*4.2.1 SIRT1*

*Type 2 Diabetes - From Pathophysiology to Modern Management*

which in turn may affect transcription [57].

induced intracellular [Ca2+] oscillations, in a reversible manner.

*4.1.3 Estrogen*

*4.1.4 Melatonin*

insulin secretion [69, 77, 78].

*4.1.5 Growth hormone*

pancreas [50, 52], human islets [51, 53, 54] and mice islets [51]. Leptin inhibits insulin secretion by antagonizing the action of elevated intracellular cAMP [55]. 3-isobutyl-1-methylxanthine (IBMX) induces leptin, elevating cAMP content by inhibiting phosphodiesterases (PDEs) [56], the enzymes which catalyze hydrolysis of cAMP. GLP-1-induced insulin secretion is also inhibited by leptin, and GLP-1 which augments insulin secretion by activation of the cAMP signaling pathways [52].

In the "classical" mechanism of action of estrogen, the estrogen molecules diffuse into cell and bind to the estrogen receptor ER located in the nucleus. Rapid or "nongenomic" effects of estrogen are thought to occur through the ER located in or adjacent to the plasma membrane and may require presence of "adaptor" proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity,

β-cells are not general estrogen targets but the presence of estrogen receptor in islets makes the effect of 17β-estradiol on β-cells noteworthy [58, 59]. 17β-estradiol enhances insulin secretion from β-cells [60] and in humans, it is known to increase insulin secretion in postmenopausal women [61, 62], thus it augments glucosestimulated insulin secretion (GSIS) [63]. Two types of are present in β-cells: (1) the estrogen receptors in the nucleus, i.e., nuclear ERs (ERα and ERβ) and (2) the estrogen receptors in the membrane, i.e., the membrane ER (ERγ) [64]. 17β-estradiol significantly decreases activity of KATP channel [60], causing membrane depolarization and opening of voltage-gated Ca2+ channels, thereby potentiating glucose-

Melatonin, a hormone secreted by pineal gland, helps in maintaining circadian rhythm and biological clock [65]. However, melatonin receptors are found on clonal β-cells [66, 67] and human islets [68]. Melatonin shows both stimulatory [69] and inhibitory effects [70, 71], as well as neutral effects [72] on insulin section. However a decent number of reports have been found in literature about the inhibitory effect of melatonin in clonal β-cells [66, 68, 69, 73]. Melatonin inhibits glucose- and KClstimulated insulin secretion in rat islets [74]. Long term melatonin administration enhances hyperinsulinemia in vivo [75]. The signaling pathway of melatonin shows that melatonin receptor is coupled to Gi, which inhibits G protein [76]. Melatonin mediates stimulatory effect on insulin secretion through its receptor MTNR1A, by activation of Gq/11 which provokes release of IP3 by activating PLC-ε to augment

Growth hormone (GH) stimulates production of insulin-like growth factor-I (IGF-I) and its binding proteins [79]. Human IGF1 and IGF2 show high sequence similarity with insulin. Insulin receptor (IR) has two isoforms, IRA and IRB. IRB only binds insulin with high affinity while IRA binds both insulin and IGF2 with equal affinity. The IGF1 receptor (IGF1R) has high affinity towards both IGF1 and IGF2 but it binds insulin with very low affinity. According to the conventional view regarding the actions of insulin and IGF-1 in mammals, insulin mediates mainly a metabolic response, and IGF-1 mediates growth promoting effects in vivo [80]. Recombinant human IGF-I decreases serum levels of insulin and C-peptide in

**8**

SIRT1, mammalian sirtuin homolog, plays a key role in energy homeostasis and extends a cell lifespan by calorie restriction [85]. Glucose metabolism is tightly coupled to the regulation of insulin secretion and β-cell function [86]. Till now there are two reports showing SIRT1 positively regulates glucose-stimulated insulin secretion in pancreatic β-cells [87, 88]. In β-cells, FoxO1 is constitutively phosphorylated in cytoplasm, and activates insulin receptor signaling [89]. Accumulation of FoxO1 in the nucleus of insulin-secreting cells is triggered by palmitate during induction of lipotoxicity and impairs insulin secretion [90, 91]. Increased expression of SIRT1 in pancreatic β cells in mice improves glucose tolerance by enhancing insulin secretion [87]; deletion of SIRT1 can impair glucose-stimulated insulin secretion [88]. In both these reports, SIRT1 enhances insulin secretion by transcriptional repression of uncoupling protein 2 (UCP2) [92]. Activation of SIRT1 gives

protection from high-fat-induced obesity and insulin resistance [92–94], and slight overexpression of SIRT1 has a protective role from high-fat induced glucose intolerance [95–97]. If SIRT1 is inhibited then insulin promoter activity is suppressed, insulin regulatory genes such as v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and NK6 homeodomain 1 (NKX6.1) mRNA expressions are down regulated leading to decreased insulin secretion. On the contrary, activation or overexpression of SIRT1 antagonizes reduced insulin transcriptional activity by exerting negative effect on pancreatic and duodenal homeobox 1 (PDX1) stimulated insulin promoter activity and also abolishes forkhead box O1 protein (FOXO1)-insulin transcriptional activity [98].

