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Abstract

Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.

Keywords

β-cell loss β-cell death glucotoxicity lipotoxicity mechanisms

Introduction

The pancreas plays an important role in digestion and metabolism homeostasis by secreting various digestive enzymes and pancreatic hormones.¹ An adult mammalian pancreas is composed of exocrine and endocrine compartments. The exocrine part is composed of acinar cells that secrete digestive enzymes, and the endocrine part consists of the islets of Langerhans that secrete hormones involved in maintaining glucose homeostasis into the bloodstream. The islets of Langerhans are mainly composed of alpha, beta, delta, and epsilon cells that secrete glucagon, insulin, somatostatin, and ghrelin, respectively.² Of these, β-cells make up 65–80% of the cells in the islet, which is the only site where insulin is synthesized.

Insulin is a peptide hormone essential for controlling the balance of blood glucose homeostasis. It helps to control blood glucose by signaling to the liver, muscle, and fat cells and enhances glucose uptake, thereby reducing blood glucose. Insulin facilitates the intracellular transport of glucose to insulin-dependent tissues, such as muscle and adipose tissue, and regulates the supply of cellular energy.³ Absolute or relative deficiency of insulin and a decrease or loss of insulin activity result in hyperglycemia. A continuous decline in β-cell functions induces a decrease in the synthesis and secretion of insulin, leading to the development of diabetes mellitus (DM).⁴

Diabetes is a chronic disease associated with defects in insulin-producing β-cells. There are two major types of DM: type 1 diabetes (T1DM) and type 2 diabetes (T2DM) (Figure 1). T1DM is a chronic autoimmune disorder (also known as juvenile diabetes) that often develops during childhood or adolescence.⁵ In T1DM, the body’s immune system attacks its own healthy endogenous pancreatic β-cells by mistake and is regarded as a foreign invader.⁶ Both genetic and environmental factors play important roles in the development of T1DM. As β-cells are attacked, the body fails to produce insulin, resulting in insulin deficiency, chronic hyperglycemia, and long-term complications⁷ (Figure 1).

Figure 1.

Pathogenesis of type 1 and type 2 diabetes. In type 1 diabetes, pancreatic β-cells are destroyed by immune cells, such as T cells, macrophages, and the cytokines produced by these immune cells, resulting in an absolute deficiency of insulin, leading to hyperglycemia. In type 2 diabetes, pancreatic β-cells are damaged by hyperglycemia, hyperlipidemia, cytokines, and amyloids. Although pancreatic β-cells produce insulin, the insulin level is insufficient to compensate for insulin resistance, resulting in a relative insulin deficiency, leading to hyperglycemia. (Created with BioRender.com).

In type 2 diabetes (T2DM), the body can produce insulin. However, the insulin level may not be sufficient, the body may not respond to insulin, or the body may not use insulin efficiently, resulting in insulin resistance³ (Figure 1). T2DM is usually diagnosed in middle-aged individuals, and its prevalence increases with age. Similar to T1DM, genetic and lifestyle factors influence the onset of T2DM. T2DM is usually identified by a defective secretion of insulin resulting from a progressive loss of β-cell mass and/or overproduction of insulin for a long period.^6,8,9 Eventually, T2DM patients experience diabetes-induced complications, including retinopathy, nephropathy, and neuropathy.¹⁰ Recent evidence has suggested that β-cell dysfunction is the main pathogenic mechanism of diabetes and is crucial for T2DM development.¹¹ In patients with T2DM, a decrease in β-cell mass was observed with duration of the disease and considered as a consequence of diabetes with impaired insulin secretion.¹² Moreover, decreased β-cell mass leads to the imbalance of α-cell/β-cell ratio which is essential for the maintenance of blood glucose homeostasis.^13,14 In some studies, it has been described that glucotoxicity and lipotoxicity are considered the major causes of defects in β-cell mass, eventually leading to β-cell apoptosis through various intracellular mediators.¹⁵ However, since the β-cell turnover is very slow,¹⁶ other priority factors contributing to the loss of β-cell function and cell death should be explored. In this review, we present the major risk factors and underlying molecular mechanisms of β-cell dysfunction and death in T2DM, based on current evidence.

