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Integration of old and recent experimental data consequences is needed to correct and help improve the hypothetical mechanism responsible for the stimulus–secretion coupling mechanism of glucose-induced insulin secretion. The main purpose of this review is to supply biochemical considerations about some of the metabolic pathways implicated in the process of insulin secretion. It is emphasized that glucose β-cells’ threshold to activate secretion (5 mM) might depend on the predominance of anaerobic glycolysis at this basal glucose concentration. This argues against the predominance of phosphoenolpyruvate (PEP) over mitochondrial pyruvate oxidation for the initiation of insulin secretion. Full quantitative and qualitative reproduction, except the threshold effect, of glucose-induced insulin release by a permeable methylated analog of succinic acid indicates that mitochondrial metabolism is enough for sustained insulin secretion. Mitochondrial PEP generation is skipped if the GABA-shunt pathway is exclusively coupled to the citric acid cycle, as proposed in the “GABA-shunt” model of stimulus–secretion coupling. Strong or maintained depolarization by KCl or sulfonylureas might induce the opening of β-cells Cx36 hemichannels, allowing the loss of adenine nucleotides and other metabolites, mimicking the effect of an excessive mitochondrial ATP demand. A few alterations of OxPhos (Oxidative Phosphorylation) regulation in human T2D islets have been described, but the responsible mechanism(s) is (are) not yet known. Finally, some experimental data arguing as proof of the relative irrelevance of the mitochondrial function in the insulin secretion coupling mechanism for the initiation and/or sustained stimulation of hormone release are discussed.

The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.

Loss of β‐cell number and function is a hallmark of diabetes. β‐cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in β‐cells. This expression was up‐regulated in β‐cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated β‐cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in β‐cells via its action on the pathway of Ndufs3 and p22 phox . Finally, we found that 2‐β‐D‐glucopyranosyloxy1‐hydroxytrideca 5,7,9,11‐tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of β‐cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes. SYNOPSIS Pancreatic β‐cell failure is associated with diabetes. Pdia4, a protein disulfide isomerase, is identified as a crucial regulator of β‐cell pathogenesis and diabetes. Pdia4 interacts with Ndufs3 and p22 phox and engages them in mitochondrial and cytosolic ROS production in β‐cells. Pharmacological inhibition of Pdia4 disrupts the interaction of Pdia4 and its downstream partners, decreases ROS production, and ameliorates β‐cell failure and diabetes. Graphical Abstract Pancreatic β‐cell failure is associated with diabetes. Pdia4, a protein disulfide isomerase, is identified as a crucial regulator of β‐cell pathogenesis and diabetes.

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

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.

Aims/Introduction Whether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in ‘adaptive’ β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in ‘basal’ β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood. Materials and Methods FoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance. Results FoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency. Conclusions Basal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age. β‐cell FoxM1 plays a critical role in basal, low‐level β‐cell proliferation throughout adult periods from youth to middle age. Long‐term FoxM1 deficiency suppresses β‐cell mass increases with advancing age, and impaired insulin secretion. Inhibition of FoxM1‐driven basal β‐cell proliferation worsen glucose tolerance, indicating inability to maintain sufficient β‐cell mass.

Accumulation of depolarized mitochondria within β‐cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run’ pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψ m ) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non‐fusing mitochondria that were found to have reduced Δψ m and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1 K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that before autophagy mitochondria lose Δψ m and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.

Dietary polyphenols have been widely investigated as antidiabetic agents in cell, animals, human study, and clinical trial. The number of publication (Indexed by Web of Science) on “polyphenols and diabetes” significantly increased since 2010. This review highlights the advances and opportunities of dietary polyphenols as antidiabetic agents. Dietary polyphenols prevent and manage Type 2 diabetes mellitus via the insulin‐dependent approaches, for instance, protection of pancreatic islet β‐cell, reduction of β‐cell apoptosis, promotion of β‐cell proliferation, attenuation of oxidative stress, activation of insulin signaling, and stimulation of pancreas to secrete insulin, as well as the insulin‐independent approaches including inhibition of glucose absorption, inhibition of digestive enzymes, regulation of intestinal microbiota, modification of inflammation response, and inhibition of the formation of advanced glycation end products. Moreover, dietary polyphenols ameliorate diabetic complications, such as vascular dysfunction, nephropathy, retinopathy, neuropathy, cardiomyopathy, coronary diseases, renal failure, and so on. The structure–activity relationship of polyphenols as antidiabetic agents is still not clear. The individual flavonoid or isoflavone has no therapeutic effect on diabetic patients, although the clinical data are very limited. Resveratrol, curcumin, and anthocyanins showed antidiabetic activity in human study. How hyperglycemia influences the bioavailability and bioactivity of dietary polyphenols is not well understood. An understanding of how diabetes alters the bioavailability and bioactivity of dietary polyphenols will lead to an improvement in their benefits and clinical outcomes. Anti‐diabetic mechanisms of dietary polyphenols .

