*4.2.8 ER stress*

In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment involved in insulin biosynthesis. ER stress elicits a signaling cascade known as the unfolded protein response (UPR) which regulates both function and survivability of β-cells [138]. Chronic high glucose leads to insulin mRNA degradation by IRE1α activation, profuse XBP-1 splicing, and induction of pro-apoptotic effectors, such as Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP), causing β-cell dysfunction and death [139–142]. Free fatty acids (FFAs) and inflammatory cytokines also induce ER stress in β-cells through upregulation of the proapoptotic effector CHOP, and JNK and caspase-12 activation by UPR [143–146].

#### *4.2.9 Inflammasome*

ER stress, oxidative stress and high glucose concentrations activates NLRP3 inflammasome leading to interleukin (IL)-1β production and caspase-1 dependent pyroptosis. Whether IL-1β or intrinsic NLRP3 inflammasome activation contributes to β-cell death is disputed [147].

The Nlrp3 inflammasome plays important role in obesity-induced insulin resistance and β-cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) promoting β-cell failure [148]. *NLRP3*-knockout mice showed improved glucose profiles after a high-fat diet, due to attenuated IL-1β release from islet cells. Hyperglycemia-induced IL-1β release leads to increased ROS, dissociation of TXNIP from thioredoxin and its binding to NLRP3 and activation of NLRP3 [149].

#### *4.2.10 TLR4*

Toll-like receptor 4 (TLR4), a pattern recognition receptor, is a crucial element in the triggering of innate immunity, which binds to pathogen-associated molecules such as Lipopolysaccharide (LPS), and initiates a cascade of pro-inflammatory events [150]. TLR4 is also known to occur in pancreatic β-cells but its function is yet to be clearly established. β-cells respond to palmitate via TLR4/MyD88 pathway and produce chemokines that recruit M1-type proinflammatory monocytes/ macrophages to the islets [151]. High fat diet-induced obesity stimulates TLR4 up-regulation in pancreatic β-cells, and lead to the recruitment of macrophage into pancreatic islet, which finally results in pancreatic β-cell dysfunction [152].

Fetuin-A, a secreted glycoprotein, can promote lipotoxicity in β-cells through the TLR4-JNK-NF-κB signaling pathway [153]. Later it was also discovered that pancreatic β-cells are capable of secreting fetuin-A under free fatty acid stimulation which ultimately leads to inflammation [154].

#### *4.2.11 G-proteins*

Medium- to long-chain fatty acids activate FFAR1/GPR40 and it is predominantly coupled to Gαq which signals through PLC-mediated hydrolysis of

**13**

tion [157] (**Figure 3**).

**5. Conclusion**

**Figure 3.**

*137, 139–142, 153–157].*

*Emerging Role of Pancreatic β-Cells during Insulin Resistance*

membrane phospholipids leading to the formation of IP3 and DAG [155, 156]. Glucose tolerance and insulin secretion is impaired in mice due to β-cell-specific inactivation of the genes encoding the G protein α-subunits Gαq and Gα11. Thus, Gq/G11-mediated signaling pathway mediates insulin secretion by glucose stimula-

*Various signaling pathways regulating insulin secretion signaling [90, 91, 98, 99, 106, 107, 120, 129, 132, 134, 135,* 

In conclusion, insulin secretion is stimulated by glucose, free fatty acids and amino acids after their breakdown in gut following ingestion. Glucose potentiates KATP channel-dependent insulin secretion. Free fatty acids result in insulin secretion from β-cells through free fatty acid receptor (FFAR)-1. Under incretin stimulation the amino acids trigger insulin secretion by binding to their cell surface receptors. Hormones like GLP-1 and estrogen stimulate insulin secretion, melatonin has both stimulatory and inhibitory effect and leptin and growth hormone have only inhibitory effects upon insulin secretion. Discussing about the various signaling pathways, mainly Wnt, G-proteins, EGFR, mTOR, SIRT1, PPARγ mediate increased insulin secretion, β-cell proliferation and improved GSIS in presence of nutrients, while in case of excessive nutrient load TLR4, MCP1, inflammasomes and Nrf2 impairs insulin secretion and conduces β-cell death. These excess of nutrients are the key players behind glucotoxicity and lipotoxicity, which ultimately lead to compensatory insulin secretion, β-cell mass expansion initially and β-cell death under chronic nutrients overload. Our major concern should be leading a healthy lifestyle, active routine, regular exercise, balanced diet and constant awareness about the incidence

of type 2 diabetes, for eradication and curing of the disease to some extent.

