Review
Death versus dedifferentiation: The molecular bases of beta cell mass reduction in type 2 diabetes

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Abstract

Diabetes Mellitus is currently affecting more than 425 million people worldwide, among which over 90 % of the cases belong to type 2 diabetes. The number is growing quickly every year. Together with its many complications, the disease is causing tremendous social and economic burden and is classified as one of the leading causes of high morbidity and mortality rate. Residing in the islets of Langerhans, pancreatic beta cell serves as a central mediator in glucose homeostasis through secreting insulin, the only hormone that could reduce glucose level in the body, into the blood. Abnormality in pancreatic beta cell is generally considered as the fundamental reason which is responsible for the development of diabetes. Evidence shows that beta cell mass is greatly reduced in the biopsy of type 2 diabetic patients. Since then, large amount of research was conducted in order to decipher the molecular mechanisms behind the phenotype above and enormous progression has been made. The aim of this review is to summarize and provide a rudimentary molecular road map for beta cell mass reduction from the aspects of apoptosis and dedifferentiation based on recent research advances. Hopefully, this review could give the community some enlightenment for the next-step research and, more importantly, could provide avenues for developing novel and effective therapies to restrain or reverse beta cell loss in type 2 diabetes in the clinic.

Introduction

Diabetes Mellitus is a metabolic disease characterized by hyperglycemia. According to the latest statistics (9th edition, 2019) provided by International Diabetes Federation (IDF), diabetes is affecting over 463 million adults (20–79 years) worldwide, and the number is estimated to exceed 700 million by the year 2045. Type 2 Diabetes Mellitus (T2DM), which constitutes more than 90 % of the diabetes patients, is generally linked with insulin resistance of peripheral tissue, reduction of beta cell mass and compromised insulin secretion ability of beta cells [1,2]. Pancreatic beta cell (write as "beta cell", hereafter) plays a central role in regulating glucose homeostasis. Act as a glucose sensor, beta cell produces and releases insulin, the only hormone that can lower blood glucose level in the body, into the bloodstream [3]. Together with four other endocrine cell types (alpha cell, delta cell, pancreatic polypeptide cell and epsilon cell), beta cell is located in the islets of Langerhans interspersed in the pancreas and composes 65–90 % of the islet cell population [4]. The proliferation activity of beta cell is dynamic during the first five years of life in human. After that the replication rate of beta cell reduces dramatically, with less than 3 % of the new beta cell being produced per day [5,6].

The etiology of diabetes is enormously complex. Initially, it was thought that insulin resistance, which serves as a hallmark of obesity and could subsequently lead to beta cell "exhaustion", is the main reason of diabetes [7]. However, based on the fact that most obese people do not develop T2DM, current diabetic research is paying more attention to the inherited beta cell dysfunction [7]. Kinds of beta cell dysfunction in T2DM includes altered cellular performance in Glucose-Stimulated Insulin Secretion (GSIS), proliferation, cell mass maintenance, cell identity maintenance and so on [8]. One straightforward thought in T2DM therapy is to promote beta cell proliferation. The molecular mechanism behind beta cell proliferation has been reviewed extensively by a serious of three articles not long ago [[9], [10], [11]].

On the other hand, numerous researches provided evidence that diabetes, especially in late stage, is closely related to beta cell mass reduction [7,[12], [13], [14]]. When insulin resistance occurs during the initial stage of T2DM, beta cell mass expands in order to compensate the increased need of insulin [14]. For those who possess inherited T2DM-associated gene defects, the long-standing requirement of insulin at high level causes exhaustion and toxicity of beta cell and eventually could lead to the reduction in beta cell mass [7,15,16]. By the time of diagnosis, T2DM patients lost around 50 % of their beta cells. The reduction in beta cell mass could precede the onset of T2DM by a decade [17]. Large amount of initial research of beta cell mass reduction concentrated on apoptosis. Butler and colleagues, based on their study on human pancreata from autopsy, reported that beta cell apoptosis frequency increases 10-fold in lean T2DM and 3-fold in obese T2DM [2]. Later on, researchers discovered that the reduction in beta cell mass should not be completely ascribed to apoptosis given the reversibility of beta cell [18]. They proposed that, due to insulin degranulation, a proportion of beta cell could not be detected using standard immunohistochemistry method, which might cause an overestimation of beta cell apoptosis [18]. Animal as well as human studies both confirmed that beta cell is able to dedifferentiate into a progenitor-like state under hyperglycemia condition instead of death [13,[19], [20], [21]].

Although the intracellular signaling road map for beta cell mass reduction in T2DM remains largely elusive at this moment, we have got a robust molecular diagram in this field. Here, we focus on some of the recent research progress regarding beta cell apoptosis and dedifferentiation. Hopefully, these new findings could provide novel ideas for T2DM therapeutic intervention from the way of preventing apoptosis/dedifferentiation or promoting beta cell redifferentiation after the occurrence of dedifferentiation.

Section snippets

Apoptosis

We know for long that beta cell apoptosis is closely linked with the development of T2DM [22,23]. Butler and colleagues firstly discovered that beta cell mass was decreased because of the increased apoptosis in T2DM [2]. Since then, enormous progression has been made to decipher the molecular “road map” behind. As shown in Fig. 1, apoptosis, the programmed cell death, could be executed through two major signaling programs: the caspase signaling as well as the Bcl family member/cytochrome

Dedifferentiation

Over a long period of time, it was believed that the development of diabetes is mainly due to the apoptosis of beta cell [2]. Later study discovered that, although the insulin positive signals in the pancreas decreased dramatically, the detected apoptosis level does not correlate proportionally with the function decline in beta cells indicating there exists other regulatory factors or cellular events [13,48].

Mature beta cells are highly plastic. Maintenance of terminal differentiated functional

Conclusion

In this review, we discussed the recent advances on the beta cell research from the areas of apoptosis and dedifferentiation. We apologize for not being able to cover all the recent discoveries in the field due to the space limitation. The molecular mechanisms behind beta cell mass reduction are complex. One thing we could conclude at this time is that, apart from apoptosis, dedifferentiation contributes significantly to the loss of beta cell mass under T2DM. However, to fully decipher the

Declaration of Competing Interest

The author has no competing interests to declare.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81420108007, 81702882) and Science and Technology Department of Jiangsu Province (No. BK20171056).

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