The impact of b-cell Replication on Diabetes Therapy

Younes S

Published on: 2024-03-31

Abstract

Type 2 diabetes is characterized by a decrease in the mass of b-cells, which is attributed to the failure of b-cell compensation. It is crucial to understand the mechanism behind the adaptive increase in b-cell mass in vivo in order to develop a cure for diabetes. The signaling pathways mediated by insulin and the insulin receptor (IR) have been found to play a significant role in promoting compensatory b-cell proliferation in response to chronic insulin resistance. However, there is still debate regarding the requirement of IR for compensatory b-cell proliferation in certain situations. It is possible that IR may act as a scaffold for the signaling complex, independent of its ligand. Furthermore, the pathway involving the forkhead box protein M1/polo-like kinase 1/centromere protein A has been identified as a key player in adaptive b-cell proliferation during various conditions such as diet-induced obesity, hyperglycemia, pregnancy, aging, and acute insulin resistance. Recent studies have also shown that the interaction between islets and adipose tissue, as well as the liver, through humoral factors contributes to adaptive b-cell proliferation. Notably, this response is particularly observed under conditions of acute insulin resistance, regardless of the IR/insulin signal, and relies on the forkhead box protein M1/polo-like kinase 1/centromere protein a pathway. However, a significant challenge in using b-cells for the treatment of human diabetes is the difference between human and rodent islets. This review focuses on the signaling pathways that regulate adaptive b-cell proliferation, considering the aforementioned issues, with the goal of advancing diabetes treatment.

Keywords

Insulin; Diabetes; Beta Cells

Introduction

Recent findings indicate that the failure of b-cells is a key factor, in addition to insulin resistance, in the advancement of type 2 diabetes [1]. As compensation by b-cells decreases, individuals move from having normal glucose tolerance to impaired glucose tolerance and eventually develop type 2 diabetes. Therefore, there is a necessity for treatments that can reverse b-cell failure and encourage a beneficial rise in b-cell mass and function [2,3]. Prior research in animal models and potentially in humans has shown the potential to boost insulin secretion in response to insulin resistance by increasing b-cell mass and enhancing b-cell function. Nevertheless, it is still unclear whether there is a genuine compensatory increase in b-cell mass in humans [4,5]. Several approaches have been suggested to expand the endogenous b-cell mass, such as promoting b-cell proliferation, preventing b-cell death, inducing b-cell neogenesis, and controlling b-cell trans-differentiation. Among these methods, promoting adaptive b-cell proliferation seems particularly promising for augmenting human b-cell mass, as studies indicate that b-cell proliferation is more common than other mechanisms in the human endocrine pancreas [6,7]. Diabetes mellitus (DM) is widely known as a metabolic and hormonal disorder that has a direct effect on how the body processes carbohydrates, fats, and proteins. Therefore, dietary intervention plays a crucial role in managing diabetes and enabling individuals to proactively manage their health. It is well established that diabetes can result from either inadequate insulin production or resistance to insulin [8-10]. This review focuses on exploring the signaling pathways involved in regulating adaptive b-cell proliferation for the treatment of diabetes.

Methods and Materials

We conducted a review by searching the Google Scholar, PubMed, and Directory Open Access Journal databases for relevant information using keywords such as diabetes, diabetes disorders, beta cells, insulin resistance, insulin, albumin, insulin receptors, and type 2 diabetes to identify primary comparative studies on the effect of beta cells on the treatment of diabetes. The quality and strength levels of the results were considered, and when available, meta-analyses and systematic reviews, large epidemiological studies, and randomized control trials represented the main source of data.

Insulin and Insulin Receptor Signaling

In the context of chronic insulin resistance, various metabolic tissues, including the liver, adipose tissue, intestine, brain, and endocrine pancreas, receive signals associated with obesity, nutrition, inflammation, and other factors. It is crucial to comprehend the mechanism by which these metabolic signals are transmitted in b-cells, as it is essential for enhancing b-cell expansion [11-13].

