scholarly journals Pancreatic β-Cell Mass as a Pharmacologic Target in Diabetes

2020 ◽  
Vol 12 (2) ◽  
Author(s):  
Stephen Hanley
Keyword(s):  
Type 2 Diabetes ◽  
Cell Expansion ◽  
Cell Mass ◽  
Basic Research ◽  
Cell Loss ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Prevalence Of Diabetes Mellitus

While the prevalence of maternal While the prevalence of diabetes mellitus reaches epidemic proportions, most available treatments still focus on the symptoms of the disease, rather than the underlying pathology. Types 1 and 2 diabetes have in common a deficit in β-cell mass. In type 1 diabetes, auto-immune β-cell destruction leads to an absolute deficit in β-cells, while in type 2 diabetes, insulin resistance and β-cell dysfunction cause a functional deficit. More recently, however, it has been suggested that type 2 diabetes is also marked by an absolute deficit in β-cell mass, although a causal relationship has not yet been established. Overall β-cell mass reflects the balance between the dynamic processes of β-cell expansion, through proliferation and neogenesis, and β-cell loss via apoptosis. Given that β-cell mass can be modified significantly by altering the rate of any of these mechanisms, therapies that modulate β-cell expansion and loss have garnered recent interest. We review herein the current therapeutics under investigation as modulators of β-cell mass dynamics, and the basic research that supports these novel therapeutic targets.

scholarly journals A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

2007 ◽  
Vol 40 (2) ◽  
pp. 37-45 ◽  
Author(s):  
Thierry Brun ◽  
Benoit R Gauthier
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Pancreatic Islet ◽  
Cell Expansion ◽  
Cell Mass ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell

Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of β-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs β-cell mass plasticity may provide a means to develop strategies to countera,ct β-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the β-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature β-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet β-cell physiology and its contribution to pathophysiology when deregulated.

scholarly journals Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 58 ◽  
Author(s):  
Michael D. Schaid ◽  
Yanlong Zhu ◽  
Nicole E. Richardson ◽  
Chinmai Patibandla ◽  
Irene M. Ong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Prostaglandin E2 ◽  
Genetic Model ◽  
Cell Mass ◽  
Arachidonic Acid Metabolite ◽  
Β Cell ◽  
Human Organ ◽  
Cell Dysfunction ◽  
Primary Mouse

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

scholarly journals Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

2016 ◽  
Vol 229 (3) ◽  
pp. 343-356 ◽  
Author(s):  
Kaiyuan Yang ◽  
Jonathan Gotzmann ◽  
Sharee Kuny ◽  
Hui Huang ◽  
Yves Sauvé ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Cell Mass ◽  
Β Cell ◽  
High Fiber ◽  
Insulin Resistant ◽  
Cell Dysfunction

We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulin-resistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D.

scholarly journals Elevated Neuropeptide Y1 Receptor Signaling Contributes to β-cell Dysfunction and Failure in Type 2 Diabetes

2021 ◽  
Author(s):  
Chieh-Hsin Yang ◽  
Danise Ann-Onda ◽  
Xuzhu Lin ◽  
Stacey Fynch ◽  
Shaktypreya Nadarajah ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycaemic Control ◽  
Neuropeptide Y ◽  
Cell Mass ◽  
Human Islets ◽  
Receptor Signaling ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Y1 Receptor

Loss of functional β-cell mass is a key factor contributing to the poor glycaemic control in type 2 diabetes. However, therapies that directly target these underlying processes remains lacking. Here we demonstrate that gene expression of neuropeptide Y1 receptor and its ligand, neuropeptide Y, was significantly upregulated in human islets from subjects with type 2 diabetes. Importantly, the reduced insulin secretion in type 2 diabetes was associated with increased neuropeptide Y and Y1 receptor expression in human islets. Consistently, pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β-cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, Y1 receptor antagonist BIBO3304 treatment improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycaemic control in both high-fat-diet/multiple low dose streptozotocin- and db/db type 2 diabetic mice. Collectively, our results uncovered a novel causal link of increased islet NPY-Y1 receptor signaling to β-cell dysfunction and failure in human type 2 diabetes. These results further demonstrate that inhibition of Y1 receptor by BIBO3304 represents a novel and effective β-cell protective therapy for improving functional β-cell mass and glycaemic control in type 2 diabetes.

scholarly journals CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis

2016 ◽  
Vol 30 (4) ◽  
pp. 446-454 ◽  
Author(s):  
T. Gurlo ◽  
J. F. Rivera ◽  
A. E. Butler ◽  
M. Cory ◽  
J. Hoang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

scholarly journals β-Cell Expansion for Therapeutic Compensation of Insulin Resistance in Type 2 Diabetes

2003 ◽  
Vol 4 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Shimon Efrat
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cell Expansion ◽  
Cell Function ◽  
Cell Mass ◽  
Disease Type ◽  
Insulin Production ◽  
Β Cell ◽  
Overt Disease

Insulin resistance is the primary cause of type 2 diabetes. However, if compensated by increased insulin production, insulin resistance by itself does not lead to overt disease. Type 2 diabetes develops when this compensation is insufficient, due to defects inβ-cell function and in regulation of theβ-cell mass.β-Cell transplantation, as well as approaches that replenish or preserve the endogenousβ-cell mass, may facilitate the treatment of type 2 diabetes in patients requiring exogenous insulin.

Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 348-352 ◽  
Author(s):  
Miriam Cnop
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.

scholarly journals A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1593
Author(s):  
Phyu-Phyu Khin ◽  
Jong-Han Lee ◽  
Hee-Sook Jun
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Dedifferentiation Process

Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

scholarly journals Revisiting regulators of human β-cell mass to achieve β-cell-centric approach toward type 2 diabetes

2021 ◽  
Author(s):  
Hironobu Sasaki ◽  
Yoshifumi Saisho ◽  
Jun Inaishi ◽  
Hiroshi Itoh
Keyword(s):  
Type 2 Diabetes ◽  
Racial Differences ◽  
Low Birthweight ◽  
Current Knowledge ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Cell Protection ◽  
Β Cell ◽  
Cell Dysfunction

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Since patients with T2DM have inadequate beta cell mass (BCM), and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed.In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the Developmental Origins of Health and Disease hypothesis, which states that the risk of developing non-communicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Since β-cell replication is more frequently observed in the five years after birth, and β-cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20-65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human β-cell mass in health and diabetes, and propose the β-cell centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.

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