*DOI: http://dx.doi.org/10.5772/intechopen.83350*

*Emerging Role of Pancreatic β-Cells during Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.83350*

**Figure 3.**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

activation, and FOXM1-mediated cell proliferation [137].

*4.2.8 ER stress*

[143–146].

*4.2.10 TLR4*

*4.2.9 Inflammasome*

to β-cell death is disputed [147].

NLRP3 and activation of NLRP3 [149].

which ultimately leads to inflammation [154].

islets leads to significantly reduced beta-cell proliferation [136]. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, is upregulated in islets from glucose and interleukin injected 6-month-old rats. β-cell mass expansion occurs in presence of chronic nutrient excess EGFR signaling, mTOR

In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment involved in insulin biosynthesis. ER stress elicits a signaling cascade known as the unfolded protein response (UPR) which regulates both function and survivability of β-cells [138]. Chronic high glucose leads to insulin mRNA degradation by IRE1α activation, profuse XBP-1 splicing, and induction of pro-apoptotic effectors, such as Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP), causing β-cell dysfunction and death [139–142]. Free fatty acids (FFAs) and inflammatory cytokines also induce ER stress in β-cells through upregulation of the proapoptotic effector CHOP, and JNK and caspase-12 activation by UPR

ER stress, oxidative stress and high glucose concentrations activates NLRP3 inflammasome leading to interleukin (IL)-1β production and caspase-1 dependent pyroptosis. Whether IL-1β or intrinsic NLRP3 inflammasome activation contributes

The Nlrp3 inflammasome plays important role in obesity-induced insulin resistance and β-cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) promoting β-cell failure [148]. *NLRP3*-knockout mice showed improved glucose profiles after a high-fat diet, due to attenuated IL-1β release from islet cells. Hyperglycemia-induced IL-1β release leads to increased ROS, dissociation of TXNIP from thioredoxin and its binding to

Toll-like receptor 4 (TLR4), a pattern recognition receptor, is a crucial element in the triggering of innate immunity, which binds to pathogen-associated molecules such as Lipopolysaccharide (LPS), and initiates a cascade of pro-inflammatory events [150]. TLR4 is also known to occur in pancreatic β-cells but its function is yet to be clearly established. β-cells respond to palmitate via TLR4/MyD88 pathway and produce chemokines that recruit M1-type proinflammatory monocytes/ macrophages to the islets [151]. High fat diet-induced obesity stimulates TLR4 up-regulation in pancreatic β-cells, and lead to the recruitment of macrophage into

pancreatic islet, which finally results in pancreatic β-cell dysfunction [152].

Medium- to long-chain fatty acids activate FFAR1/GPR40 and it is predominantly coupled to Gαq which signals through PLC-mediated hydrolysis of

Fetuin-A, a secreted glycoprotein, can promote lipotoxicity in β-cells through the TLR4-JNK-NF-κB signaling pathway [153]. Later it was also discovered that pancreatic β-cells are capable of secreting fetuin-A under free fatty acid stimulation

**12**

*4.2.11 G-proteins*

*Various signaling pathways regulating insulin secretion signaling [90, 91, 98, 99, 106, 107, 120, 129, 132, 134, 135, 137, 139–142, 153–157].*

membrane phospholipids leading to the formation of IP3 and DAG [155, 156]. Glucose tolerance and insulin secretion is impaired in mice due to β-cell-specific inactivation of the genes encoding the G protein α-subunits Gαq and Gα11. Thus, Gq/G11-mediated signaling pathway mediates insulin secretion by glucose stimulation [157] (**Figure 3**).