The diet-induced obesity (DIO) mouse model is extensively employed to investigate adaptive b-cell proliferation in response to chronic insulin resistance. In this model, mice are subjected to a high-fat diet for an extended period of time. Another mouse model, referred to as b-cell-specific insulin receptor knockout (bIRKO) mice, exhibits the development of hyperglycemia and increased proinsulin levels as they age, similar to type 2 diabetes in humans. These mice also demonstrate reduced b-cell mass due to impaired b-cell proliferation under high-fat diet conditions. Insulin receptor substrate-2 (IRS-2) has been identified to play a role in compensatory b-cell replication in DIO mice, partly through glucokinase-mediated glycolysis [14,15]. Interestingly, the expression of proteins involved in the insulin receptor (IR) signaling cascade, such as IR, IRS-2, and protein kinase B, is diminished in human islets from individuals with type 2 diabetes compared to non-diabetic controls. This suggests that pathways promoting b-cell multiplication independent of insulin signaling could serve as potential therapeutic targets for restoring b-cell mass in patients with type 2 diabetes. Recent research has revealed that a molecule called the inceptor, also known as the insulin inhibitory receptor, can reduce IR signaling through clathrin-mediated endocytosis, resulting in decreased b-cell proliferation [16-18]. This discovery supports the notion that IR in b-cells plays a role in regulating b-cell proliferation. Nevertheless, the precise function of insulin secreted by b-cells in regulating b-cell proliferation remains uncertain. The manner in which high concentrations of insulin secreted by b-cells affect the b-cells themselves, whether through autocrine or paracrine mechanisms, is still unclear. Two hypotheses, namely the "ligand-receptor interaction" hypothesis and the "signaling scaffold" hypothesis, have been proposed to elucidate the role of the insulin receptor (IR) in b-cell proliferation [19].

The ligand-receptor interaction hypothesis, specifically the insulin-dependent signal known as the ligand-dependent receptor activation signal, lacks clarity regarding the phosphorylation state of the insulin receptor (IR) in b-cells. On the other hand, the signaling scaffold provided by IR facilitates the formation of signaling complexes at the plasma membrane, allowing for the transmission of intracellular signals through adaptor proteins such as IRS-2. Furthermore, the nuclear translocation of IR has been identified as a transcriptional regulator. Therefore, a comprehensive investigation into the phosphorylation state and intracellular localization of IR in b-cells is imperative for comprehending b-cell adaptation to insulin resistance [20-21].

The Pathway Involving Forkhead Box Protein M1 (FOXM1), Polo-Like Kinase 1 (PLK1), and Centromere Protein a (CENP-A) Plays a Crucial Role in Promoting the Proliferation of B-Cells by Controlling the Progression of the M Phase in the Cell Cycle

To gain a deeper comprehension of the regulation of the cell cycle in b-cells, it is crucial to recognize that mature pancreatic b-cells are predominantly in a state of dormancy known as the G0 phase. The transition of these cells from the G0 to the G1 phase of the cell cycle is influenced by glucose or IR/insulin signaling. Nevertheless, the precise mechanisms that govern the subsequent stages of the cell cycle, such as the G2/M checkpoint and M phase, have remained ambiguous in b-cells. Notably, bIRKO b-cells lacking IR not only experienced G0 cell cycle arrest but also M-phase arrest, indicating a potential link between IR signaling pathways and the G2/M cell cycle checkpoint in b-cells. Analysis of gene expression in bIRKO b-cells unveiled the down regulation of specific genes related to the M phase of the cell cycle, including centromere protein A (CENP-A) and polo-like kinase 1 (PLK1), which are crucial for chromosome segregation [22,23]. Hence, the Forkhead Box Protein M1/Polo-like Kinase/Centromere Protein A pathway may have a role in governing b-cell proliferation by regulating the M phase of the cell cycle. CENP-A, a variant of histone H3 specific to centromeres, is indispensable for the recruitment and assembly of kinetochore proteins, as well as for the advancement of mitosis and the separation of chromosomes in mammalian cells. PLK1, a kinase involved in mitosis, serves diverse functions, particularly in the control of mitotic initiation and completion [24,25]. The transcription factor FoxM1, belonging to the forkhead box protein M1 family, has been identified as a direct regulator of CENP-A and PLK1 expression in b-cells. Knocking out CENP-A specifically in the b-cells of mice resulted in reduced adaptive proliferation of b-cells in models of aging, pregnancy, diet-induced obesity (DIO) through a high-fat diet (HFD), hyperglycemia caused by high glucose levels, and acute insulin resistance induced by the administration of the insulin receptor antagonist S96124. This pathway involving FoxM1, PLK1, and CENP-A is also necessary for b-cell replication through sympathetic nerve relay 27. Notably, the expression of CENP-A was significantly decreased in b-cells of individuals with type 2 diabetes compared to non-diabetic control participants [26,27]. Therefore, the FoxM1/PLK1/CENP-A pathway plays a central role in the adaptive proliferation of b-cells in mice and likely also in humans (Figure 2).

