Review Volume 13, Issue 5 pp 7691—7706
β cell aging and age-related diabetes
- 1 Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China
- 2 Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, P.R. China
Received: October 23, 2020 Accepted: December 23, 2020 Published: March 3, 2021https://doi.org/10.18632/aging.202593
How to Cite
Copyright: © 2021 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Type 2 diabetes is characterized by insulin resistance and loss of β cell mass and function. Aging is considered as a major risk factor for development of type 2 diabetes. However, the roles of pancreatic β cell senescence and systemic aging in the pathogenesis of type 2 diabetes in elderly people remain poorly understood. In this review, we aimed to discuss the current findings and viewpoints focusing on β cell aging and the development of type 2 diabetes.
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, which results from the defects of insulin secretion, insulin action or both [1–3]. As insulin secreted by islet β cells is the only hypoglycemic hormone in the body, the normal physiological activities of pancreatic islets, particularly β cells, are pivotal for glucose and lipids metabolism in the whole body, and β cell mass loss or function failure would profoundly contribute to diabetes mellitus.
Aging is characterized by gradual functional decline of organs. It is a major risk factor for several chronic diseases, such as cardiovascular disease, stroke, neurodegenerative disorders, as well as diabetes [4, 5]. The 9th edition of International Diabetes Federation (IDF) diabetes Atlas reported that diabetes affects about 136 million people aged 65-99 years in 2019, accounting for 19.3% of the elderly people . China has the largest population of diabetes over the world, and the morbidity of diabetes and prediabetes in people over 60 years old is significantly higher than those under 60 years old, and strikingly, the prevalence of prediabetes in old people is as high as 45.8% . The accumulation of senescent cells in aged organisms is one of the hallmarks of aging [8–10]. Over the past few decades, some studies indicated that the occurrence and progression of type 2 diabetes (T2D) in elderly individuals are tightly associated with senescent β cells, but the specific mechanisms linking systemic aging or cellular senescence with diabetes are still unclear. Here, we review the biology and pathology of pancreatic islets in diabetes, and further discuss the up to date recognition of the relationship between β cell senescence and diabetes.
The development of pancreas
The pancreas is a highly brunched organ with endocrine and exocrine tissues simultaneously, exerting essential functions for maintenance of body nutrients metabolism homeostasis . The endocrine pancreas is pancreatic islets, mainly composed of five cell types, namely α cells, β cells, δ cells, PP cells and ε cells, responsible for producing glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin, respectively . There are about 1 million islets in a human pancreas, accounting for 1-2% of the pancreas mass. The majority of islets are located in the body and tail of pancreas, embraced with a dense microvascular network to supply sufficient oxygen and sense the nutrients changes in blood.
The pancreas of human originates as two pancreatic buds, ventral and dorsal bud, from the primitive duodenum. The dorsal bud first appears at the 4th week of gestation, which gives rise to the superior part of the head, neck, body and tail of the pancreas. The ventral bud appears approximately after 30 days of gestation, forming the inferior part of the head of pancreas. With the rotation of stomach and duodenum in the process of embryonic development, the two pancreatic buds fuse tightly at the 7th week of gestation to form the pancreatic ducts , which communicate with duodenum through the major duodenal papilla . In contrast to the earlier presence of glucagon producing cells in mouse pancreatic buds, the first endocrine cells appear in human embryo are β cells. The β cells can be detected after around 7-8 weeks of gestation, and represent the main endocrine cell type during the first trimester. Soon after that, the occurrence of α and δ cells are detected at the 8th and 9th week of gestation, respectively . The proportions of α and β cells in pancreas at the 21st week of gestation are similar to that in adult pancreas, while the islets mature after birth . Traditionally, the islets are considered as terminally differentiated and almost impossible to be long-term cultured in vitro . However, differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (IPSCs) to insulin-secreting cells by mimicking the intercellular signaling during the β cells development, is an ambitious hope for cell therapy in diabetes. More interestingly, recent studies found a group of cells in adult mice and monkeys through single-cell RNA sequencing. Besides able to response to glucose stimulation, these cells express procr on cell surface and have progenitor properties, capable to differentiate into all types of islet cells in vivo. Furthermore, the authors established an in vitro system to generate islet-like organoids, which could be long term expansion and possess similar function and structure to islets in vivo [16, 17]. These new findings enlarge our knowledge of islet embryogenesis and give hopes to the regeneration of islets for diabetes in the future.
During the course of embryogenesis, the pancreas development is regulated by multiple signals and transcription factors at different stages, in which signals from notochord, mesenchyme, epithelia and endothelia are essential for the initiation of pancreas development and exocrine or endocrine cell fate decision. Importantly, some transcription factors play a dominant role in the generation of fetal islet. The transcription factor pancreatic and duodenal homeobox 1 (PDX-1 also known as IPF-1, IDX-1, STF-1 or IUF-1) is a marker of pancreatic progenitor cells at early pancreas development stage, playing a crucial role in the growth, differentiation and morphogenesis of pancreas development . PDX-1 can be detected at the fourth week of human gestation . Researches have shown that mice lack of PDX-1 fail to form pancreas and die a few days after birth [13, 19]. Neurogenin (also called Neurog3 or Ngn3) is a basic-helix-loop-helix (bHLH) protein, which is transiently required for the endocrine cell fate decision during pancreas development. The expression level of Ngn3 reaches the peak around 12 weeks post-conception, but it is not detected in human fetal after 35 weeks of gestation . Researches indicate that loss or mutation of Ngn3 in mice cause absence of endocrine cells in pancreas and intestinal, resulting in diabetes, congenital diarrhea, or nutrients absorption failure . In addition, Ngn3 plays a key role in β cell differentiation through regulating multiple target genes required for pancreatic fate. NeuroD1, Pax6, Arx, Nkx2.2 and MNX1 are the downstream transcription factors of Ngn3, being identified as causative factors for permanent neonatal diabetes mellitus (PNDM) when they are mutated. Other transcription factors critical for pancreas development include PTF1A, Sox9, GATA4/GATA6, Nkx6.1, Hes1 and others, and the details of these factors are not included in this review.