Insulin secretion in pancreatic β-cells

Shortly after a meal, the carbohydrates in food are broken down into glucose, which mainly supplies energy to the body’s cells.¹⁷ Glucose stimulates insulin release by entering β-cells through the glucose transporter located on the plasma membrane. Once inside a β-cell, glucose is phosphorylated to glucose-6-phosphate (G6P) by the enzyme glucokinase. G6P generatespyruvate via glycolysis.¹⁸ Then, pyruvate enters the mitochondria and is further oxidized to produce adenosine triphosphate (ATP) through the tricarboxylic acid cycle (TCA), which increases the intracellular ATP/ADP ratio.¹⁹ This increase induces the ATP-dependent potassium channels to close, resulting in depolarization of the plasma membrane, which blocks the exit of potassium from β-cells. This results in an influx of Ca²⁺ into the cell, triggering the exocytosis of insulin granules^20,21 (Figure 2). Recently, it has been proposed that the active zone (AZ)-specific protein, ELKS, is also expressed in pancreatic β-cells²² and plays a role in enhancing the influx of Ca²⁺ and insulin exocytosis during the first phase of insulin secretion. However, β-cell-specific ELKS-knockout mice exhibit impaired glucose-stimulated first-phase insulin secretion.²³ Thus, exploring the involvement of ELKS in the regulation of Ca²⁺ influx in future studies may provide new insights into the exocytosis of insulin.

Figure 2.

Secretion of insulin in response to glucose in pancreatic β-cells. Upon glucose stimulation, glucose enters the β-cell through glucose transporters2 (GLUT2) residing at the β-cell plasma membrane. Once inside the β-cell, glucose is phosphorylated to glucose-6-phosphate (G6P) by the enzyme glucokinase. G6P generates pyruvate via glycolysis. Pyruvate then enters the mitochondria, produces ATP through the tricarboxylic acid cycle (TCA), and increases the intracellular ATP/ADP ratio. The increase in the ATP/ADP ratio closes the ATP-dependent potassium channel, resulting in depolarization of the plasma membrane, which blocks potassium exit from the β-cells. This results in an influx of Ca2+ into the cell, which triggers the exocytosis of insulin granules. Upon stimulation, insulin is released from the granules and secreted into the bloodstream by exocytosis. (Created with BioRender.com).

As described above, potassium channels also play a crucial role in insulin secretion from pancreatic β-cell. During depolarization, increased intracellular calcium [Ca2+]i and membrane depolarization cooperatively activate BK channels (K+ channels of large unitary conductance). BK channel current and delayed rectifier K+ current (I_ks) coordinate to repolarize action potential (AP).^24,25 Delayed rectifier potassium (K_D) channels are the main component of the K+ channel and control resting potential and AP repolarization in many cell types.²⁶ Reduced I_ks results in long QT syndrome, a cardiac disorder, increasing the cardiac arrhythmia and sudden cardiac death.^27,28 A study reported that long QT syndrome 2 (LQT2) is caused by the loss-of-function (LoF) mutations in K_v11.1 voltage K⁺ channel that is also present in pancreatic α and β cells, intestinal L and K cells. Thus, Kv11.1 is involved in the secretion of glucagon, insulin and glucagon-like peptide-1 (GLP-1), hormones that are related to glucose regulation. Blockage of Kv11.1 channel impairs glucagon secretion and increased high insulin secretion, leading to decreased glucose level. Thus, patients with long QT syndrome showed hyperinsulinemia with subsequent hypoglycemia after an oral glucose challenge.^29,30 Also in young healthy population, taking a drug that is known to block Kv11.1 channel, moxifloxacin, decreased glucose levels with higher hypoglucaemia questionnaire scores were observed.³¹ Knockout of Kcnh6 or knockin of Kcnh6 (Kv11.3) in mice has been shown changing characteristics from hyperinsulinemia to hypoinsulinemia. Kcnh6 dysfunction induces intracellular calcium and insulin secretion disorders and causing failure of β-cells in the long term.³² It has been proved that inhibitor of Kcnh6, cisapride, ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose and revealed a novel significant effect of Kcnh6 in diabetes.³³ In addition, LoF mutations in K_v7.1 represent LQT1 and it has been proved that K_v7.1 dysfunction is also involved in changing transition from hyper-to hypo-insulinemia.³⁴ However, a few studies have been published concerning about voltage-gated ion channels in human β-cells and targeting K⁺ channels would become a therapeutic strategy for the study of β-cell failure in the future.

