Open access peer-reviewed chapter
Abstract
In today’s world, type 2 diabetes has become a part of every household and leads to various complications including high blood sugar level, diabetic retinopathy, diabetic foot, diabetic nephropathy and diabetic neuropathy. Yet people lack awareness about this disease and its detrimental effects. For a better understanding of this disease we must know about the causes and preventive measures since the medications used in treating type 2 diabetes have moderate to severe side effects. Type 2 diabetes is characterized by loss of insulin receptor activity in skeletal muscle and adipocytes, compensatory insulin secretion from pancreatic β-cells, β-cell dysfunction and death. The proper functioning of β-cells is a major criterion for preventing advent of type 2 diabetes. The different natural or physiological insulin secretagogues include glucose, amino acids and fatty acids, which stimulate insulin secretion under the influence of various hormones like incretins, leptin, growth hormone, melatonin and estrogen. However, excess of nutrients lead to β-cell dysfunction and dearth of insulin involving various signal molecules like SIRT1, PPARγ, TLR4, NF-ΚB, Wnt, mTOR, inflammasomes, MCP1, EGFR, and Nrf2. A deeper insight into the functioning of these signaling molecules will also create new avenues for therapeutic interventions of curing β-cell dysfunction and death.
Keywords
- insulin resistance
- pancreatic β-cell dysfunction
- lipotoxicity
- glucotoxicity
- type 2 diabetes
1. Introduction
Changing food habits, sedentary lifestyle and obesity has made type 2 diabetes (T2D) a global epidemic. T2D has various characteristic features such as insulin resistance caused when peripheral tissues such as liver, muscle and adipocytes have a decreased response to insulin. The progression from normal glucose tolerance to type 2 diabetes involves several transitional stages of impaired fasting glucose and impaired glucose tolerance which is known as prediabetes. The mechanism leading to the development of these glucose metabolic alterations is multifactorial. The most prevalent factor of T2D is insulin resistance that occurs when peripheral tissues such as liver, muscle and adipocytes, the main target organs of Insulin hormone, loses the ability to respond to insulin [1]. Generally in the obese patients without T2D and initially in people who develop insulin resistance, pancreatic β-cells are able to compensate for insulin resistance by increasing insulin secretion by increasing β-cell mass via increased proliferation and hypertrophy [2, 3]. Increasing of β-cells in a compensatory mechanism to avoid the complications caused due to insulin resistance and henceforth prevents diabetes [4]. This unique mechanism of β-cell mass expansion has been observed in normal individuals during physiological growth [5] as well as in insulin resistant patients, especially pregnant women [6] and obese people [7]. In patients having T2D the initial stage of β-cell compensation is followed by dysfunction or failure of β-cells due to less proliferation and increased apoptosis [1, 8].
Pancreatic β-cell dysfunction plays a critical role in progression of T2D. Insulin is produced as preproinsulin and then processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretory granules. Synthesis of insulin is regulated at both transcription and translational level. Several transcription factors in the cis-acting sequences within the 5′ region and trans-activators regulate insulin gene transcription. These transcription factors are paired homeobox gene 6 (PAX6), pancreatic and duodenal homeobox-1 (Pdx-1), MafA and B-2/Neurogenic differentiation 1 (NeuroD1). Insulin secretion from β-cells contains a series of events and is controlled by variety of factors and signaling pathways that ultimately leads to the fusion of secretory granules with the plasma membrane. The various stimulants that regulate insulin secretion are glucose, free fatty acids, amino acids, also various hormones like melatonin, estrogen, leptin, growth hormone and glucagon like peptide-1 [9].
2. Structure of insulin
The monomeric structure of insulin is made up of “A” chain with 21 amino acids and “B” chain with 30 amino acids, which are bound by disulfide bonds. Actually three disulfide bonds are present in the structure of insulin monomer, two in between the A and B chains (A7–B7, A20–B19) and one within the A chain (A7–A11) [10]. The secondary structure of the A chain is made up of two anti-parallel α-helices in between A2–A8 and A13–A19 residues. Also the helices are connected by residues at A9–A12. As a result of this particular arrangement the two ends remains in close proximity to each other and side by side [11].
The B chain is made up of α-helices and β-pleated sheets [11] and in the T state it exists in two different conformations in crystallized form [12]. The α-helix exists between B9 and B19, a β-turn between B20 and B23 and the chain folds in a “V” due to Gly20 and Gly23. An extended β-strand structure in between residues B24 and B30 which allows the chain to be in close proximity to form a β-sheet with PheB24 and TyrB26 which are in close contact with B11 and B15 leucine residues of α-helix. There is a continuous α-helix from B1 to B19 in the R state. The stability of the native insulin structure is due to the disulfide bonds in between Cys residues A7–B7 and A20–B19. The affinity of insulin towards the insulin receptor is determined by the side chain interactions in between A chain and B chain. These disulfide bonds between the A and B chain provide the tertiary structure of insulin monomer which is very highly organized. The various amino acid interactions in the side chain also contribute to the stable tertiary structure of the insulin monomer molecule. These interactions are also responsible for the interaction or affinity of insulin towards its receptor [11].