Compensatory Proliferation of Beta Cells in Models of Acute and Chronic Insulin Resistance is Observed

In both chronic and acute models of insulin resistance, compensatory proliferation of beta-cells is observed to increase beta-cell mass in rodents. The chronic model of insulin resistance is represented by the diet-induced obesity (DIO) model through high-fat diet (HFD) feeding and genetic causes of insulin resistance. In mice with severe obesity and insulin resistance, such as db/db and ob/ob mice, increased beta-cell proliferation is observed, although glucotoxicity and lipotoxicity also affect beta-cells. Impaired beta-cell proliferation in DIO models is observed in beta-cell-specific IRS-2 knockout mice (bIRKO mice) and in beta-cell-specific glucokinase knockout mice, indicating the crucial role of insulin receptor (IR)/IRS-2-mediated signaling in adaptive beta-cell replication in response to chronic insulin resistance. The adaptive increase in beta-cell proliferation observed in liver-specific IR knockout (LIRKO) mice disappears in IR-deficient beta-cells (bIRKO/LIRKO mice) [30]. In DIO mice, the process of beta-cell proliferation is regulated by various signaling pathways, depending on the type of insulin resistance model. In acute models such as pregnancy, glucose infusion, partial pancreatectomy, and administration of insulin receptor antagonists, insulin signaling-mediated FoxO1 nuclear export and subsequent Cyclin D2 expression play a role in promoting beta-cell proliferation. Additionally, serotonin receptor 2B stimulation on beta-cells with serotonin, produced by the beta-cells themselves through prolactin, contributes to adaptive beta-cell proliferation during pregnancy through autocrine and paracrine signaling. Glucose infusion enhances beta-cell proliferation mediated by IRS-2, while beta-cell proliferation after partial pancreatectomy occurs through an IRS-2-independent pathway. Pharmacological inhibition of the insulin receptor with S961 or OSI-906 can also facilitate potent beta-cell proliferation [31-33]. Interestingly, the activation of the insulin receptor is not necessary for b-cell replication in response to acute insulin resistance, as demonstrated by the lack of suppression of S961-induced b-cells in knockout mice of the insulin receptor and IRS-2. Furthermore, the FoxO1-mediated insulin signal is dispensable for b-cell compensation induced by S961. In OSI-906-treated mice, b-cell proliferation persists even after normalization of blood glucose levels, indicating that glucose/glucokinase-mediated insulin signaling is also unnecessary [34-36]. The b-cell proliferation induced by acute models is mediated by M phase-related cell cycle genes and the FoxM1/PLK1/CENP-A pathway, but not IRS-2 or cyclin D2, which are induced in the chronic DIO model. Therefore, there are distinct signaling pathways that regulate adaptive b-cell proliferation between acute and chronic insulin resistance models [37].