Similar to glucose, free fatty acids (FFAs) stimulate insulin secretion. FFAs act as the main substrates for energy production in islets and enhance insulin secretion at low glucose concentration.³⁵ Binding of FFAs to the G-protein-coupled receptor (GPCR), free fatty acid receptor 1(Gpr40/FFAR1), which is selectively expressed in β-cells, activates protein kinase C (PKC) and increases intracellular Ca²⁺ to stimulate the release of insulin granules³⁶ in the presence of glucose. It has also been established that high concentrations of palmitate which fully activate FFA1, improve glucose-stimulated insulin secretion (GSIS).³⁷ Long-chain fatty acids (LCFAs) which are transported across the plasma membrane are metabolized to their corresponding coenzyme A (CoA) esters (FA-CoA) by acyl-CoA synthase via the glycerolipid/FFA (GL/FFA) cycle, which stimulates the secretion of insulin by producing several lipids signaling molecules.³⁸ Meanwhile, short-chain fatty acids, sodium acetate (SA) and sodium propionate (SP), potentiate glucose-stimulated insulin secretion and protect β-cell apoptosis via free fatty acid receptor 2 (FFAR2).³⁹ Both long-and short-chain fatty acids induce insulin secretion via the activation of different signaling pathways. Nevertheless, the role of FFARs in the stimulation of insulin secretion is interesting, and more studies are needed to elucidate the intracellular pathways that are activated by FFARs.

β-cell failure in type 2 diabetes

Beta-cells regulate insulin secretion in response to plasma glucose concentration, which should be within a relatively narrow physiological range. However, in diabetic patients, β-cells are unable to secrete insulin to meet the increased insulin demand in response to glucose and other secretagogues.⁴⁰ The pathogenesis of T2DM typically begins with insulin resistance, and there is an increase in β-cell-insulin secretion to compensate for this resistance, thereby maintaining normal blood glucose levels. However, β-cell function and mass continuously decline, thereby exacerbating inadequate insulin secretion. This eventually leads to β-cell failure to compensate for insulin resistance, resulting in overt diabetes.⁴¹

The ability of β-cells to secrete insulin is decreased, and a significant proportion of the β-cell mass is lost before the onset of T2DM.⁴² Usually, the identities and mass of β-cells are lost in T2DM patients, and these β-cells may even gain the features of other cell types of the islets.⁴³ Moreover, β-cells have been reported to dedifferentiate and convert to α- and δ-like cells in T2DM patients.⁴⁴ Stressed β-cells in diabetes are derived from their mature differentiated state to a dedifferentiated state through the reduction of β-cell-enriched genes such as GLUT2, PDX1, FOXO1, and MafA, which regulate normal β-cell functions.⁴⁵ Treatment with incretin-based drugs, such as liraglutide and sitagliptin, which limit the conversion of β-cells to the α-phenotype, restored β-cell mass and function in mice.⁴⁶ Thus, β-cell dedifferentiation and/or trans-differentiation propose a mechanism of β-cell failure in T2DM.

Glucotoxicity, lipotoxicity and glucolipotoxicity are the major detrimental factors responsible for defects in β-cells.⁴⁷ While short-term exposure of β-cells to increased glucose concentration induces β-cell proliferation, long-term exposure suppresses β-cells, decreases glucose-stimulated insulin secretion (GSIS), and induces β-cell apoptosis.⁴⁸ Meanwhile, studies indicated that chronic exposure to elevated levels of free fatty acids (FFA) induced β-cell dysfunction and reversal or inhibition of triglyceride accumulation or synthesis protected pancreatic β-cells.^49–51 In addition, the increase in circulating free fatty acids, which is usually found in diabetic patients, contributes to β-cell dysfunction and death, particularly in the presence of hyperglycemia.⁴⁸ Therefore, it is important to maintain a satisfactory β-cell function in response to various metabolic demands.

Risk factors for β-cell dysfunction in type 2 diabetes

Glucotoxicity and glucolipotoxicity

The term ‘glucotoxicity’ describes the irreversible structural and functional damage of β-cells caused by chronic exposure to extremely high glucose levels.^50,52 Under medium to high glucose condition (30∼60 mmol/L), increased reactive oxygen species (ROS) level induced β-cell apoptosis,^53,54 while prolonged exposure of human islets to mild to moderate glucose concentration (under 20 mmol/L) did not induce β-cell apoptosis. However, the sensitivity of β-cells to glucose increased, stimulating to secrete more insulin although the content of insulin was declined, leading to β-cell dysfunction rather than β-cell apoptosis.⁵⁵ Under such circumstance, the adaptive actions are termed as glucoadaptation rather than glucotoxicity.⁵⁰