The hydrophobic inner core of the insulin monomer is composed of the following amino acids residues: A6–A11 and Leu A11, B1 and B15, Ile A2, Phe B24, Val A3, Ile A13, Val B18 and Val B12. The amino acid residues from B20 to B23 are necessary for stabilizing the β-turn thereby leading to the folding of the β-sheet in between B23 and B30 towards the α-helix and hydrophobic inner core. In the dimeric form of insulin these non-polar amino acids remain in the inner side. The insulin subunits generally remain as dimers [12]. The dimeric form of insulin is stabilized by the antiparallel β-sheets at the carboxy terminals of the B chains which remain expose on the surface of the dimeric structure. The hydrophobic core of the insulin dimer is composed of non-polar residues [11].
There are three dimers made up of six molecules of insulin peptide to make a hexamer. Some differences in the side chain like in the 25th residue (Phe) in the B chain, which is arranged to be inside the hydrophobic core of the peptide chain on one side of the dimer, deforms the perfect two-fold symmetry [11]. Also there are two zinc atoms with the imidazole groups in three histidine residues in the B chain along with two water molecules in the insulin hexamer [12].
The knowledge about the structure of insulin is necessary to understand its interaction with insulin receptor. The amino acids in the specific regions of the insulin molecule that facilitate its binding with the receptor are located at the amino terminal of the A chain: GlyA1, IleA2, ValA3, GluA4: carboxy terminal of the A chain: TyrA19, CysA20, AsnA21; and carboxy terminal of the B chain: GlyB23, PheB24, PheB25, TyrB26. These residues have are denoted as the “cooperative site” of the insulin due to their negative cooperativity [13, 14].
Out of the two chains in the structure of insulin, the A chain has more significant role for binding to the receptor. Acetylation of the amino terminal reduces binding to receptor by 30% which makes a free amino terminus necessary for binding to receptor [15].
Gly1 deletion reduces binding to receptor by 15% which may be due to some salt bridge formation between Gly1 and B chain carboxy terminus [16].
Also TyrA19, CysA20 and AsnA21 in the carboxy terminus of the A chain are also necessary for insulin receptor activity [16].
The carboxy terminal of the B chain has also a significant role in the receptor binding activity, specially the first four residues, whose deletion reduces receptor binding activity by 30% [17, 18].
Fifteen percent of the receptor binding activity is detained when HisB5 is deleted and 1% of binding activity is reduced when LeuB6 is deleted [19].
For the maintenance of disulfide bonds between A and B chain, CysB7 is critical [20].
HisB10 is necessary for activity because when substituted with AspB10, proinsulin is not converted to insulin [21].
However, synthetic insulin containing AspB10 has 500% greater binding affinity than normal insulin [22].
PheB24 forms hydrogen bonds important for dimer formation and PheB25 is important for conformation of the native insulin structure [16].
GlyB23, PheB24, PheB25 and TyrB26 in the B chain carboxy terminus are evolutionarily conserved residues needed for receptor binding [16] (Figure 1).
Figure 1.
Structure of insulin [
3. Insulin synthesis
The various stimulants in blood that lead to insulin secretion are glucose, monosaccharide, amino acid and fatty acid.
3.1 Glucose stimulated insulin secretion
Glucose acts as the main stimulus for insulin secretion in rodents as well as human beings because it is one of the major constituents of their diet and enters the circulation immediately after digestion of food. Glucose transporter 2, i.e., GLUT2 is the main glucose sensor found in the plasma membrane of β-cells. Translocation of GLUT2 to plasma membrane is dependent on insulin and it bears low substrate affinity, hence leading to high uptake of glucose. Upon entry into β-cell glucose is phosphorylated to glucose-6-phosphate by glucokinase, a type of hexokinase. Glucokinase is the rate-limiting step in the glucose metabolism in β-cells [23]. Since pyruvate dehydrogenase is not found in β-cells, pyruvate is metabolized to produce metabolic coupling factors via two pathways: (a) pyruvate is metabolized to acetyl-coA and thereby it enters glucose oxidation: the main signaling pathway couple to pyruvate oxidation through the tricarboxylic acid cycle (TCA) by mitochondria “ATP-sensitive potassium (KATP) channel-dependent insulin release.” The other pathway is anaplerosis where pyruvate, like other TCA cycle intermediates is replenished. However, some of the products of these processes can act as signals stimulating release of insulin, like malonyl-CoA, NADPH, and glutamate. These products are known to amplify KATP channel-dependent insulin secretion [24, 25].