In the last two decades, more and more attentions have been drawn on the causative link between suboptimal pancreas development and T2D risk. Interesting results reported by Hardikar et al. revealed that undernourished rats with low birth weight for over 50 generations display epigenetic modifications, leading to significant decrease of PDX1 binding at insulin-2 gene promoter. And this change is associated with increased metabolic abnormality and diabetes in adults, and is unable to be reversed following nutrient recuperation for two generations . De Rooij et al. demonstrated that non-diabetic people prenatally exposed to famine during the Dutch Hunger Winter of 1944–1945 present impaired insulin secretion and glucose tolerance, and people exposed to famine at midgestation have a significant lower disposition index, compared with people unexposed to famine. But these phenomena did not appear in people experiencing famine after 32 weeks of gestation . The time points greatly match to the profile of Ngn3 expression during embryonic pancreas development. These striking findings suggest that epigenetic changes in fetal pancreas programming might get transgenerational effects on adult metabolic risks, which might be an explanation for the explosive increase of diabetes in developing countries in the last decade.
β cell dysfunction in type 2 diabetes
Insulin is a low molecular weight protein secreted by β cells of pancreatic islets. Insulin plays a central role in glucose homeostasis. The secretion of insulin is regulated by blood nutrients, hormones, as well as nerves, among which, glucose is the prime modulator. Glucose enters the β cells through GLUT1 (GLUT2 in rodent) on the cell membrane, then, participates in citric acid cycle and causes a rapid increased ratio of ATP to ADP, which further reduces the K+ efflux through inhibiting an ATP-sensitive K+ channel, leading to the depolarization of cell membrane and activation of a voltage-gated Ca2+ channel to promote Ca2+ influx. The increased intracellular Ca2+ triggers insulin granule exocytosis from β cells into blood circulation . Once insufficient insulin secretion fails to compensate the high demand for insulin, the hyperglycemia occurs. β cell mass loss is a prominent feature in diabetes (Figure 1). Piles of evidence demonstrates that long term exposure to hyperglycemia and hyperlipidemia results in glucotoxicity and lipotoxicity in β cells, which lead to the gradually deterioration of their function and loss of β cell mass, and ultimately aggravation of diabetic state [24, 25]. The β cell defects in T2D are comprehensively studied in the last two decades. The traditional recognition of its underlying mechanisms suggests that endoplasmic reticulum (ER) and oxidative stress, chronic inflammation and mitochondrial dysfunction are the major aspects responsible for the impairments of β cell expansion, insulin production and secretion, and final β cell apoptosis in T2D. But recently, increasing evidence indicates that the inherent β cell plasticity may play an important role in the development of T2D, including dedifferentiation and transdifferentiation .
Figure 1. β cell loss in T2D. In normal conditions, glucose and nutrients influx stimulate β cells to secrete insulin to cope with increased blood glucose level. Under chronic high blood glucose and high free fatty acids condition, β cells secrete more insulin to compensate hyperglycemia, while simultaneously, co-secrete more islets amyloid polypeptide (IAPP). The deposition of IAPP further aggregate into amyloid plaque in β cells. Glucotoxicity, lipotoxicity and amyloid deposit lead to the accumulation of reactive oxygen species (ROS), unfolded protein and so on, which results in oxidative stress, ER stress, inflammation and other cytotoxicity of β cells, and ultimately induces apoptosis of β cells. Additionally, high glucose and lipid lead to the downregulation of critical transcriptional factors, such as PDX1, FoxO1 and MafA, and re-express of progenitor marker Ngn3, which lead to the dedifferentiation and/or transdifferentiation of β cells. Both the apoptosis and dedifferentiation/transdifferentiation could contribute the mass loss of β cells.
β cell apoptosis
Studies of pancreatic samples from T2D patients and rodent models reported that β cell mass decreases up to 60%, and they found β cell apoptosis is predominantly responsive for the β cells loss in the progression of T2D [27, 28].
Apoptosis is a form of programmed cell death, which is implicated in the normal physiology of pancreatic development and final β cell mass formation . The dynamic β cell mass is determined by the balance between β cell replication or neogenesis and apoptosis . Glucotoxicity, lipotoxicity and islet amyloid polypeptide (IAPP) are the primary causative factors for increased β cell apoptosis in T2D, while ER stress and oxidative stress, as well as autophagy could be the link between upstream metabolic stimuli and downstream apoptotic machinery .
Glucotoxicity and β cell apoptosis
Oxidative stress is extensively involved in many pathologies, including the development of β cell dysfunction and insulin resistance, and it is the most commonly accepted mechanism of β cell dysfunction caused by hyperglycemia . Hyperglycemia activates intrinsic apoptosis pathway of β cells by increasing oxidative and nitrosative stress, as well as crosstalk between proapoptotic Bcl-2 family members and caspase cascade. β cells are particularly sensitive to ROS, because they contain low content of intrinsic antioxidant proteins . It is shown that low grade of ROS is beneficial to stimulate insulin secrete , on the contrary, prolonged glucotoxicity results in free-radical damage to DNA, protein, and lipids, and increases apoptosis in β cells as a consequence .
High glucose increases ROS production by 1) activating NADPH oxidase on the cell membrane; 2) interrupting mitochondrial electron transport chain at complex III; and 3) impairing antioxidant system including SOD, GPx and CAT. ROS accumulation in mitochondria is a main cause of mitochondrial dysfunction . It results in the formation of lipid peroxides, imbalance of mitochondrial fission and fusion, interruption of mito-autophagy process and importantly block of transduction of signals coupling glucose metabolism to insulin secretion. Oxidative stress in β cells also increases a series of proinflammatory cytokines (IFN-γ, IL-1β, TNF-α, etc). These changes in cytokine profile contribute to the activation of the key transcription factors, nuclear factor (NF)-kB and STAT-1, and consequently the expression of Fas and TNFaR1, responsible for the extrinsic pathway of apoptosis .
Recently, it has been found that the decreased expressions of transcription factors PDX1, MafA, FoxO1, and Nkx6.1 in T2D might be associated with β cell apoptosis. As PDX1 is important for islets development and adult β cell survival, its complete deficiency results in pancreatic agenesis, leading to increased β cell dysfunction and death . Research indicated that its partial deficiency increases islets apoptosis in a PDX1+/- mice model . Antioxidants treatment in high fat/high sucrose fed mice model and INS-1 cells exposed to high glucose and lipid could enhance the PDX1 level and improve apoptosis of β cells .
