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity [53, 54]. This finding may provide an additional link between innate immunity, cellular stress, and IR. The protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat dietinduced obesity. The PTPRT-modulated STAT3 signaling in the regulation of high-fat diet-

have high or elevated plasma concentration fatty acids [42, 43, 44].

limiting step for FA-induced IR [45].

68 Treatment of Type 2 Diabetes

induced obesity [34]. Figures 3 and 4 with Table 1.

Secreted predominantly by WAT, to lesser degree, in ypothalamus, gastric epithelium,

placenta & gonads.

Secreted exclusively by adipocytes. mRNA & protein in

Sc AT > Omental AT.

Leptin

Adiponektin

**Adipokine Distribution Function Effect in obesity**

Regulates energy intake, expenditure & feeding

Also regulates storage of fat &

Improves energy homeostasis,

Anti-Inflammatory properties.

↑ in mouse models of obesity. ↑ in human obesity & correlated with BMI & ↓ in weight loss.

↓ in mouse models of obesity and

IR (ob/ob and db/db).

behavior.

insulin signaling.

IS & Glucose uptake.


**Table 1.** Adipokines increased in obesity and/or diabetes [58, 59].

**Adipokine Distribution Function Effect in obesity**

Interferes with insulin signaling in muscle.

Regulates adipocyte development & metabolic

function.

Omentin Secreted by omental AT. ↑ IS ↓ in obesity.

Role in IS, insulin secretion & inflammatory properties.

Improves IS mainly acting in

Varied role in proliferation, differentiation, apoptosis and

↑ gene expression in AT.

Synthetic prepin ↑ insulin secretion from glucose stimulated β TC6-F7 in a concentration- dependent and saturable manner [61].

It protects cell function from damage and it impairs insulin secretion from β-cells [64].

skeletal muscle & adipocytes in mice.

Central action to ↓ Appetite.

development.

Circulating levels are higher in obese IR individuals than in obese IS & ↓ after a 4-weeks period on

↑ in obesity & correlates with visceral adiposity in humans.

↑ circulating levels in obese & T2DM patients and correlated with

↑ in obesity, IGT & T2DM patients. ↓ after weight loss following diet &

↑ preadipocyte cell proliferation as with TNFα. ↑ in obesity, T2DM

No correlation of serum level with

Plasma preptin level ↑ with higher

It is ↑ in patients with T2DM compared with patients with IGT and normal subjects [61].

Anti-oxidant in pancreatic β-cells

The level and activity has impact on glucose stimulated insulin

body fat, glucose & lipid

metabolism.

bariatric surgery.

patients & CVD.

obesity.

BMI [62].

[65].

secretion [66].

↑ ob/ob and db/db mice.

↓ in obesity.

Improves IS. ↑ in obesity & T2DM patients

low-calorie diet.

CXCL5 Secreted by macrophages within

lymphocytes

Chemerin In rodents & humans, expressed in placenta & WAT.

Secreted by WAT,

& skin.

Apelin Produced in a wide range of tissues.

Nesfatin Secreted in brain tissue, Β cells and AT.

differentiation.

degree in WAT.

system [63].

Multifunctional, produced By variety of cells. Inhibitor of

Pro -inflammatory secreted by T cells, monocytes & to lesser

It is a novel hormone that is cosecreted with insulin and amylin from pancreatic β-cells [60].

It is expressed in AT, skeletal muscle and tissue of immune

**Table 1.** Adipokines increased in obesity and/or diabetes [58, 59].

hypothalamus, pancreatic islets

Visfatin

70 Treatment of Type 2 Diabetes

Vaspin

TGFβ

Rantes

Preptin

Uncoupling protein 2

the stromal vascular fraction.

Expressed in liver, muscle, WAT, bone marrow &

**Figure 3.** The molecular linked pathway between obesity and IR. (*A*) IR triggered by the increase in FAs through intra‐ cellular metabolites that activate PKC, leading to inhibit insulin signaling by activation of serine/threonine kinases. (*B*) Insulin signaling modulated by changes in adipokines secretion. (*C*) In the adipose tissue; the increased in the ATMs mediated the increase of the inflammatory cytokines that inhibit insulin signaling. (*D*) Insulin signaling inhibited by mediators (Endocrine and Inflammatory) converging on serine/threonine kinases. (*E*) IR exacerbated by activation of NF-κB heightens inflammatory responses. (*F*) Adipokines induced SOCS family proteins interfering with IRS-1 and IRS-2 tyrosine phosphorylation or by targeting IRS-1 and IRS-2 for proteosomal degradation inducing IR. (*G*) IR trig‐ gered by activation TLR4 and innate immune response by FAs. (*H*) Alteration in peripheral IS is related to the central response to hormonal and nutrient signals [57].

**Figure 4.** There are several cell-intrinsic mediators and pathways dysregulation in obesity with negative impact on IR. (*A*) Activation of PKC in the liver and muscles inhibits insulin signaling by increasing FA from ectopic adipose tissue. (*B*) Direct inhibition of insulin signaling through IRS-1 or IRS-2 serine phosphorylation or indirectly through a series of

transcriptional events mediated by NF-κB. Inhibition occurs due to activation of several serine/threoning kinases (JNK, IKK, and p38 MAPK) by excess in ROS. The later generation increased by mitochondrial β- oxidation triggered by ex‐ cess fat accumulation. (*C*) IR exacerbated by mitochondrial dysfunction through increasing intracellular lipid accumu‐ lation. (*D*) Insulin signaling suppressed by activation of JNK or through a potential increase in ROS production and both activated by cellular ER stresses responses. (*E*) The cell-extrinsic modulators such as endocrine and inflammatory signals can intensified IR [57].

WAT: White adipose tissue, AT: adipose tissue, T2DM: type 2 diabetes mellitus, IR: insulin resistance, IS: insulin sensitivity, IGT: impaired glucose tolerance, TNF-α: tumor necrosis alpha, IL: interleukin, RBP4: Retinol binding protein, SC: subcutaneous, MCP-1: monocyte chemotactic protein 1, PAI: plasminogen activator inhibitor, CXCL5: chemokines molecules (CXCL5 ligand 5), TGFβ: transforming growth factor β.