Formation of glycerol-3-phosphate (Gly3P) is the third glucose signal. Glucokinase phosphorylates glucose into glucose-6-phosphate (G6P), G6P then enters glycolysis to produce pyruvate. Gly3P can also be produced by G6P via dihydroxyacetone phosphate (DHAP) pathway. These compounds stimulate insulin secretion. Gly3P also promotes β-cell glycolysis via the mitochondrial Gly3P NADH shuttle process, which activates mitochondrial energy metabolism and augments insulin secretion [26, 27]. Dysfunction of β-cells after prolonged exposure to elevated levels of glucose has been linked to changes in glucose detection and metabolism, apoptosis, and calcium handling. Now it has already been reported that glucotoxicity impedes final steps in insulin secretion, i.e., exocytosis [28].
3.2 Fatty acids and insulin secretion
Free fatty acids (FFAs) exert both positive and negative effects on β-cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Insulin secretion from β-cell is also stimulated by free fatty acids (FFAs). The FFAs can also upregulate glucose stimulated insulin secretion (GSIS) from β-cells. In total absence of FFAs the β-cells lose their insulin secreting capability which can again be restored when exogenous fatty acids are added [29, 30, 31]. The FFAs act upon β-cells through free fatty acid receptor (FFAR)-1, hence controlling β-cell function [32, 33]. The intracellular metabolism of FFA leads to the production of lipid signal molecules like long-chain acyl-CoA and DAG [34]. DAG in turn activates protein kinase C (PKC), which in turn tales part in insulin secretion [35]. The effect of fatty acids on pancreatic islet insulin release depends mainly on degree and time of exposure. Circulating low levels of free fatty acids in the range of physiologic postprandial values actually aids in enhancing glucose-induced insulin secretion. However, excessive accumulation of lipids within islets impairs insulin secretion [36].
3.3 Amino acid stimulated insulin secretion
At individual concentrations amino acids found in physiological concentrations are poor insulin secretagogues. Some combinations of amino acids at physiological concentrations are capable of enhancing GSIS [37], like that of, glutamine cannot stimulate insulin secretion or enhance GSIS alone, but in combination with leucine, glutamine is capable of stimulating insulin secretion from β-cells and enhancing GSIS [38]. Leucine activates glutamate dehydrogenase, and glutamate dehydrogenase can convert glutamate to α-ketoglutarate, leading to production of ATP and stimulating insulin secretion [37]. Two important incretin hormones secreted from K-cells and L-cells in the gastrointestinal tract, Glucose dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), are stimulated to be secreted after ingestion of nutrients like glucose and amino acids. These hormone levels rise in the circulation after feeding food rich in protein and carbohydrates. Then they directly trigger insulin secretion from β-cells by binding to their specific cell-surface receptors, hence enhancing GSIS [39, 40, 41].
4. Regulation of insulin secretion
4.1 Neural and hormone regulation
4.1.1 GLP-1
GLP-1 is an incretin hormone secreted from small intestinal L-cells along with GIP when the nutrient content in blood is high generally after ingestion [42, 43]. Nutrient load from oral route triggers more insulin secretion than intravenous nutrient load [44]. GLP1-agonists and analogues are already used as an effective therapy for type 2 diabetes that are safe due to the glucose dependent effect on the insulin secretion and large randomized clinical trials proved their additional cardiovascular benefits [45]. GLP-1 acts upon β-cells due to the presence of GLP-1 receptor (GLP-1R). Activation of GLP-1R leads to activation of adenylyl cyclase, which in turn generates cAMP. Elevated level of cAMP in the cytosol enhances GSIS. Hence GLP-1 secretion is dependent on high blood glucose levels [45, 46].
4.1.2 Leptin
Leptin, secreted from adipocytes, regulates function of insulin upon the glucose storing fat and liver cells [47, 48]. However, in absence of leptin, hyperinsulinemia leads to drop in blood glucose levels [47, 49]. The inhibitory action of leptin has been well known in clonal β-cells [50], cultured rodent islets [51], perfused rodent 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].
4.1.3 Estrogen
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, which in turn may affect transcription [57].
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 glucose-stimulated 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-induced intracellular [Ca2+] oscillations, in a reversible manner.
4.1.4 Melatonin
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 KCl-stimulated 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 insulin secretion [69, 77, 78].
4.1.5 Growth hormone
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 human [81]. IGF-1 also suppresses insulin secretion in isolated rat islets [82]. This inhibitory activity of growth hormone is mediated through PDE3B activation [83], which is responsible for breaking down cAMP in β-cells.