Lipotoxicity and β cell apoptosis
Besides high level of blood glucose, hyperlipidemia is also a major characteristic of T2D. It is well known that saturated fatty acids show strong toxicity to pancreatic β cells. Our data demonstrated that exposure to palmitic acid for 24 hours results in substantial apoptosis and elevated ER stress in INS-1 cells. However, unsaturated fatty acids do not show toxicity and further rescue cell viability when treated with palmitate together . A great amount of evidence suggests that ER stress is the most important link between lipotoxicity and β cell dysfunction or cell death [41, 42]. ER stress activates inositol-requiring protein 1 α (IRE1α), which activates c-Jun N-terminal kinase (JNK) via phosphorylation . JNK can inhibit the anti-apoptotic properties via suppressing the expression of Bcl-2 family while upregulating the pro-apoptotic protein BAX to induce mitochondria-mediated apoptosis . Apart from JNK pathway, the activations of protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), NLRP3 inflammasome, and Akt (also known as protein kinase B (PKB) kinase) signals have also contributed to fatty acids induced lipoapoptosis .
It is worthy to mention that ceramide, the metabolite of palmitate, is also a key component of apoptosis signal transduction. It is considered as a critical contributor to lipoapoptosis. Ceramide promotes lipid raft fusion, which promotes the clustering of death receptors, and allows the recruitment of various apoptotic proteins to the receptors. As a consequence, the activations of adapter proteins such as Fas-associated death domain (FADD) and tumor necrosis factor receptor type 1-associated death domain (TRADD) trigger the caspase cascade. In addition, ceramide can activate NFκB to increase inducible nitric oxide synthase, and result in an increase in nitric oxide generation, and ultimately increase of apoptosis .
IAPP and β cell apoptosis
Islet amyloid polypeptide (IAPP, or Amylin), is a 37-aa residues long peptide neuroendocrine hormone, which is co-secreted with insulin from pancreatic β cells. Due to the presence of a hydrophobic amino acid proline in the middle region of IAPP, human IAPP is prone to aggregate into insoluble amyloid plaque. Previous studies indicated that the polypeptide involved in the regulate of glucose homeostasis, but the function of IAPP remains not fully understood [46, 47]. It was shown that IAPP inhibits the secretion of insulin and suppress the insulin-stimulated glucose transport in vitro by a post-insulin-receptor effect. [46, 48]. Studies of human pancreas from people with or without T2D showed that β cell loss and apoptosis is associated with the islet amyloid deposition [49, 50]. Previous studies demonstrated that the deposition of amyloid induces ER stress, and the ER stress inhibitor 4-phenylbutyrate (PBA) can alleviate β cell apoptosis . Westermark P. demonstrated that β cells nearby amyloid are penetrated by bundles of fibrils . In addition, Kawahara M. and colleagues have shown that the amyloid affects β cell function through interaction with β cell membrane, leading to upregulated Ca2+ influx, increased oxidative and ER stress , and further activated apoptosis via JNK and caspase pathways . Taken together, how IAPP damages β cells is still elusive, but it is likely to involve in multiple pathological processes and affect β cell functionality in different ways.
Loss of β cell identity
The loss of β cell has commonly been proposed to be attributable to cell apoptosis. But recently, this concept has been challenged by some new ideas, that the deficit of β cell mass may be due to aberrant dedifferentiation and transdifferentiation of β cells [55, 56]. Adult mature β cells express a series of transcription factors to maintain their identity, including PDX1, MafA, Nkx6.1, Nkx2.2 and FoxO1. Dedifferentiation is a state that cell changes its gene expression profile accompanied by the loss of its phenotype and back to a more immature state. Meanwhile, transdifferentiation is defined as the transformation of one terminally differentiated cell type into another without reverting to a more primitive progenitor-like state .
MafA is the last identity transcription factor appearing in mature β cells, inactivation of which impairs β cell function and glucose stimulated insulin secretion (GSIS) without mass loss . It has been found that the loss of MafA in β cells is one of the earliest feature in T2D of human and rodents . In adult mouse β cells, gradual loss of β cell identity transcription factors, such as PDX1 and FoxO1, leads to β cell re-expresses the endocrine progenitor markers [58, 59]. Likewise, the loss of PDX1 leads to express glucagon and α cell identity transcription factor Arx in the mice β cells. A study of human pancreas has found some evidence of dedifferentiation and transdifferentiation in islets. They reported that in T2D donors, there were increased expression of β cell markers in glucagon or somatostatin positive cells, which suggests the loss of lineage specific identity in some islet cells . These alterations cause β cell reconfiguration in structure and function ultimately.
FoxO1 is a multifunctional transcription factor in β cells, which inhibits β cell proliferation and promotes apoptosis, while resists oxidative stress via the induction of antioxidant enzymes. FoxO1 also promotes the differentiation of pancreatic cells . In normal conditions, FoxO1 is localized in cytoplasm of β cells in response to insulin stimulation. FoxO1 binds to PDX1 promoter competitively with FoxA2, a crucial transcription factor for pancreas development, to inhibit β cell proliferation. In hyperglycemia conditions, FoxO1 could be found in nucleus or even losing its expression, to response oxidative stress, which is associated with the loss of insulin secretion . Kobayashi et al. found that β-cell-specific FoxO1 knockout mice exhibit loss of β cell mass and correspondingly elevation of α cell number under increased physiological demand conditions. Moreover, these FoxO1-deficient β cells do not express PDX1 and MafA, but re-express progenitor marker Ngn3 . Nilsson et al. found that the FoxO1-deficient β cells express glucagon , suggesting the dedifferentiation occurs in these mice.
β cell is a specialized cell type distinct from other cells in terms of function and physiological responsibility. Its identity maintenance is not only the consequence of expressions of β cell unique genes, but also the selective repression of some housekeeping genes . There have been identified at least 60 disallowed genes of β cells, such as monocarboxylate carrier 1 (MCT1), lactate dehydrogenase A (LDHA), low Km hexokinase I (HKI) and repressor element 1 silencing transcription factor (REST). Overexpression of these disallowed genes results in destruct of GSIS and proper insulin secretion, and β cell mass loss and dysfunction may be the fate of these cells [66, 67].
Aging and diabetes
Aging is a result of accumulation of cellular damage, which leads to the function decline of tissues and organs over time . The previous studies suggested the β cell dysfunction with age is mainly caused by the loss of functional β cell mass. However, in recent years, some researchers have put forward different opinions, suggesting that the intrinsic function of β cells does not significantly change with age, but their fully functioning is affected by the systemic senescent environment [68, 69].