The effects of chronic hyperglycemia on β-cells have been studied in vitro using animal models. Exposure of human neonatal diabetes mouse model to a high glucose concentration resulted in a significant glycogen accumulation and increased β-cell apoptosis.⁵⁶ Also, islets isolated from diabetes βV59 M mice: a model of human neonatal diabetes showed deleterious effects on β-cells. Meanwhile, inhibition of glucokinase prevented the changes in metabolic gene expressions induced by chronic hyperglycaemia and regained insulin content.⁵⁷ The underlying mechanisms of β-cell impairment by hyperglycemia has been unclear for decades, and, restricting glucose metabolism would be a solution to control β-cells impairment under diabetic condition.

There are numerous GPCRs on β-cells that can activate or inhibit insulin secretion by β-cells.⁵⁸ Almost 300 GPCRs are expressed in the pancreatic islets, which significantly affect the function of islet cells. These GPCRs couple and produce cyclic adenosine monophosphate (cAMP) molecules.⁵⁹ Some orphan GPCRs also influence intracellular Ca2 + metabolism. As GPCRs mediate glucose-stimulated insulin secretion (GSIS), these receptors may act as potential therapeutic targets for the treatment of diabetes. The G protein-coupled receptor 183 (Gpr 183) is highly expressed in the human islets of diabetic patients. Gpr 142 is expressed in the pancreatic β-cells of both rodents and humans, and its activation promotes GSIS by increasing the levels of cAMP in INS1832/13 cells. Gpr 142 and 183 are implicated in insulin secretion in a hyperglycemic in vitro model. GPCR agonists have been demonstrated to potentiate insulin secretion and protect against glucotoxicity-induced β-cell damage.^60,61 Thus, activation of Gpr on β-cells could be a potential therapeutic target to prevent or reverse β-cell dysfunction. However, further studies are required to determine the expression levels and functional impacts of GPCRs on insulin secretion by β-cells.

The combination of elevated glucose and fatty acid (FFA) showed worsening effects on β-cells in many experimental studies and led to the thought of glucolipotoxicity.⁶² Many studies have been revealed that increased oxidative stress, inflammation and mitochondria dysfunction by high glucose and FFA-induced glucolipotoxicity resulted in β-cell dysfunction and apoptosis.^63–65 When glucose and FFA levels are elevated, glucose determines the partitioning of FFAs by blocking fatty acid oxidation and activating the expression of genes involved in lipogenesis. Another key player is the enzyme AMP-activated protein kinase (AMPK) which act as a metabolic sensor in beta cells and the metabolic signaling sensed by AMPK are translated to increase lipid synthesis.⁶⁶ In type 2 diabetes db/db mice, IP injection of nonmitogenic fibroblast growth factor 1 (FGF1) lacking N-terminal residues 1–27, ∆nFGF1, promoted blood glucose level and prevented β-cell apoptosis. In MIN6 cells, β-cell dysfunction induced by glucolipotoxicity were inhibited by ∆nFGF1 via activation of the AMPK/SIRT1/PGC-1α signaling pathway.⁶⁷ Through phenotypic screening, compounds that are capable to protect β-cells were identified in rat insulinoma cell line INS-1E. Among them, KD025, ETP-45,658, BMS-536,924, AT-9283, PF-03,814,735, torin-2, AZD5438, CP-640,186, ETP-46,464, and GSK2126458 were observed to decrease the markers of glucolipotoxicity including caspase activation and mitochondrial depolarization.⁶⁸ Thus, in future, use of phenotypic screening could become a time saving method to identify the novel compounds and molecules to study changes in β-cells.

Lipotoxicity

Apart from hyperglycemia, hyperlipidemia is also a major risk factor for the development of T2DM.⁶⁹ The unbalanced lipid homeostasis in T2DM increased the production and release of different lipids, including FFA, ceramides, triglyceride (TAG), cholesterol, and various bioactive lipids, into plasma and the interstitial space, which later bring to adaptive or toxic effects on the cells within the exposed tissues.⁷⁰ Excess accumulation of circulating lipids has been linked to metabolic diseases. The term “lipotoxicity” is used to describe how a lipid overload of the pancreatic islets causes the inhibition of pancreatic β-cell function and the development of T2DM.⁷¹