4.1.6 Adrenergic and cholinergic agents
Adrenergic drugs (epinephrine, norepinephrine and isoproterenol) are known to inhibit insulin secretion by binding to alpha receptors present in rat pancreas. On the other hand cholinergic drugs (acetylcholine and carbamylcholine) stimulate insulin secretion but this effect is suppressed by simultaneous addition of atropine. Thus the autonomic nervous system regulates insulin secretion under physiological conditions [84] (Figure 2).
Figure 2.
Hormonal and nutrient regulation of insulin secretion [
4.2 Regulation by signaling pathways
4.2.1 SIRT1
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, 93, 94], and slight overexpression of SIRT1 has a protective role from high-fat induced glucose intolerance [95, 96, 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 (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.
4.2.4 mTOR
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, 127, 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].
4.2.5 MCP1
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 obesity and insulin resistance [132].
4.2.6 Nrf2
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 ROS overproduction and impaired GSIS caused by lipotoxicity [135].
4.2.7 EGFR
Epidermal growth factor receptors are crucial regulators of β-cell proliferation and β-cell mass regulation. Partial tissue-specific attenuation of EGFR signaling in 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 activation, and FOXM1-mediated cell proliferation [137].
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, 140, 141, 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, 144, 145, 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].
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 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).
Figure 3.
Various signaling pathways regulating insulin secretion signaling [
5. Conclusion
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.
Acknowledgments
AM is thankful to the Science & Engineering Research Board (SERB), Department of Science & Technology, Govt. of India, for her JRF fellowship (Grant No. ECR/2017/001028). DC thankful DBT for JRF. SD thanks UGC, New Delhi for SRF. The authors are thankful to Dr. Rakesh Kundu and Dr. Sandip Mukherjee for their technical assistance and constant encouragement.
Notes/thanks/other declarations
The authors thank to the Head of the Department of Zoology, for providing the assistance in their research work.
References
- 1.
Golson ML et al. High fat diet regulation of β-cell proliferation and β-cell mass. The Open Endocrinology Journal. 2010; 4 . DOI: 10.2174/1874216501004010066 - 2.
Weyer C et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. The Journal of Clinical Investigation. 1999; 104 :787-794 - 3.
Cnop M et al. Progressive loss of b-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care. 2007; 30 :677-682 - 4.
Brüning JC et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997; 88 :561-572 - 5.
Meier JJ et al. β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes. 2008; 57 :1584-1594 - 6.
Butler AE et al. Adaptive changes in pancreatic β-cell fractional area and β-cell turnover in human pregnancy. Diabetologia. 2010; 53 :2167-2176 - 7.
Butler AE et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003; 52 :102-110 - 8.
Sachdeva MM et al. Minireview: Meeting the demand for insulin: Molecular mechanisms of adaptive postnatal beta-cell mass expansion. Molecular Endocrinology. 2009; 23 (6):747-758 - 9.
Fu Z et al. Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Current Diabetes Reviews. 2013; 9 (1):25-53 - 10.
Abel JJ. Crystalline insulin. Proceedings of the National Academy of Sciences. 1926; 12 :132-136 - 11.
Pittman I et al. Insulin biosynthesis, secretion, structure, and structure-activity relationships. 2004. Available from: http://diabetesmanager.pbworks.com/w/page/17680216/Insulin%20Biosynthesis,%20Secretion,%20Structure,%20and%20Structure-Activity%20Relationships - 12.
Baker EN et al. The structure of 2 Zn pig insulin crystals at 1.5 a resolution. Philosophical Transactions. Royal Society of London. 1988; B319 :369-456 - 13.
Blundell TL et al. The crystal structure of rhombohedral 2 zinc insulin. Cold Spring Harbor Symposia on Quantitative Biology. 1972; 36 :233-241 - 14.
Pullen RA et al. Receptor-binding region of insulin. Nature. 1976; 259 (5542):369-373 - 15.
Wollmer A et al. Phenol-promoted structural transformation of insulin in solution. Biological Chemistry Hoppe-Seyler. 1987; 368 (8):903-911 - 16.
Blundell TL et al. Three-dimensional atomic structure of insulin and its relationship to activity. Diabetes. 1972; 21 (2 Suppl):492-505 - 17.
Ogawa H et al. Effect of N-methylation of selected peptide bonds on the biological activity of insulin. [2-N-methylisoleucine-A]insulin and [3-N-methylvaline-A]insulin. International Journal of Peptide and Protein Research. 1987; 30 (4):460-473 - 18.
Schwartz G et al. Synthesis of des(tetrapeptide B(1-4)) and des(pentapeptide B(1-5)) human insulins. Two biologically active analogues. Biochemistry. 1978; 17 (21):4550-4556 - 19.
Nakagawa SH et al. Implications of invariant residue LeuB6 in insulin-receptor interactions. The Journal of Biological Chemistry. 1991; 266 (18):11502-11509 - 20.