Abnormality of non-β cells
Many researchers have held the viewpoint that β cell function decreasing with advancing age, is the main cause of the high morbidity of age-related diabetes. However, some studies draw different conclusions, suggesting that the intrinsic decline of β cell function with age is so limited, and may not the predominant cause of age-related diabetes, but the non-β cells in islets and even in other aged organs or tissues, as well as aged microenvironment may play an important role in the pathogenesis of age-related diabetes. A study of aged mice showed that there are increased AGEs and p16INK4a expressing in pancreas with aging, but the deposition of AGEs is obvious in blood vessels rather than endocrine cells in islets. Consistently, ROS production and expressions of iNOS and 3-NT are upregulated in aged mice, while they are also located in the blood vessels of pancreatic islets . In another research, to elucidate whether β cell function declines with age, Joana et al. isolated islets from non-diabetic, young or old mice and human, and found that islets from old mice and human remain glucose-sensitive and capable to secrete enough insulin to response glucose stimulation, but the glucose tolerance is impaired in old mice. More importantly, the blood vessels of islets in old mice and human are inflamed and fibrotic, suggesting that either glucose homeostasis or microenvironment homeostasis in islets are disturbed in old mice. Furthermore, the authors transplanted islets from non-diabetic mature young or old mice into the anterior chamber of STZ-induced diabetic young or old mice. After transplantation, blood glucose returned to normal in both young recipient mice with young or aged islets, but old hosts with aged islets reversed diabetes only in half of the recipients under a prolonged time. Monitoring the old grafts in young hosts found that the grafts were well revascularized after transplantation . This experiment perfectly demonstrated that with advanced age, the β cell function may has little intrinsic decline, which is insufficient to drive the onset of T2D, however, islet vascular aging is supposed to play a key role in the age-related β cell dysfunction. These researches suggest that in the process of aging, the β cells may still functional, but their function is affected by the system senescent milieu, which provides a new insight to age-related diabetes mechanism.
Type 2 diabetes is a complex systemic syndrome, with impacts on a wide spectrum of organs and tissues. Mounting pieces of evidence discloses that its morbidity increases with age. Although increasing number of studies have been carried out, aiming to disclose possible mechanistic interpretation for age-related T2D, our knowledge about it is still so limited. Taken together the up to date researches, we draw a conclusion that with advancing age, the pathological alterations of pancreatic β cells are supposed to be the key contributor to age-related T2D, and the decreased proliferation and regeneration potential, disturbed transcriptome and proteostasis, increased senescent cell accumulation and the influence of systemic environmental stress may lead to the loss of functional β cell mass and ultimately deficient insulin secretion and insulin action (Figure 2).
Figure 2. Molecular mechanisms involving in age-related diabetes. In the process of aging, there are increased accumulation of ROS, unfolded protein, DNA damage, IAPP, AGEs and other cellular stress in aged β cells. These intracellular stresses make β cells more susceptible to apoptosis. And with age, there are increased cell cycle inhibitors, such as p16INK4a, and decreased cell cycle activators, such as CDK4 and CDK6 in β cells. These changes lead to the reduce of the proliferation and regeneration potential and induce the cellular senescence of β cells. Senescent β cells secrete a series of senescence-associated secretory phenotype (SASP), promoting the senescence of neighboring healthy β cells through induction of paracrine senescence. In addition, islet blood vessels are undergoing aging as well. Oxidative damage, inflammation and fibrosis in islet blood vessels may disturb β cell function. Besides islets, the external factors include the reduction of insulin sensitivity in peripheral insulin responsive tissues with advanced age, responsible for the increased demand for insulin and final exhaustion of β cells. Taken together, the decreased insulin secretion capacity of β cells and increased insulin resistance with age lead to the failure of glucose control in elderly body, and ultimately the onset and development of age-related diabetes.
Since the pathogenesis of aging is complicated, it is reasonable to think age-related diabetes is a result of gradual accumulation of multiple abnormalities in metabolic system including β cells. A great amount of studies indicated that elderly individuals secrete more insulin to response the glucose challenge, suggesting that β cell compensation occurs in the early age, while the declined number of baseline and compensatory β cells with age, contributes to the onset and progression of T2D. But the process of β cell compensation to compensation failure is still unclear.
It is worth noting that the function and architecture heterogeneity of β cells is reported in both rodents and human, and the reprogramming of β cell heterogeneity also exists in the process aging. Therefore, it is hard to simply explain the occurrence of age-related diabetes just by a general β cell aging but ignoring the complicated heterogeneity in islets.
At present, due to the limitation of human pancreas samples, the animal models used to study the relationship between natural aging and age-related diabetes are mainly focusing on rodents, which still has big gap with human aging in some degree. To further study the pathogenesis of this disease, more ideal animal models and more new technology such as single-cell sequencing and multi-omics studies focusing on β cell function and glucose homeostasis would help to enlarge our limited knowledge about β cell aging and reveal its relationship with the increasing prevalence of age-related diabetes.
AGEs: Advanced glycation end products; Arx: Aristaless-related homeobox; ATF6: Activating transcription factor 6; BAX: BCL2 associated X, apoptosis regulator; Bcl-2: B cell leukemia/lymphoma 2; ER: Endoplasmic reticulum; FoxO1: Forkhead box O1; GATA4: GATA binding protein 4; GATA6: GATA binding protein 6; GSIS: Glucose stimulated insulin secretion; IAPP: Islet amyloid polypeptide; IGF1R: Insulin like growth factor 1 receptor; JNK: c-Jun N-terminal kinase; MafA: v-Maf musculoaponeurotic fibrosarcoma oncogene homologue A; PDX-1: Pancreatic and duodenal homeobox 1; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; Sox9: Sex-determining Region Y (SRY) box 9; STZ: Streptozotocin; T1D: Type 1 Diabetes; T2D: Type 2 Diabetes; UPR: Unfolded protein response.
Younan Chen edited the manuscript. Min Zhu wrote the manuscript. Xiaohong Liu and Wen Liu revised the manuscript. All authors have agreed upon the submission and publication of this work.
Conflicts of Interest
The authors declare that they have no conflicts of interest with the contents of this article.
This study was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18014). and the Program of National Natural Science Foundation of China (81870609).