In healthy individuals, FFAs serve as an energy storage in the form of triglycerides (TAGs) in adipocytes.⁷² In general, FFAs potentiate glucose-stimulated insulin secretion (GSIS) on the basis of elevated blood glucose levels.⁷³ Under low glucose concentrations, FFAs are converted to long-chain fatty acid coenzyme A (LC-CoA) by long-chain acyl-CoA synthetase and enter the mitochondria where they undergo β-oxidation to generate energy,⁷⁴ thus, the hypoglycemia is prevented.^75–77 However, in one study it has been demonstrated that FFA induced insulin secretion independent on the oxidation of the fuel⁷⁸ and/or presence of glucose.⁷⁶ In contrast, excess consumption of dietary fats and oils has a negative impact on β-cells.⁷⁹

In an in vitro study, chain length and saturation of FFAs are crucial factors for the toxicity of β-cells. Exposure of human EndoC-βH1 β-cells to physiologically saturated and monounsaturated long-chain FFAs induces apoptosis of β-cells, whereas polyunsaturated FFAs are not toxic. It has been shown that FFAs toxicity is dependent on the induction of peroxisomal, mitochondrial and ER stress. Plӧtx, T. et al. proposed the optimal composition of the lipid component of our daily diet to protect the pancreatic β-cells against lipotoxicity.⁸⁰ Many studies reported that prolonged exposure to palmitate, the most abundant long chain saturated fatty acid (LC-SFA) in the circulation, induces changes in the gene expression and apoptosis of β-cells.^71,81,82 In a recent study, it was demonstrated that chronic exposure of palmitate to human EndoC-βH1 cells did not cause the demise of human β-cell and also showed protective effect against cytokine induced cell death.⁸³ It was revealed that in human β-cells, palmitate is incorporated into lipid droplet unlike in rodent β-cells, in which palmitate accumulates in the Golgi apparatus.⁸⁴ These imply that earlier scientific studies with rodent cells may require to reconsider.

Inflammatory cytokines

As β-cell failure is one of the major components of the pathogenesis of T2DM, islet inflammation can be considered a part of it. It has been reported that increased circulating levels of IL-1β, and IL-6 are found in the islets of T2DM patients.⁸⁵ As β-cells express a huge amount of interleukin 1 receptors (IL-1R) which are involved in regulating the secretion of insulin,⁸⁶ pancreatic β-cell become a target for IL-1β action. Acute elevation of IL-1β induced β-cell apoptosis and inhibition of it restored the functions of β-cells.⁸⁷ In rat pancreatic β-cell line, INS-1, chronic treatment with IL-6 significantly induced early apoptosis. IL-6 is a pleiotropic pro-inflammatory produced by several cell types. It can directly act on β-cell and enhance glucose-stimulated insulin secretion.⁸⁸ Exposure of IL-6 to INS-1 for 48 h induced β-cell apoptosis through STAT-3 mediated nitric oxide production.⁸⁹ It was also observed that IL-6 treatment increased the mRNA level of tumor necrosis factor-alpha (TNF-α) while decreasing the mRNA level of TNF-α regulator, (miR)-181c.⁹⁰ Treatment of cytokine mixture to INS-1 β-cells and isolated islets from SD rats increased the expression of caveolin-1 (cav-1), a member of the family of cholesterol-binding membrane proteins. Thus, IL-1 receptor and TNF receptor are recruited to the caveolae and induce β-cell apoptosis.⁹¹ However, silencing the expression of cav-1 increased insulin secretion and β-cell viability. Thus, targeting cav-1 could be a potential therapeutic strategy for attenuating cytokine-induced β-cell apoptosis.

During obesity and diabetes, macrophage-mediated inflammation which impairs insulin signaling, also participates in β-cell dysfunction by releasing cytokines. Ying et al. demonstrated that obesity induced the expansion of resident intra-islet macrophages.⁹² Pathohistological analysis revealed that the number of galectin 3 (GAL3) cells in the islets was increased in C57BL/6J mice treated with HFD. GAL3 released from initial β-cell damage stimulated macrophage migration to the islet and facilitated β-cell apoptosis via nitric oxide (NO2)-induced oxidative stress and pro-apoptotic factor BAX.⁹³

Islet amyloid

Islet amyloid is a pathological hallmark, and amyloid deposition is a typical finding in the islets of T2DM patients.⁹⁴ Islet amyloid polypeptide (IAPP), also known as amylin, is co-expressed and co-secreted with insulin, and abnormal aggregation of human IAPP (hIAPP) is associated with β-cell death.⁹⁵ Fibrous amyloid deposits cause a decrease in β-cell mass and insulin production by inducing inflammation in β-cells and their apoptosis.⁹⁶ Transgenic expression of human islet amyloid polypeptide (hIAPP) in mice leads to the formation of intracellular human IAPP oligomers and the development of diabetes.^97–99 The formation of amyloid increases IL-1β and inhibition of amyloid formation by the amyloid inhibitor, anakinra, reduces β-cell apoptosis and restores their survival¹⁰⁰