Chan SJ et al. A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proceedings of the National Academy of Sciences of the United States of America. 1987; 84 (8):2194-2197 - 21.
Gruppuso PA et al. Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. The New England Journal of Medicine. 1984; 311 (10):629-634 - 22.
Schwartz GP et al. A superactive insulin: [B10-aspartic acid]insulin(human). Proceedings of the National Academy of Sciences of the United States of America. 1987; 84 (18):6408-6411 - 23.
Suckale J et al. Pancreas islets in metabolic signaling—Focus on the beta-cell. Frontiers in Bioscience. 2008; 13 :7156-7171 - 24.
Chang TW et al. The metabolic fates of amino acids and the formation of glutamine in skeletal muscle. The Journal of Biological Chemistry. 1978; 253 (10):3685-3693 - 25.
Maechler P et al. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature. 1999; 402 (6762):685-689 - 26.
Eto K et al. Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science. 1999; 283 (5404):981-985 - 27.
Bender K et al. The importance of redox shuttles to pancreatic beta-cell energy metabolism and function. Biochemical Society Transactions. 2006; 34 (Pt 5):811-814 - 28.
Mathilde D et al. Glucotoxicity inhibits late steps of insulin exocytosis. Endocrinology. 2007; 148 (4):1605-1614 - 29.
Crespin SR et al. Stimulation of insulin secretion by infusion of free fatty acids. The Journal of Clinical Investigation. 1969; 48 (10):1934-1943 - 30.
Roduit R et al. A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes. 2004; 53 (4):1007-1019 - 31.
Stein DT et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. The Journal of Clinical Investigation. 1996; 97 (12):2728-2735 - 32.
Briscoe CP et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. The Journal of Biological Chemistry. 2003; 278 (13):11303-11311 - 33.
Itoh Y et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003; 422 (6928):173-176 - 34.
Prentki M. New insights into pancreatic beta-cell metabolic signaling in insulin secretion. European Journal of Endocrinology. 1996; 134 (3):272-286 - 35.
Prentki M et al. Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiological Reviews. 1987; 67 (4):1185-1248 - 36.
Guenther B et al. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995; 44 (10):1239-1242 - 37.
Sener A et al. L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature. 1980; 288 (5787):187-189 - 38.
Dixon G et al. A comparative study of amino acid consumption by rat islet cells and the clonal beta-cell line BRIN-BD11—The functional significance of L-alanine. The Journal of Endocrinology. 2003; 179 (3):447-454 - 39.
Tang CM et al. Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion. Ugeskrift for Laeger. 2001; 163 (3):287-291 - 40.
MacDonald PE et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes. 2002; 51 (Suppl 3):S434-S442 - 41.
MacDonald PE et al. Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: A possible glucose-dependent insulinotropic mechanism. Diabetes. 2002; 51 (Suppl 3):S443-S447 - 42.
Orskov C. Glucagon-like peptide-1, a new hormone of the entero-insular axis. Diabetologia. 1992; 35 (8):701-711 - 43.
Flint A et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. The Journal of Clinical Investigation. 1998; 101 (3):515-520 - 44.
Nauck MA et al. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. The Journal of Clinical Endocrinology and Metabolism. 1993; 76 (4):912-917 - 45.
Ahren B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nature Reviews. Drug Discovery. 2009; 8 (5):369-385 - 46.
Doyle ME, Egan JM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacology & Therapeutics. 2007; 113 (3):546-593 - 47.
Zhang Y et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372 (6505):425-432 - 48.
Rossetti L et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. The Journal of Biological Chemistry. 1997; 272 (44):27758-27763 - 49.
Montague CT et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997; 387 (6636):903-908 - 50.
Fehmann HC et al. Leptin: A potent inhibitor of insulin secretion. Peptides. 1997; 18 (8):1267-1273 - 51.
Kulkarni RN et al. Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. The Journal of Clinical Investigation. 1997; 100 (11):2729-2736 - 52.
Fehmann HC et al. Interaction of GLP-I and leptin at rat pancreatic B-cells: Effects on insulin secretion and signal transduction. Hormone and Metabolic Research. 1997; 29 (11):572-576 - 53.
Fehmann HC et al. Leptin inhibition of insulin secretion from isolated human islets. Acta Diabetologica. 1997; 34 (4):249-252 - 54.
Lupi R et al. Effects of acute or prolonged exposure to human leptin on isolated human islet function. Biochemical and Biophysical Research Communications. 1999; 256 (3):637-641 - 55.
Ahren B, Havel PJ. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). The American Journal of Physiology. 1999; 277 (4 Pt 2):R959-R966 - 56.
Poitout V et al. Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology. 1998; 139 (3):822-826 - 57.