Interorgan Networks for the Regulation of Adaptive B-Cell Proliferation

The islets' function, encompassing insulin secretion and b-cell proliferation, is not solely under their own regulation. Instead, it is a product of reciprocal regulation with other organs or cells through various means like metabolites, hormones, exosomes, or neurons in vivo. While metabolic organs such as the liver, adipose tissue, and skeletal muscle are key players in this regulation, other systems and organs like the gastrointestinal system, bone, placenta, kidney, thyroid, endothelial cells, reproductive organs, adrenal and pituitary glands, gut microbiota, and immune cells are also thought to contribute to b-cell biology [38]. This interorgan communication is vital for adaptive b-cell proliferation, as peripheral tissues must detect and convey the status of insulin resistance to b-cells to uphold precise glucose homeostasis. Previous research has pinpointed circulating factors that influence b-cell proliferation in different models. For example, LIRKO mice display significantly increased adaptive b-cell proliferation, partly due to a circulating factor originating from the liver [39-45].

LIRKO mice demonstrate a notable rise in adaptive b-cell proliferation, partly due to the presence of serpin B1, a liver-derived circulating factor that inhibits leukocyte-neutrophil elastase. The liver-derived protease inhibitor-induced b-cell proliferation is impeded by insulin receptor (IR) deficiency in b-cells, indicating a potential role of IR signaling in mediating the effects of serpin B1 on b-cell replication in the context of chronic liver insulin resistance. Conversely, serum factors from adipocytes are likely to stimulate b-cell replication during acute insulin resistance induced by S961 through the activation of the E2F1 and FoxM1/PLK1/CENP-A pathways, independently of IR. These results suggest that different tissues may influence adaptive b-cell proliferation under chronic or acute conditions [46].

Moreover, while glucagon-like peptide-1 alone does not boost human b-cell proliferation, the combination of a glucagon-like peptide-1 receptor agonist with a DRYK1A inhibitor can enhance cell replication in human islet b-cells. This implies that a variety of humoral factors secreted by different tissues may be required to regulate b-cell functions in vivo [47,48]. Given the intricate regulation of b-cell proliferation by various organs through multiple factors, an in vitro culture system may not fully replicate the in vivo environment for evaluating b-cell proliferation. Therefore, the establishment of an in vivo culture system where multiple organs are transplanted and cultured simultaneously could be a valuable approach for investigating compensatory b-cell proliferation [49].

The disparity between mouse and human islets poses a significant challenge in advancing research on adaptive B-cell proliferation. In recent years, there has been a growing utilization of human islets in studies, particularly in Asian countries. However, it is important to note that human islets exhibit considerable variability in experimental outcomes, especially in terms of cell proliferative capacity among different donors. This variability makes it difficult to fully comprehend the underlying mechanisms solely through studies using human islets. Therefore, the integration of animal models with human islets in research becomes necessary [50].

An autopsy analysis of human pancreas samples has shed light on the differences in B-cell mass between obese and lean individuals in the USA and Japanese populations. In the USA population, obese individuals were found to have a 1.5-fold increase in B-cell mass compared to lean individuals. However, this increase was not observed in the Japanese population. It is worth noting that Asian individuals, in general, tend to have a leaner physique compared to white individuals and may have a lower tolerance for obesity due to genetic and epigenetic factors. As a result, Asian diabetes patients may have a limited ability to increase B-cell mass in response to obesity compared to their European or American counterparts.

To fully understand the mechanisms of adaptive B-cell proliferation in Asian diabetes patients, it is crucial to consider studies using human islets from Asian donors. These studies should take into account the ethnic, genetic, and epigenetic differences that exist among different populations. By doing so, researchers can unravel the intricate mechanisms underlying adaptive B-cell proliferation and gain valuable insights into the management and treatment of diabetes in Asian populations [51-53].

Conclusion

The mechanism of adaptive b-cell proliferation is diverse and involves interorgan communication. Additionally, the b-cell mass can be influenced by genetic background, racial and ethnic disparities, environmental factors, diet, exercise, aging, comorbidities, medications, and lifestyle choices. As a result, the development of diabetes due to the failure of compensatory b-cell responses can stem from a wide range of causes. Therefore, comprehensive reverse translational research incorporating integrated analysis of adaptive b-cell responses is necessary to bridge the gap between preclinical and clinical studies.

International Journal of Endocrinology and Diabetes