It has been reported that divalent ions such as Zinc (Zn) and copper (Cu) play an important role in the aggregation of amylin.¹⁰¹ High concentration of zinc ions is found in insulin secretory granules.¹⁰² They are stored and packed together with amylin, and when their balance is disrupted, amyloid aggregation occurs.¹⁰³ Recent studies have demonstrated that zinc accumulation is related to the synthesis and aggregation of IAPP. Treatment of hIAPP-transfected INS-1 cells with zinc resulted in higher levels of IAPP deposition and reduced insulin levels in the cytoplasm of INS-1 cells. However, chelation of zinc with a zinc chelator, N, N, N, N-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), increased the insulin content and β-cell survival.¹⁰⁴ Moreover, another major aggregating protein that is co-localized in the amyloid of β-cells from pancreases of hIAPP transgenic mice and human β-cells is alpha-synuclein (αSyn).¹⁰⁵ αSyn is a neuronal protein, regulating synaptic vesicle trafficking and the release of neurotransmitters. Abnormal accumulation of αSyn aggregates in Lewy bodies that is also expressed in pancreatic β-cell.¹⁰⁶ It has been shown that αSyn regulates insulin secretion and glucose transport both in peripheral tissues and pancreatic β-cells¹⁰⁷ and the formation of IAPP fibrils increases as the dose of αSyn increased both in vivo and in vitro.¹⁰⁵ However, further studies are required to determine whether the accumulation of IAPP fibrils can form in the absence of αSyn.

Potential molecular mechanisms of β-cell dysfunction in type 2 diabetes

Mitochondrial dysfunction and oxidative stress

In pancreatic β-cells, mitochondria play a key role in glucose metabolism and insulin secretion. Mitochondria are the major generator of ROS production in cells, and defects in the functions of mitochondria generate free radicals, eventually leading to β-cell apoptosis, metabolic disorders, and diabetes.¹⁰⁸ Under chronic hyperglycemic conditions, the number of mitochondria decreased, including the number of proteins in the inner membrane, and the morphology of the β-cell mitochondria changed, allowing the release of apoptotic mediators

¹⁰⁹ Recently, it has been reported that stimulator of interferon genes (STING), a cytosolic DNA sensor, can recognize its own DNA released into the cytoplasm from damaged mitochondria. The activation of STING and phosphorylation of its downstream factor, interferon regulatory factor 3 (IRF3), triggers the apoptosis of pancreatic β-cells, and knockdown of STING or IRF3 reversed high glucose-stimulated insulin secretion or lipotoxicity-induced islet β-cell injury.¹¹⁰

Comprehensive transcriptomic and proteomic profiling combined with mitochondrial function analysis revealed rapid and dramatic changes in metabolism via the downregulation of SLC25A42 (a Coenzyme A importer) or translocase of the inner mitochondrial membrane 13 (TIMM13) in islets isolated from βV59M diabetic mice, in which glycolysis was reduced, and mitochondrial metabolism was significantly impaired. A similar result was observed when INS-1 β-cells were cultured under chronic hyperglycemic conditions. This revealed that reduction in mitochondrial metabolism is one of the underlying causes of β-cell failure due to hyperglycemia in diabetes.¹¹¹