Deroo BJ, Korach KS. Estrogen receptors and human disease. The Journal of Clinical Investigation. 2006; 116 (3):561-570 - 58.
Nadal A et al. Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97 (21):11603-11608 - 59.
Sutter-Dub MT. Rapid non-genomic and genomic responses to progestogens, estrogens, and glucocorticoids in the endocrine pancreatic B cell, the adipocyte and other cell types. Steroids. 2002; 67 (2):77-93 - 60.
Nadal A et al. Rapid insulinotropic effect of 17beta-estradiol via a plasma membrane receptor. The FASEB Journal. 1998; 12 (13):1341-1348 - 61.
Stevenson JC et al. Hormone replacement therapy and the cardiovascular system. Nonlipid effects. Drugs. 1994; 47 (Suppl 2):35-41 - 62.
Brussaard HE et al. Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia. 1997; 40 (7):843-849 - 63.
Ropero AB et al. A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. Molecular Endocrinology. 2002; 16 (3):497-505 - 64.
Hawkins MB et al. Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97 (20):10751-10756 - 65.
Arendt J. Melatonin and the Mammalian Pineal Gland. London: Chapman and Hall; 1994 - 66.
Peschke E et al. Receptor (MT(1)) mediated influence of melatonin on cAMP concentration and insulin secretion of rat insulinoma cells INS-1. Journal of Pineal Research. 2002; 33 (2):63-71 - 67.
Kemp DM et al. Identification and functional characterization of melatonin Mel 1a receptors in pancreatic beta cells: Potential role in incretin-mediated cell function by sensitization of cAMP signaling. Molecular and Cellular Endocrinology. 2002; 191 (2):157-166 - 68.
Ramracheya RD et al. Function and expression of melatonin receptors on human pancreatic islets. Journal of Pineal Research. 2008; 44 (3):273-279 - 69.
Peschke E, Bach AG, Muhlbauer E. Parallel signaling pathways of melatonin in the pancreatic beta-cell. Journal of Pineal Research. 2006; 40 (2):184-191 - 70.
Peschke E. Melatonin, endocrine pancreas and diabetes. Journal of Pineal Research. 2008; 44 (1):26-40 - 71.
Bailey CJ et al. Melatonin inhibition of insulin secretion in the rat and mouse. Hormone Research. 1974; 5 (1):21-28 - 72.
Frankel BJ, Strandberg MJ. Insulin release from isolated mouse islets in vitro: No effect of physiological levels of melatonin or arginine vasotocin. Journal of Pineal Research. 1991; 11 (3-4):145-148 - 73.
Lyssenko V et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nature Genetics. 2009; 41 (1):82-88 - 74.
Peschke E et al. Influence of melatonin and serotonin on glucose-stimulated insulin release from perifused rat pancreatic islets in vitro. Journal of Pineal Research. 1997; 23 (3):156-163 - 75.
Nishida S et al. Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity. Journal of Pineal Research. 2002; 32 (1):26-33 - 76.
von Gall C et al. Mammalian melatonin receptors: Molecular biology and signal transduction. Cell and Tissue Research. 2002; 309 (1):151-162 - 77.
Bach AG et al. Melatonin stimulates inositol-1,4,5-trisphosphate and Ca2+ release from INS1 insulinoma cells. Journal of Pineal Research. 2005; 39 (3):316-323 - 78.
Godson C, Reppert SM. The Mel1a melatonin receptor is coupled to parallel signal transduction pathways. Endocrinology. 1997; 138 (1):397-404 - 79.
Sonksen PH. Insulin, growth hormone and sport. The Journal of Endocrinology. 2001; 170 (1):13-25 - 80.
Siddle K et al. Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors. Biochemical Society Transactions. 2001; 29 :513-525 - 81.
Guler HP et al. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proceedings of the National Academy of Sciences of the United States of America. 1989; 86 (8):2868-2872 - 82.
Van Schravendijk CF et al. Direct effect of insulin and insulin-like growth factor-I on the secretory activity of rat pancreatic beta cells. Diabetologia. 1990; 33 (11):649-653 - 83.
Zhang F et al. Attenuation of insulin secretion by insulin-like growth factor binding protein-1 in pancreatic beta-cells. Biochemical and Biophysical Research Communications. 2007; 362 (1):152-157 - 84.
Malaisse W et al. Effects of adrenergic and cholinergic agents upon insulin Secretion in vitro. Endocrinology. 1967; 80 (5):975-978 - 85.
Vetterli L, Maechler P. Resveratrol-activated SIRT1 in liver and pancreatic β-cells: A Janus head looking to the same direction of metabolic homeostasis. Aging (Albany NY). 2011; 3 (4):444-449 - 86.