## *4.2.2 PPARγ*

PPAR-γ regulates the major β cell genes involved in glucose sensing, insulin secretion and insulin gene transcription and protects from glucose, lipid, cytokine and islet amyloid polypeptide (lAPP)-induced stress pathways [99]. PPAR-γ is a member of nuclear hormone receptor superfamily of ligand-activated transcription factors and TZDs are oral agents that are high-affinity activators of PPAR-γ [100]. PPARγ ablation protects mice from high fat diet induced insulin resistance [101] and isolated islets from these mice show blunted TZD response towards GSIS [102]. Mice with PPAR-γ ablated pancreas show glucose intolerance at baseline with downregulated Pdx-1 and GLUT2 expression in their isolated islets [103]. Chronic high glucose can decrease PPAR-γ mRNA levels in mouse islets [104]. PPAR-γ is upregulated after 60% pancreatectomy procedure in rats changing to pro differentiation state from proliferative state [105]. Promoters of GLUT2 and glucokinase have functional PPREs that bind PPAR-γ/RXRα heterodimer, and lead to transcriptional upregulation of these genes in β cell [106, 107]. The expression of these genes is impaired in diabetic rodent models [108, 109].

PPARγ agonists modulate IAPP-induced ER stress [110]. The islet-specific KO of the ATP-binding membrane cassette transporter protein A1 (ABCA1) and PPAR-γ KO model both show increased intra-islet triglyceride accumulation and lowered GSIS [101, 111]. Rosiglitazone restores GSIS and decreases apoptosis in isolated human lipotoxic islets with a reduction in intra-islet triglyceride accumulation and reduced inducible nitric oxide synthase (iNOS) expression [112, 113]. PPAR-γ agonists also inhibit cytokine-induced activation of JNK in insulinoma cell lines [114]. PPAR-γ agonists have been shown to increase AKT phosphorylation in the setting of both IAPP-and lipid-inducted toxicity. These effects were blocked by PI3 kinase inhibitors and associated with increased levels of insulin receptor substrate 2 (IRS2) proteins [115].

Activation of PPAR-γ inhibits IL-1β and IFN-γ stimulated nuclear translocation of p65 subunit of NF-ΚB and DNA binding activity leading to reduced inducible nitric oxide synthase and cyclooxygenase-2 expression [116].

PPAR-γ activation also increases intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene upregulation [117]. Thus PPAR-γ agonists not only improve insulin sensitivity in the target tissues, but also act within the β-cells.

#### *4.2.3 Wnt*

Wnt signaling stimulates β-cell proliferation, specifically Wnt3a promotes expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of cell cycle progression [118]. Single nucleotide polymorphisms (SNPs) in TCF7L2 are linked to etiology of T2D [119]. Expression of three Tcf genes

**11**

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

(Tcf7, Tcf7l1, Tcf7l2) in pancreas is reduced by treatment with insulin or high fat diet feeding [120]. A significant elevation of TCF7L2 mRNA expression occurs in pancreatic islets along with impaired insulin secretion [121]. TCF7L2 depletion in isolated human or mouse pancreatic islets results in significant increased β-cell apoptosis and decreased proliferation with attenuated GSIS. Over-expression of TCF7L2 protects islets from glucose- and cytokine-mediated apoptosis [122]. These findings suggest that β-cell function and survival are positively regulated by the

Rapamycin, an mTORC1 complex inhibitor, reduces the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors suffer from hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking

Obesity induced by excess nutrient intake leads to the upregulation of mTORC1/ S6K1 signaling in insulin-sensitive tissues, including β-cells [126–128]. mTORC1 activation play an initial role in adaptation to nutrient excess and obesity, but chronic and persistent hyperactivation could lead to development of insulin resis-

Monocyte chemoattractant protein-1 (MCP-1) a chemokine that regulates migration and infiltration of monocytes/macrophages, is constitutively present in normal human islet β-cells in the absence of an inflammatory infiltrate and plays a key role in monocyte recruitment [130]. NF-kappaB plays an important role for MCP-1 expression in β-cells [131]. MCP-1 also induces amylin expression through ERK1/2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in

The Keap1-Nrf2 signaling plays an important role in oxidative stress response and metabolism. Nrf2 prevents reactive oxygen species ROS mediated damage in pancreatic β-cells [133]. β-cells have low expression levels of antioxidant enzymes, making them susceptible to damage caused by ROS. GLP-1 effectively inhibits oxidative stress and cell death of β-cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH) [134]. NOX activation through Src signaling plays an important role in

Epidermal growth factor receptors are crucial regulators of β-cell proliferation and β-cell mass regulation. Partial tissue-specific attenuation of EGFR signaling in

ROS overproduction and impaired GSIS caused by lipotoxicity [135].

AMP-activated protein kinase (AMPK) is a controller of β-cell function. Inhibition of AMPK in β-cells by high glucose inversely correlates with activation of the mammalian Target of Rapamycin (mTOR) pathway. Glucose and amino acid sensing ability of AMPK is important in regulation of insulin secretion [124]. Rapamycin also induces fulminant diabetes by increasing insulin resistance and

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

expression of Tcf7l2 in type 2 diabetes.

differentiated acinar and endocrine cells [123].

tance by a negative feedback loop on IRS signaling [129].

reducing-cell function and mass [125].

obesity and insulin resistance [132].

*4.2.4 mTOR*

*4.2.5 MCP1*

*4.2.6 Nrf2*

*4.2.7 EGFR*

(Tcf7, Tcf7l1, Tcf7l2) in pancreas is reduced by treatment with insulin or high fat diet feeding [120]. A significant elevation of TCF7L2 mRNA expression occurs in pancreatic islets along with impaired insulin secretion [121]. TCF7L2 depletion in isolated human or mouse pancreatic islets results in significant increased β-cell apoptosis and decreased proliferation with attenuated GSIS. Over-expression of TCF7L2 protects islets from glucose- and cytokine-mediated apoptosis [122]. These findings suggest that β-cell function and survival are positively regulated by the expression of Tcf7l2 in type 2 diabetes.