Furthermore, oxidative stress and imbalance in redox signaling also play a pivotal role in β-cell apoptosis. Reactive oxygen species are signaling molecules that are essential for regulating physiological cellular functions, and overproduction of ROS in pathological conditions causes organellar stress, injury, and cell death. The change in the balance between antioxidants and the production of ROS, such as superoxide and hydrogen peroxide (H2O2), causes oxidative stress leading to a failure in functional β-cells and, thus, β-cell death.¹¹² In fact, pancreatic β-cells express lower levels of antioxidant enzymes. Under hyperglycemic conditions, the electron transfer system of mitochondria, which produces ROS as an intermediate product, is increased¹¹³ and contributes to oxidative stress-mediated β-cell dysfunction in diabetic conditions. It has been demonstrated that superoxide production in response to glucose stimulation in INS-1E cells was prevented by mitochondria-targeted antioxidants, mitochondria-targeted plastoquinone (SkQ1), and suppressor of respiratory chain complex III site Q electron leak (S3QEL). SkQ1 also prevents mitochondrial network fragmentation induced by fatty acids and palmitate. Fission of the mitochondrial network is required to maintain the balance of mitophagy; however, excessive mitochondrial fission leads to apoptosis of pancreatic β-cells. Thus, further study of mitochondria-targeted antioxidants could be beneficial for the development of novel therapeutic strategy.¹¹⁴ Fragmentation of the mitochondrial network caused by mitochondrial dynamics in pancreatic β-cells is associated with oxidative stress, mitophagy, and β-cell apoptosis. However, the mechanism by which mitochondrial fission or fusion is regulated in response to redox signaling in diabetic conditions and its role in the induction of β-cell death remains unclear and needs to be investigated further in future studies.

Impaired autophagy

Autophagy is a physiologically regulated cellular mechanism that balances the synthesis, degradation, and recycling of cellular components. It allows for orderly degradation and recycling under starvation conditions. Therefore, it maintains key cellular organelles such as mitochondria or ER responsible for the survival or cellular function in pancreatic β-cells, and dysregulation of autophagy leads to dysfunction or death of β-cells.¹¹⁵ In β-cells of T2DM patients, autophagy is dysregulated, the number of autophagic vacuoles and autophagosomes is increased, whereas the expression of lysosomal-associated membrane protein 2 (LAMP2) and cathepsin are decreased.¹¹⁶ The incidence of autophagy is frequently evaluated by measuring the conversion rate of the cytosolic form of microtubule-associated protein 1 A/1B-light chain 3 (LC3 I) to its lipidated form, LC3 II, which is a necessary step for autophagosome formation. Exposure to high glucose and palmitate concentrations increases LC3 II levels relative to those of LC3 I, and suppresses several genes involved in autophagy and lysosomal function.^117,118 In particular, Ji J et al. showed that lipid droplet accumulation in β-cells of T2DM was accompanied by the inhibition of the translocation of transcription factor EB (TFEB), a master regulator of autophagy, to the nucleus and by the down-regulation of the lysosomal biomarker LAMP2.¹¹⁹ Under insulin-resistant conditions, free fatty acid influx induces autophagy in pancreatic β-cell death through activation of JNK1, independent of oxidative and ER stress.¹²⁰

In the absence of stress, autophagy can act as a housekeeping mechanism, recycling and removing damaged intracellular organelles such as mitochondria.¹²¹ Under stress conditions such as oxidative and ER stress in β-cells, its disruption results in increased β-cell stress, cellular degeneration, and disruption of insulin secretion.^122,123 Particularly in mice, autophagy-related 7 (Atg-7) deficiency decreased β-cell mass by increasing apoptosis and decreasing proliferation, thereby reducing insulin secretion and inducing glucose intolerance.¹²³ Likewise, loss of β cell-specific autophagy increases human islet amyloid polypeptide (hIAPP) accumulation and induces β-cell apoptosis.^124–126

However, recent studies have suggested that balanced regulation of autophagy for β-cell survival and function is more important than one or the other. Activation of autophagy leads to increased apoptosis of β-cells and reduced β-cell mass.¹²⁷ In addition, β-cell-specific autophagy activation reduced intracellular calcium levels after glucose stimulation, indicating the implication of insulin secretion.¹²⁷ Collectively, these studies suggest that autophagy may play an important role in the maintenance of β-cell function and survival through multiple mechanisms.

Nevertheless, autophagy enhancement could be a novel therapeutic target for the treatment or prevention of T2DM. The plant-derived compound ginsenoside Rg2 enhanced autophagy and improved insulin sensitivity and metabolic profile in HFD-induced type 2 diabetic models.¹²⁸ Moreover, tonicity-responsive enhancer-binding protein (TonEBP), also known as nuclear factor of activated T-cells 5 (NFAT5), enhances β-cell survival by enhancing autophagy.¹²⁹ However, its effects on several novel agents in β-cells have not been well studied. Future studies should investigate the effects of autophagy enhancers on β-cell apoptosis and dysfunction.