Maechler P et al. Role of mitochondria in beta-cell function and dysfunction. Advances in Experimental Medicine and Biology. 2010; 654 :193-216 - 87.
Moynihan KA et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metabolism. 2005; 2 :105-117 - 88.
Bordone L et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biology. 2006; 4 :e31 - 89.
Kitamura YI et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metabolism. 2005; 2 :153-163 - 90.
Harbeck MC et al. Expression of insulin receptor mRNA and insulin receptor substrate 1 in pancreatic islet beta-cells. Diabetes. 1996; 45 :711-717 - 91.
Hennige AM et al. Overexpression of kinase-negative protein kinase Cdelta in pancreatic beta-cells protects mice from diet-induced glucose intolerance and beta-cell dysfunction. Diabetes. 2010; 59 :119-127 - 92.
Vetterli L et al. Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through Sirt1 dependent mechanism. The Journal of Biological Chemistry. 2010; 286 :6049-6060 - 93.
Baur JA et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444 :337-342 - 94.
Lagouge M et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006; 127 :1109-1122 - 95.
Milne JC et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007; 450 :712-716 - 96.
Pfluger PT et al. Sirt1 protects against high-fat diet-induced metabolic damage. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105 :9793-9798 - 97.
Banks AS et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metabolism. 2008; 8 :333-341 - 98.
Ling W et al. Activation of SIRT1 protects pancreatic β-cells against palmitate-induced dysfunction. Biochimica et Biophysica Acta. 2012; 1822 :1815-1825 - 99.
Gupta D et al. The role of peroxisome proliferator-activated receptor γ in pancreatic β-cell function and survival: Therapeutic implications for the treatment of type 2 diabetes mellitus. Diabetes, Obesity & Metabolism. 2010; 12 (12):1036-1047 - 100.
Yki-Jarvinen H. Thiazolidinediones. The New England Journal of Medicine. 2004; 351 :1106-1118 - 101.
Matsui J et al. Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma deficient mice on a high-fat diet. Diabetes. 2004; 53 :2844-2854 - 102.
Rosen ED et al. Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. Molecular and Cellular Biology. 2003; 23 :7222-7229 - 103.
Gupta D et al. In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter. The Journal of Biological Chemistry. 2008; 283 :32462-32470 - 104.
Chuang JC et al. Research resource: Nuclear hormone receptor expression in the endocrine pancreas. Molecular Endocrinology. 2008; 22 :2353-2363 - 105.
Moibi JA et al. Peroxisome proliferator activated receptor-{gamma} regulates expression of PDX-1 and NKX6. 1 in INS-1 cells. Diabetes. 2007; 56 :88-95 - 106.
Im SS et al. Identification and characterization of peroxisome proliferator response element in the mouse GLUT2 promoter. Experimental & Molecular Medicine. 2005; 37 :101-110 - 107.
Kim HI et al. Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. Diabetes. 2000; 49 :1517-1524 - 108.
Evans-Molina C et al. PPAR-{gamma} activation restores islet function in diabetic mice through reduction of ER stress and maintenance of euchromatin structure. Molecular and Cellular Biology. 2009; 29 :2053-2067 - 109.
Laybutt DR et al. Influence of diabetes on the loss of beta cell differentiation after islet transplantation in rats. Diabetologia. 2007; 50 :2117-2125 - 110.
Hull RL et al. Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress. Diabetologia. 2009; 52 :1102-1111 - 111.
Brunham LR et al. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nature Medicine. 2007; 13 :340-347 - 112.
Vandewalle B et al. PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets. Biochemical and Biophysical Research Communications. 2008; 366 :1096-1101 - 113.
Lupi R et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: Evidence for a role of PPARgamma2 in the modulation of insulin secretion. American Journal of Physiology. Endocrinology and Metabolism. 2004; 286 :E560-E567 - 114.
Maggi LBJ et al. Anti-inflammatory actions of 1 5-deoxy-delta 12, 14-prostaglandin J2 and troglitazone: Evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. Diabetes. 2000; 49 :346-355 - 115.
Kulkarni RN et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999; 96 :329-339 - 116.
Kim EK et al. Activation of peroxisome proliferator-activated receptor-γ protects pancreatic β-cells from cytokine-induced cytotoxicity via NFκB pathway. The International Journal of Biochemistry & Cell Biology. 2007; 39 :1260-1275 - 117.
Kim HS et al. PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells. PLoS One. 2013; 8 (1):e50128 - 118.
Rulifson IC et al. Wnt signaling regulates pancreatic beta cell proliferation. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104 (15):6247-6252 - 119.
Grant SF et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genetics. 2006; 38 :320-323 - 120.
Ip W et al. The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective. Cell & Bioscience. 2012; 2 (1):28 - 121.
Lyssenko V et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. The Journal of Clinical Investigation. 2007; 117 :2155-2163 - 122.