Purpose of ReviewThis review summarizes the alterations in the β-cell observed in type 2 diabetes (T2D), focusing on changes in β-cell identity and mass and changes associated with metabolism and intracellular signaling.Recent FindingsIn the setting of T2D, β-cells undergo changes in gene expression, reverting to a more immature state and in some cases transdifferentiating into other islet cell types. Alleviation of metabolic stress, ER stress, and maladaptive prostaglandin signaling could improve β-cell function and survival.SummaryThe β-cell defects leading to T2D likely differ in different individuals and include variations in β-cell mass, development, β-cell expansion, responses to ER and oxidative stress, insulin production and secretion, and intracellular signaling pathways. The recent recognition that some β-cells undergo dedifferentiation without dying in T2D suggests strategies to revive these cells and rejuvenate their functionality.

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin‐producing β‐cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of β‐cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of β‐cell function and the prevention of β‐cell death. Phosphoinositide 3‐kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of β‐cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide‐based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the β‐cell processes to ultimately determine the fate of β‐cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance β‐cell function and prevent β‐cell death without inducing excessive β‐cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite‐derived protein, termed FhHDM‐1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in β‐cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM‐1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by β‐cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance β‐cell function and survival. 1型糖尿病(T1D)是一种自身免疫性疾病，由胰腺内分泌胰岛素的β细胞破坏引起。胰岛移植是一种治疗方法，然而，在胰岛准备和移植后期间，大量的β细胞会发生死亡。因此，T1D的防治有赖于β细胞功能的保护和β细胞死亡的预防。磷脂酰肌醇3‐激酶(PI3K)/Akt信号通路对细胞存活、增殖和代谢有显著影响，是治疗T1D的有效靶点。越来越多的证据表明，PI3K/AKT信号是决定β细胞质量和功能的关键因素。通过直接(使用高度特异的蛋白质或基于多肽的生物制剂、寄生虫的产物和植物提取物的复杂成分)或间接(通过microRNA相互作用)调节PI3K/Akt通路，从而调节β‐细胞过程，可最终决定β‐细胞团的结局。一个重要的考虑是确定特定的PI3K/AKT途径调节剂，这些调节剂可以增强β细胞的功能，防止β细胞死亡，而不会诱导β细胞过度增殖，这可能会带来致癌副作用。在潜在的PI3K/Akt途径激动剂中，我们已经发现了一种新的寄生虫衍生蛋白，称为FhHDM‐1(肝片吸虫蠕虫防御分子1)，能有效刺激β‐细胞的PI3K/Akt途径，增强功能并防止死亡，而不像其他几个已发现的PI3K/Akt信号刺激因子那样同时诱导增殖。因此，FhHDM‐1将为针对PI3K/Akt途径的生物制剂设计提供信息，以预防/改善T1D和T2D，T2D现在被广泛认为是一种以β细胞功能障碍和死亡为特征的炎症性疾病。本文将探讨PI3K/Akt信号通路的调控作为提高β细胞功能和存活的新策略 Highlights Phosphoinositide 3‐kinase (PI3K)/Akt signaling is an emerging promising therapeutic target for diabetes. Modulation of the PI3K/Akt signaling pathway, via protein and peptide‐based biologics, parasite‐derived molecules, plant extracts, or through microRNA interactions, will regulate the processes that determine the function of β‐cells and the fate of β‐cell mass. Therapeutic approaches targeting PI3K/Akt signaling will have broad‐reaching applications for the prevention of type 1 diabetes, the preservation of islets prior and post transplantation, and the treatment of type 2 diabetes