- 1. Bardsley JK, Want LL. Overview of diabetes. Crit Care Nurs Q. 2004; 27:106–12. https://doi.org/10.1097/00002727-200404000-00002 [PubMed]
- 2. Salinno C, Cota P, Bastidas-Ponce A, Tarquis-Medina M, Lickert H, Bakhti M. B-cell maturation and identity in health and disease. Int J Mol Sci. 2019; 20:5417. https://doi.org/10.3390/ijms20215417 [PubMed]
- 3. Öztürk E, Arslan AK, Yerer MB, Bishayee A. Resveratrol and diabetes: a critical review of clinical studies. Biomed Pharmacother. 2017; 95:230–34. https://doi.org/10.1016/j.biopha.2017.08.070 [PubMed]
- 4. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685–705. https://doi.org/10.1146/annurev-physiol-030212-183653 [PubMed]
- 5. Shakeri H, Lemmens K, Gevaert AB, De Meyer GR, Segers VF. Cellular senescence links aging and diabetes in cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018; 315:H448–62. https://doi.org/10.1152/ajpheart.00287.2018 [PubMed]
- 6. Sinclair A, Saeedi P, Kaundal A, Karuranga S, Malanda B, Williams R. Diabetes and global ageing among 65-99-year-old adults: findings from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract. 2020; 162:108078. https://doi.org/10.1016/j.diabres.2020.108078 [PubMed]
- 7. Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, Li Y, Zhao Z, Qin X, Jin D, Zhou M, Tang X, Hu Y, Wang L. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017; 317:2515–23. https://doi.org/10.1001/jama.2017.7596 [PubMed]
- 8. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015; 21:1424–35. https://doi.org/10.1038/nm.4000 [PubMed]
- 9. He S, Sharpless NE. Senescence in health and disease. Cell. 2017; 169:1000–11. https://doi.org/10.1016/j.cell.2017.05.015 [PubMed]
- 10. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194–217. https://doi.org/10.1016/j.cell.2013.05.039 [PubMed]
- 11. Shih HP, Wang A, Sander M. Pancreas organogenesis: from lineage determination to morphogenesis. Annu Rev Cell Dev Biol. 2013; 29:81–105. https://doi.org/10.1146/annurev-cellbio-101512-122405 [PubMed]
- 12. Jennings RE, Berry AA, Strutt JP, Gerrard DT, Hanley NA. Human pancreas development. Development. 2015; 142:3126–37. https://doi.org/10.1242/dev.120063 [PubMed]
- 13. Leung PS. Overview of the pancreas. Adv Exp Med Biol. 2010; 690:3–12. https://doi.org/10.1007/978-90-481-9060-7_1 [PubMed]
- 14. Henry BM, Skinningsrud B, Saganiak K, Pękala PA, Walocha JA, Tomaszewski KA. Development of the human pancreas and its vasculature - an integrated review covering anatomical, embryological, histological, and molecular aspects. Ann Anat. 2019; 221:115–24. https://doi.org/10.1016/j.aanat.2018.09.008 [PubMed]
- 15. Docherty K. Growth and development of the islets of langerhans: implications for the treatment of diabetes mellitus. Curr Opin Pharmacol. 2001; 1:641–50. https://doi.org/10.1016/s1471-4892(01)00109-6 [PubMed]
- 16. Wang D, Wang J, Bai L, Pan H, Feng H, Clevers H, Zeng YA. Long-term expansion of pancreatic islet organoids from resident Procr+ progenitors. Cell. 2020; 180:1198–211.e19. https://doi.org/10.1016/j.cell.2020.02.048 [PubMed]
- 17. Li J, Zheng Y, Yan P, Song M, Wang S, Sun L, Liu Z, Ma S, Belmonte JCI, Chan P, Zhou Q, Zhang W, Liu GH, et al. A Single-cell Transcriptomic Atlas of Primate Pancreatic Islet Aging. National Science Review. 2021; 8:nwaa127. https://doi.org/10.1093/nsr/nwaa127
- 18. Marty-Santos L, Cleaver O. Pdx1 regulates pancreas tubulogenesis and E-cadherin expression. Development. 2016; 143:1056. https://doi.org/10.1242/dev.135806 [PubMed]
- 19. Bastidas-Ponce A, Roscioni SS, Burtscher I, Bader E, Sterr M, Bakhti M, Lickert H. Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol Metab. 2017; 6:524–34. https://doi.org/10.1016/j.molmet.2017.03.007 [PubMed]
- 20. Zhang X, McGrath PS, Salomone J, Rahal M, McCauley HA, Schweitzer J, Kovall R, Gebelein B, Wells JM. A comprehensive structure-function study of Neurogenin3 disease-causing alleles during human pancreas and intestinal organoid development. Dev Cell. 2019; 50:367–80.e7. https://doi.org/10.1016/j.devcel.2019.05.017 [PubMed]
- 21. Hardikar AA, Satoor SN, Karandikar MS, Joglekar MV, Puranik AS, Wong W, Kumar S, Limaye A, Bhat DS, Januszewski AS, Umrani MR, Ranjan AK, Apte K, et al. Multigenerational undernutrition increases susceptibility to obesity and diabetes that is not reversed after dietary recuperation. Cell Metab. 2015; 22:312–19. https://doi.org/10.1016/j.cmet.2015.06.008 [PubMed]
- 22. de Rooij SR, Painter RC, Phillips DI, Osmond C, Michels RP, Godsland IF, Bossuyt PM, Bleker OP, Roseboom TJ. Impaired insulin secretion after prenatal exposure to the Dutch famine. Diabetes Care. 2006; 29:1897–901. https://doi.org/10.2337/dc06-0460 [PubMed]
- 23. Kalwat MA, Cobb MH. Mechanisms of the amplifying pathway of insulin secretion in the β cell. Pharmacol Ther. 2017; 179:17–30. https://doi.org/10.1016/j.pharmthera.2017.05.003 [PubMed]
- 24. Kaneto H. Pancreatic β-cell glucose toxicity in type 2 diabetes mellitus. Curr Diabetes Rev. 2015; 11:2–6. https://doi.org/10.2174/1573399811666141216160217 [PubMed]
- 25. Liang C, Hao F, Yao X, Qiu Y, Liu L, Wang S, Yu C, Song Z, Bao Y, Yi J, Huang Y, Wu Y, Zheng L, et al. Hypericin maintians PDX1 expression via the Erk pathway and protects islet β-cells against glucotoxicity and lipotoxicity. Int J Biol Sci. 2019; 15:1472–87. https://doi.org/10.7150/ijbs.33817 [PubMed]