Shu L et al. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes. 2008; 57 :645-653 - 123.
Elghazi L et al. Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development. Molecular Metabolism. 2017; 6 (6):560-573 - 124.
Gleason CE et al. The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells. The Journal of Biological Chemistry. 2007; 282 :10341-11035 - 125.
Fraenkel M et al. mTOR inhibition by rapamycin prevents β-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes. 2008; 57 (4):945-957 - 126.
Um SH et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004; 431 :200-205 - 127.
Khamzina L et al. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: Possible involvement in obesity-linked insulin resistance. Endocrinology. 2005; 146 :1473-1481 - 128.
Shigeyama Y et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Molecular and Cellular Biology. 2008; 28 :2971-2979 - 129.
Elghazi L et al. Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in betacells. Diabetes. 2010; 59 :2390-2399 - 130.
Lorenzo P et al. Human pancreatic islets produce and secrete MCP-1/CCL2: Relevance in human islet transplantation. Diabetes. 2002; 51 (1):55-65 - 131.
Kutlu B et al. Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic β-cells. Diabetes. 2003; 52 (2):348-355 - 132.
Cai K et al. MCP-1 upregulates amylin expression in murine pancreatic β-cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. PLoS One. 2011; 6 (5):e19559 - 133.
Yagishita Y et al. Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes. 2014; 63 (2):605-618 - 134.
Fernandez-Millan E et al. Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation. Free Radical Biology & Medicine. 2016; 95 :16-26 - 135.
Sato Y et al. Palmitate induces reactive oxygen species production and β-cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling. Journal of Diabetes Investigation. 2013; 5 (1):19-26 - 136.
Miettinen P et al. EGF receptor in pancreatic β-cell mass regulation. Biochemical Society Transactions. 2008; 36 (3):280-285 - 137.
Zarrouki B et al. Epidermal growth factor receptor signaling promotes pancreatic β-cell proliferation in response to nutrient excess in rats through mTOR and FOXM1. Diabetes. 2014; 63 (3):982-993 - 138.
Fonseca SG et al. Endoplasmic reticulum stress and pancreatic β-cell death. Trends in Endocrinology and Metabolism. 2011; 22 (7):266-274 - 139.
Lipson KL. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metabolism. 2006; 4 :245-254 - 140.
Lipson KL et al. The role of IRE1alpha in the degradation of insulin mRNA in pancreatic betaCells. PLoS One. 2008; 3 :e1648 - 141.
Hou ZQ et al. Involvement of chronic stresses in rat islet and INS-1 cell glucotoxicity induced by intermittent high glucose. Molecular and Cellular Endocrinology. 2008; 291 :71-78 - 142.
Jonas JC et al. Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes, Obesity & Metabolism. 2009; 11 (Suppl 4):65-81 - 143.
Cnop M et al. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. The Journal of Biological Chemistry. 2007; 282 :3989-3997 - 144.
Karaskov E et al. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology. 2006; 147 :3398-3407 - 145.
Kharroubi I et al. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: Role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004; 145 :5087-5096 - 146.
Cardozo AK et al. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes. 2005; 54 :452-461 - 147.
Wali JA et al. Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets. PLoS One. 2014; 9 (11):e113128 - 148.
Jourdan T et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nature Medicine. 2013; 19 (9):1132-1140 - 149.
Zhou R et al. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunology. 2010; 11 :136-141 - 150.
Garay-Malpartida HM et al. Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis. BMC Immunology. 2011; 12 :18 - 151.
Eguchi K et al. Saturated fatty acid and TLR signaling link β-cell dysfunction and islet inflammation. Cell Metabolism. 2012; 15 (4):518-533 - 152.
Li J et al. TLR4 is required for the obesity-induced pancreatic beta cell dysfunction. Acta Biochimica et Biophysica Sinica. 2013; 45 (12):1030-1038 - 153.
Shen X et al. Fetuin-a promoteslipotoxicity in β-cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity. Molecular and Cellular Endocrinology. 2015; 412 :1-11 - 154.
Mukhuty A et al. Palmitate induced Fetuin-A secretion from pancreatic β-cells adversely affects its function and elicits inflammation. Biochemical and Biophysical Research Communications. 2017; 491 :1118-1124 - 155.
Amisten S et al. An atlas and functional analysis of G-prote n coupled receptors in human islets of Langerhans. Pharmacology & Therapeutics. 2013; 139 (3):359-391 - 156.
Mancini AD et al. The fatty acid receptor FFA1/GPR40 a decade later: How much do we know? Trends in Endocrinology and Metabolism. 2013; 24 (8):398-407 - 157.
Sassmann A et al. The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice. The Journal of Clinical Investigation. 2010; 120 (6):2184-2193