*4.2.4 mTOR*

*Type 2 Diabetes - From Pathophysiology to Modern Management*

(FOXO1)-insulin transcriptional activity [98].

*4.2.2 PPARγ*

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

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 expres-

sion of these genes is impaired in diabetic rodent models [108, 109].

nitric oxide synthase and cyclooxygenase-2 expression [116].

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

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

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

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

**10**

*4.2.3 Wnt*

(IRS2) proteins [115].

tissues, but also act within the β-cells.

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 differentiated acinar and endocrine cells [123].

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 reducing-cell function and mass [125].

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