- 26. Mezza T, Cinti F, Cefalo CM, Pontecorvi A, Kulkarni RN, Giaccari A. B-cell fate in human insulin resistance and type 2 diabetes: a perspective on islet plasticity. Diabetes. 2019; 68:1121–29. https://doi.org/10.2337/db18-0856 [PubMed]
- 27. Moin AS, Butler AE. Alterations in beta cell identity in type 1 and type 2 diabetes. Curr Diab Rep. 2019; 19:83. https://doi.org/10.1007/s11892-019-1194-6 [PubMed]
- 28. Remedi MS, Emfinger C. Pancreatic β-cell identity in diabetes. Diabetes Obes Metab. 2016 (Suppl 1); 18:110–16. https://doi.org/10.1111/dom.12727 [PubMed]
- 29. Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology. 1997; 138:1736–41. https://doi.org/10.1210/endo.138.4.5069 [PubMed]
- 30. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008; 57:1584–94. https://doi.org/10.2337/db07-1369 [PubMed]
- 31. Wali JA, Masters SL, Thomas HE. Linking metabolic abnormalities to apoptotic pathways in beta cells in type 2 diabetes. Cells. 2013; 2:266–83. https://doi.org/10.3390/cells2020266 [PubMed]
- 32. Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med. 2011; 51:993–99. https://doi.org/10.1016/j.freeradbiomed.2010.12.005 [PubMed]
- 33. Robertson R, Zhou H, Zhang T, Harmon JS. Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes. Cell Biochem Biophys. 2007; 48:139–46. https://doi.org/10.1007/s12013-007-0026-5 [PubMed]
- 34. Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, Colombani AL, Ktorza A, Casteilla L, Pénicaud L. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes. 2009; 58:673–81. https://doi.org/10.2337/db07-1056 [PubMed]
- 35. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem. 2004; 279:42351–54. https://doi.org/10.1074/jbc.R400019200 [PubMed]
- 36. Supale S, Li N, Brun T, Maechler P. Mitochondrial dysfunction in pancreatic β cells. Trends Endocrinol Metab. 2012; 23:477–87. https://doi.org/10.1016/j.tem.2012.06.002 [PubMed]
- 37. Anuradha R, Saraswati M, Kumar KG, Rani SH. Apoptosis of beta cells in diabetes mellitus. DNA Cell Biol. 2014; 33:743–48. https://doi.org/10.1089/dna.2014.2352 [PubMed]
- 38. Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab. 2009 (Suppl 4); 11:30–37. https://doi.org/10.1111/j.1463-1326.2009.01121.x [PubMed]
- 39. Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, Misler S, Edlund H, Polonsky KS. Increased islet apoptosis in Pdx1+/- mice. J Clin Invest. 2003; 111:1147–60. https://doi.org/10.1172/JCI16537 [PubMed]
- 40. Liu X, Zeng X, Chen X, Luo R, Li L, Wang C, Liu J, Cheng J, Lu Y, Chen Y. Oleic acid protects insulin-secreting INS-1E cells against palmitic acid-induced lipotoxicity along with an amelioration of ER stress. Endocrine. 2019; 64:512–24. https://doi.org/10.1007/s12020-019-01867-3 [PubMed]
- 41. Bachar E, Ariav Y, Ketzinel-Gilad M, Cerasi E, Kaiser N, Leibowitz G. Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1. PLoS One. 2009; 4:e4954. https://doi.org/10.1371/journal.pone.0004954 [PubMed]
- 42. Natalicchio A, Labarbuta R, Tortosa F, Biondi G, Marrano N, Peschechera A, Carchia E, Orlando MR, Leonardini A, Cignarelli A, Marchetti P, Perrini S, Laviola L, Giorgino F. Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway. Diabetologia. 2013; 56:2456–66. https://doi.org/10.1007/s00125-013-3028-4 [PubMed]
- 43. Šrámek J, Němcová-Fürstová V, Kovář J. Kinase Signaling in Apoptosis Induced by Saturated Fatty Acids in Pancreatic β-Cells. Int J Mol Sci. 2016; 17:1400. https://doi.org/10.3390/ijms17091400 [PubMed]
- 44. Chen X, Li L, Liu X, Luo R, Liao G, Li L, Liu J, Cheng J, Lu Y, Chen Y. Oleic acid protects saturated fatty acid mediated lipotoxicity in hepatocytes and rat of non-alcoholic steatohepatitis. Life Sci. 2018; 203:291–304. https://doi.org/10.1016/j.lfs.2018.04.022 [PubMed]
- 45. Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta. 2002; 1585:202–12. https://doi.org/10.1016/s1388-1981(02)00342-6 [PubMed]
- 46. Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011; 91:795–826. https://doi.org/10.1152/physrev.00042.2009 [PubMed]
- 47. Raleigh D, Zhang X, Hastoy B, Clark A. The β-cell assassin: IAPP cytotoxicity. J Mol Endocrinol. 2017; 59:R121–40. https://doi.org/10.1530/JME-17-0105 [PubMed]
- 48. Haataja L, Gurlo T, Huang CJ, Butler PC. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev. 2008; 29:303–16. https://doi.org/10.1210/er.2007-0037 [PubMed]
- 49. Westermark P, Engström U, Johnson KH, Westermark GT, Betsholtz C. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci USA. 1990; 87:5036–40. https://doi.org/10.1073/pnas.87.13.5036 [PubMed]
- 50. Gunasekaran U, Gannon M. Type 2 diabetes and the aging pancreatic beta cell. Aging (Albany NY). 2011; 3:565–75. https://doi.org/10.18632/aging.100350 [PubMed]
- 51. Montane J, de Pablo S, Castaño C, Rodríguez-Comas J, Cadavez L, Obach M, Visa M, Alcarraz-Vizán G, Sanchez-Martinez M, Nonell-Canals A, Parrizas M, Servitja JM, Novials A. Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment. FASEB J. 2017; 31:5296–306. https://doi.org/10.1096/fj.201700236R [PubMed]
- 52. Westermark P. Fine structure of islets of langerhans in insular amyloidosis. Virchows Arch A Pathol Pathol Anat. 1973; 359:1–18. https://doi.org/10.1007/BF00549079 [PubMed]