Endoplasmic reticulum stress (ER stress)

Pancreatic β-cells possess a highly developed ER, which is required for the synthesis of insulin.¹³⁰ The ER is an intracellular organelle that plays an important role in the quality control of proteins and their folding, lipid synthesis, and regulating storage and release of Ca 2+.¹³¹ When proteins fail to fold properly, accumulation of unfolded or misfolded proteins occurs in the ER lumen, continuing to a condition called “ER stress”.¹³² Many studies have demonstrated that ER stress in β-cells can be activated by various factors, including islet amyloid accumulation, prolonged exposure to high glucose or FAs, and elevated pro-inflammatory cytokine levels.¹³³ In the islets of db/db mice and β-cells of T2DM patients, the expression of ER stress markers, PERK (protein kinase R-like ER kinase), IRE1α (inositol requiring enzyme 1), and ATF6 (activating transcription factor 6), were increased.¹³⁴ Inhibition of the PERK-CHOP pathway of ER stress by a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaB), alleviated insulin resistance and protected islet cells from apoptosis.¹³⁵

Under glucotoxicity or lipotoxicity conditions, pancreas/duodenum homeobox protein 1 (PDX1) is reduced significantly, inducing ER stress. Studies have observed that enhancing the expression of PDX1 protected and repaired pancreatic β-cells under diabetic conditions. Tectorigenin (TG), an O-methylated isoflavone, protects β-cells against glucotoxicity and lipotoxicity by promoting the expression of PDX1.¹³⁶ It has been proposed that FFAs induce ER stress by triggering protein load rather than disrupting the protein-folding mechanism of ER.¹³⁷ Treatment of INS-1E and MIN6 β-cell lines with palmitate initiated ER stress via the activation of ER stress markers, PERK, IRE1α, and ATF6. Moreover, palmitate-induced ER stress interacts with the inflammatory response by activating several pro-inflammatory pathways, such as NF-κB and JNK.^71,138–140 Prolonged culture with palmitic acid (PA) induces ER stress in INS-1β-cells with increased gene expression levels of C/EBP homologous protein (CHOP), immunoglobulin heavy chain-binding protein (BiP), and X-box binding protein 1 (XBP-1).¹⁴¹ In contrast, overexpression of perilipin 5, a regulator of fatty acid oxidation (FAO), attenuates oxidative damage by enhancing the Nrf2-ARE antioxidant defense responses by regulating the phosphoinositide 3-kinase/serine-threonine kinase (PI3K/Akt) and extracellular signal‐regulated kinase (ERK) signaling pathways.¹⁴² There are five members of the mammalian perilipin protein family.⁹⁹ However, the roles of some perilipins (PLINs), such as PLIN2 and PLIN5, in lipotoxicity-induced ER stress in β-cells are still unknown. Further studies are needed to determine their roles in the regulation of lipid metabolism and establish the relationship between them under normal and pathological conditions.

Conclusion

Almost half a billion people are living with diabetes worldwide, resulting in decreased quality of life and decreased life expectancy. Thus, diabetes has become one of the most challenging health problems in the 21^st century. Although diabetes begins with insulin resistance, β-cell dysfunction (decline of β-cell function and β-cell mass and consequent deficiency in insulin secretion) is the major contributor to the development of diabetes. Glucotoxicity, glucolipotoxicity, lipotoxicity, inflammatory cytokines, and islet amyloids are known to be major risk factors for β-cell dysfunction. These factors contribute to β-cell dedifferentiation, β-cell dysfunction, and β-cell death through diverse mechanisms, such as mitochondrial dysfunction and oxidative stress, impaired autophagy, and ER stress. These molecular pathways likely play complementary roles; therefore, their crosstalk needs to be studied further at different levels to elucidate β-cell dysfunction, including the mechanism of insulin secretion and the processes responsible for the death of β-cells, such as apoptosis and necrosis. Understanding the molecular mechanisms underlying pancreatic β-cell failure may pave the way for developing T2DM prevention and treatment strategies.

Footnotes

Author contributions

P.P.K, JHL, and H.-S. J. collected the information and wrote the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2019R1A2B5B02070355) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR14C0001).

ORCID iD

Phyu Phyu Khin

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Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

Abstract

Keywords

Introduction

Insulin secretion in pancreatic β-cells

β-cell failure in type 2 diabetes

Risk factors for β-cell dysfunction in type 2 diabetes

Glucotoxicity and glucolipotoxicity

Lipotoxicity

Inflammatory cytokines

Islet amyloid

Potential molecular mechanisms of β-cell dysfunction in type 2 diabetes

Mitochondrial dysfunction and oxidative stress

Impaired autophagy

Endoplasmic reticulum stress (ER stress)

Conclusion

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References