- 53. Zraika S, Hull RL, Udayasankar J, Aston-Mourney K, Subramanian SL, Kisilevsky R, Szarek WA, Kahn SE. Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis. Diabetologia. 2009; 52:626–35. https://doi.org/10.1007/s00125-008-1255-x [PubMed]
- 54. Subramanian SL, Hull RL, Zraika S, Aston-Mourney K, Udayasankar J, Kahn SE. cJUN n-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets. Diabetologia. 2012; 55:166–74. https://doi.org/10.1007/s00125-011-2338-7 [PubMed]
- 55. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012; 150:1223–34. https://doi.org/10.1016/j.cell.2012.07.029 [PubMed]
- 56. Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. B-cell dedifferentiation in diabetes is important, but what is it? Islets. 2013; 5:233–37. https://doi.org/10.4161/isl.27494 [PubMed]
- 57. Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Kudo T, Engel JD, Yamamoto M, Takahashi S. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005; 25:4969–76. https://doi.org/10.1128/MCB.25.12.4969-4976.2005 [PubMed]
- 58. Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest. 2013; 123:3305–16. https://doi.org/10.1172/JCI65390 [PubMed]
- 59. Kluth O, Mirhashemi F, Scherneck S, Kaiser D, Kluge R, Neschen S, Joost HG, Schürmann A. Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia. 2011; 54:605–16. https://doi.org/10.1007/s00125-010-1973-8 [PubMed]
- 60. Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, Marselli L, Suleiman M, Ratner LE, Marchetti P, Accili D. Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016; 101:1044–54. https://doi.org/10.1210/jc.2015-2860 [PubMed]
- 61. Kitamura T, Kitamura YI, Kobayashi M, Kikuchi O, Sasaki T, Depinho RA, Accili D. Regulation of pancreatic juxtaductal endocrine cell formation by FoxO1. Mol Cell Biol. 2009; 29:4417–30. https://doi.org/10.1128/MCB.01622-08 [PubMed]
- 62. Kitamura T. The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol. 2013; 9:615–23. https://doi.org/10.1038/nrendo.2013.157 [PubMed]
- 63. Kobayashi M, Kikuchi O, Sasaki T, Kim HJ, Yokota-Hashimoto H, Lee YS, Amano K, Kitazumi T, Susanti VY, Kitamura YI, Kitamura T. FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and β-cell-specific FoxO1 knockout mice. Am J Physiol Endocrinol Metab. 2012; 302:E603–13. https://doi.org/10.1152/ajpendo.00469.2011 [PubMed]
- 64. Clark A, Nilsson MR. Islet amyloid: a complication of islet dysfunction or an aetiological factor in type 2 diabetes? Diabetologia. 2004; 47:157–69. https://doi.org/10.1007/s00125-003-1304-4 [PubMed]
- 65. Quintens R, Hendrickx N, Lemaire K, Schuit F. Why expression of some genes is disallowed in beta-cells. Biochem Soc Trans. 2008; 36:300–05. https://doi.org/10.1042/BST0360300 [PubMed]
- 66. Martin D, Grapin-Botton A. The importance of REST for development and function of beta cells. Front Cell Dev Biol. 2017; 5:12. https://doi.org/10.3389/fcell.2017.00012 [PubMed]
- 67. Lemaire K, Thorrez L, Schuit F. Disallowed and allowed gene expression: two faces of mature islet beta cells. Annu Rev Nutr. 2016; 36:45–71. https://doi.org/10.1146/annurev-nutr-071715-050808 [PubMed]
- 68. Kehm R, König J, Nowotny K, Jung T, Deubel S, Gohlke S, Schulz TJ, Höhn A. Age-related oxidative changes in pancreatic islets are predominantly located in the vascular system. Redox Biol. 2018; 15:387–93. https://doi.org/10.1016/j.redox.2017.12.015 [PubMed]
- 69. Almaça J, Molina J, Arrojo E Drigo R, Abdulreda MH, Jeon WB, Berggren PO, Caicedo A, Nam HG. Young capillary vessels rejuvenate aged pancreatic islets. Proc Natl Acad Sci USA. 2014; 111:17612–17. https://doi.org/10.1073/pnas.1414053111 [PubMed]
- 70. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006; 443:453–57. https://doi.org/10.1038/nature05092 [PubMed]
- 71. Tschen SI, Dhawan S, Gurlo T, Bhushan A. Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes. 2009; 58:1312–20. https://doi.org/10.2337/db08-1651 [PubMed]
- 72. Helman A, Avrahami D, Klochendler A, Glaser B, Kaestner KH, Ben-Porath I, Dor Y. Effects of ageing and senescence on pancreatic β-cell function. Diabetes Obes Metab. 2016 (Suppl 1); 18:58–62. https://doi.org/10.1111/dom.12719 [PubMed]
- 73. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114:1299–307. https://doi.org/10.1172/JCI22475 [PubMed]
- 74. Helman A, Klochendler A, Azazmeh N, Gabai Y, Horwitz E, Anzi S, Swisa A, Condiotti R, Granit RZ, Nevo Y, Fixler Y, Shreibman D, Zamir A, et al. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med. 2016; 22:412–20. https://doi.org/10.1038/nm.4054 [PubMed]
- 75. Riley WJ, McConnell TJ, Maclaren NK, McLaughlin JV, Taylor G. The diabetogenic effects of streptozotocin in mice are prolonged and inversely related to age. Diabetes. 1981; 30:718–23. https://doi.org/10.2337/diab.30.9.718 [PubMed]
- 76. Téllez N, Vilaseca M, Martí Y, Pla A, Montanya E. B-cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats. Am J Physiol Endocrinol Metab. 2016; 311:E554–63. https://doi.org/10.1152/ajpendo.00502.2015 [PubMed]
- 77. Reers C, Erbel S, Esposito I, Schmied B, Büchler MW, Nawroth PP, Ritzel RA. Impaired islet turnover in human donor pancreata with aging. Eur J Endocrinol. 2009; 160:185–91. https://doi.org/10.1530/EJE-08-0596 [PubMed]
- 78. Gu Z, Du Y, Liu Y, Ma L, Li L, Gong Y, Tian H, Li C. Effect of aging on islet beta-cell function and its mechanisms in wistar rats. Age (Dordr). 2012; 34:1393–403. https://doi.org/10.1007/s11357-011-9312-7 [PubMed]
- 79. Welsh M, Claesson-Welsh L, Hallberg A, Welsh N, Betsholtz C, Arkhammar P, Nilsson T, Heldin CH, Berggren PO. Coexpression of the platelet-derived growth factor (PDGF) B chain and the PDGF beta receptor in isolated pancreatic islet cells stimulates DNA synthesis. Proc Natl Acad Sci USA. 1990; 87:5807–11. https://doi.org/10.1073/pnas.87.15.5807 [PubMed]
- 80. Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK. PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature. 2011; 478:349–55. https://doi.org/10.1038/nature10502 [PubMed]
- 81. Vijg J. Impact of genome instability on transcription regulation of aging and senescence. Mech Ageing Dev. 2004; 125:747–53. https://doi.org/10.1016/j.mad.2004.07.004 [PubMed]
- 82. Enge M, Arda HE, Mignardi M, Beausang J, Bottino R, Kim SK, Quake SR. Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell. 2017; 171:321–30.e14. https://doi.org/10.1016/j.cell.2017.09.004 [PubMed]
- 83. Moldogazieva NT, Mokhosoev IM, Mel’nikova TI, Porozov YB, Terentiev AA. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases. Oxid Med Cell Longev. 2019; 2019:3085756. https://doi.org/10.1155/2019/3085756 [PubMed]
- 84. Guimarães EL, Empsen C, Geerts A, van Grunsven LA. Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. J Hepatol. 2010; 52:389–97. https://doi.org/10.1016/j.jhep.2009.12.007 [PubMed]
- 85. Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015; 5:194–222. https://doi.org/10.3390/biom5010194 [PubMed]
- 86. Press M, Jung T, König J, Grune T, Höhn A. Protein aggregates and proteostasis in aging: amylin and β-cell function. Mech Ageing Dev. 2019; 177:46–54. https://doi.org/10.1016/j.mad.2018.03.010 [PubMed]
- 87. Su Y, Misumi Y, Ueda M, Shono M, Tasaki M, Guo J, Jono H, Obayashi K, Senokuchi T, Yamagata K, Ando Y. The occurrence of islet amyloid polypeptide amyloidosis in Japanese subjects. Pancreas. 2012; 41:971–73. https://doi.org/10.1097/MPA.0b013e318249926a [PubMed]
- 88. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018; 28:436–53. https://doi.org/10.1016/j.tcb.2018.02.001 [PubMed]
- 89. An S, Cho SY, Kang J, Lee S, Kim HS, Min DJ, Son E, Cho KH. Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proc Natl Acad Sci USA. 2020; 117:31535–46. https://doi.org/10.1073/pnas.1920338117 [PubMed]
- 90. Wen J, Xue T, Huang Y, Chen X, Xue Y, Lin W, Zhang L, Yao J, Huang H, Liang J, Li L, Lin L, Shi L, et al. Is β-cell aging involved in the pathogenesis of diabetes? J Diabetes. 2017; 9:707–16. https://doi.org/10.1111/1753-0407.12481 [PubMed]
- 91. Thompson PJ, Shah A, Ntranos V, Van Gool F, Atkinson M, Bhushan A. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 2019; 29:1045–60.e10. https://doi.org/10.1016/j.cmet.2019.01.021 [PubMed]
Aguayo-Mazzucato C, Andle J, Lee TB
Jr, Midha A, Talemal L, Chipashvili V, Hollister-Lock J, van Deursen J, Weir G, Bonner-Weir S. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019; 30:129–42.e4. https://doi.org/10.1016/j.cmet.2019.05.006 [PubMed]
Aguayo-Mazzucato C, van Haaren M, Mruk M, Lee TB
Jr, Crawford C, Hollister-Lock J, Sullivan BA, Johnson JW, Ebrahimi A, Dreyfuss JM, Van Deursen J, Weir GC, Bonner-Weir S. B cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 2017; 25:898–910.e5. https://doi.org/10.1016/j.cmet.2017.03.015 [PubMed]
- 94. Kahn SE, Larson VG, Schwartz RS, Beard JC, Cain KC, Fellingham GW, Stratton JR, Cerqueira MD, Abrass IB. Exercise training delineates the importance of B-cell dysfunction to the glucose intolerance of human aging. J Clin Endocrinol Metab. 1992; 74:1336–42. https://doi.org/10.1210/jcem.74.6.1592879 [PubMed]
- 95. Shimizu M, Kawazu S, Tomono S, Ohno T, Utsugi T, Kato N, Ishi C, Ito Y, Murata K. Age-related alteration of pancreatic beta-cell function. Increased proinsulin and proinsulin-to-insulin molar ratio in elderly, but not in obese, subjects without glucose intolerance. Diabetes Care. 1996; 19:8–11. https://doi.org/10.2337/diacare.19.1.8 [PubMed]
- 96. Ahrén B, Pacini G. Age-related reduction in glucose elimination is accompanied by reduced glucose effectiveness and increased hepatic insulin extraction in man. J Clin Endocrinol Metab. 1998; 83:3350–56. https://doi.org/10.1210/jcem.83.9.5107 [PubMed]
- 97. Westacott MJ, Farnsworth NL, St Clair JR, Poffenberger G, Heintz A, Ludin NW, Hart NJ, Powers AC, Benninger RK. Age-dependent decline in the coordinated [Ca2+] and insulin secretory dynamics in human pancreatic islets. Diabetes. 2017; 66:2436–45. https://doi.org/10.2337/db17-0137 [PubMed]
- 98. Basu R, Dalla Man C, Campioni M, Basu A, Klee G, Toffolo G, Cobelli C, Rizza RA. Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes. 2006; 55:2001–14. https://doi.org/10.2337/db05-1692 [PubMed]
- 99. Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, Nair KS. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes. 2003; 52:1888–96. https://doi.org/10.2337/diabetes.52.8.1888 [PubMed]
- 100. Ehrhardt N, Cui J, Dagdeviren S, Saengnipanthkul S, Goodridge HS, Kim JK, Lantier L, Guo X, Chen YI, Raffel LJ, Buchanan TA, Hsueh WA, Rotter JI, et al. Adiposity-independent effects of aging on insulin sensitivity and clearance in mice and humans. Obesity (Silver Spring). 2019; 27:434–43. https://doi.org/10.1002/oby.22418 [PubMed]