scholarly journals Human Islet Microtissues as an In Vitro and an In Vivo Model System for Diabetes

2021 ◽  
Vol 22 (4) ◽  
pp. 1813
Author(s):  
Joan Mir-Coll ◽  
Tilo Moede ◽  
Meike Paschen ◽  
Aparna Neelakandhan ◽  
Ismael Valladolid-Acebes ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islet ◽  
Critical Event ◽  
In Vivo Model ◽  
Β Cell

Loss of pancreatic β-cell function is a critical event in the pathophysiology of type 2 diabetes. However, studies of its underlying mechanisms as well as the discovery of novel targets and therapies have been hindered due to limitations in available experimental models. In this study we exploited the stable viability and function of standardized human islet microtissues to develop a disease-relevant, scalable, and reproducible model of β-cell dysfunction by exposing them to long-term glucotoxicity and glucolipotoxicity. Moreover, by establishing a method for highly-efficient and homogeneous viral transduction, we were able to monitor the loss of functional β-cell mass in vivo by transplanting reporter human islet microtissues into the anterior chamber of the eye of immune-deficient mice exposed to a diabetogenic diet for 12 weeks. This newly developed in vitro model as well as the described in vivo methodology represent a new set of tools that will facilitate the study of β-cell failure in type 2 diabetes and would accelerate the discovery of novel therapeutic agents.

Managing the β-cell with GLP-1 in type 2 diabetes

2008 ◽  
Vol 8 (2_suppl) ◽  
pp. S19-S25 ◽  
Author(s):  
Baptist Gallwitz
Keyword(s):  
Type 2 Diabetes ◽  
Phase Ii ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Neonatal Rat ◽  
Β Cell ◽  
Β Cell Function

The clinical course of type 2 diabetes mellitus is characterised by a progressive decline in β -cell mass. The changing β-cell mass reflects a shifting balance between β-cell neogenesis, islet neogenesis and β-cell apoptosis. In persons with diabetes, administration of exogenous glucagon-like peptide-1 (GLP-1) improves glucose sensitivity and insulin synthesis and may help increase β cell mass. As the effects of GLP-1 on the β cell are becoming better understood at both the molecular and cellular levels, it has become possible to develop therapies with the potential to harness and sustain the positive effects of endogenous GLP-1 in patients with type 2 diabetes. Data from in vitro, preclinical and phase II studies show promising results with GLP-1 analogues in improving β-cell function in patients with type 2 diabetes. For example, in vitro models have shown the GLP-1 analogue liraglutide inhibits β-cell apoptosis in isolated neonatal rat islets. In vitro, animal models demonstrate increasing β-cell mass with liraglutide administration. Results from a recently completed phase II clinical trial with liraglutide in patients with type 2 diabetes demonstrate that daily treatment markedly improves β -cell function as shown by an increased first-phase insulin response and secretory capacity and a decreased proinsulin:insulin ratio. Now, phase III trials continue to bear out the potential for liraglutide for treatment of patients with type 2 diabetes.Br J Diabetes Vasc Dis 2008;8 (Suppl 2): S19-S25

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

2011 ◽  
Vol 300 (2) ◽  
pp. E255-E262 ◽  
Author(s):  
Adria Giacca ◽  
Changting Xiao ◽  
Andrei I. Oprescu ◽  
Andre C. Carpentier ◽  
Gary F. Lewis
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

scholarly journals Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β-cell are associated with glucose intolerance in humans and mice

2016 ◽  
Vol 311 (2) ◽  
pp. E488-E507 ◽  
Author(s):  
Zenobia B. Mehta ◽  
Nicholas Fine ◽  
Timothy J. Pullen ◽  
Matthew C. Cane ◽  
Ming Hu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Disease Risk ◽  
Cell Mass ◽  
Eqtl Analysis ◽  
Β Cell ◽  
Enhancer Activity ◽  
Increased Risk

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female ( n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.

scholarly journals Neratinib protects pancreatic beta cells in diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Amin Ardestani ◽  
Sijia Li ◽  
Karthika Annamalai ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell

Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

scholarly journals A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 624-635 ◽  
Author(s):  
Joon Ha ◽  
Leslie S. Satin ◽  
Arthur S. Sherman
Keyword(s):  
Mathematical Model ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Metabolic Defects ◽  
Normal Individuals ◽  
Β Cell Function

Abstract Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing β-cell mass. We add to that model regulation of 2 aspects of β-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into “Starling's Law of the Pancreas,” whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals.

scholarly journals XOMA 052, an Anti-IL-1β Monoclonal Antibody, Improves Glucose Control and β-Cell Function in the Diet-Induced Obesity Mouse Model

2010 ◽  
Vol 31 (2) ◽  
pp. 261-261
Author(s):  
Alexander M. Owyang ◽  
Kathrin Maedler ◽  
Lisa Gross ◽  
Johnny Yin ◽  
Lin Esposito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Monoclonal Antibody ◽  
Type 2 Diabetes Mellitus ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Diet Induced Obesity ◽  
Β Cell Function

ABSTRACT Recent evidence suggests that IL-1β-mediated glucotoxicity plays a critical role in type 2 diabetes mellitus. Although previous work has shown that inhibiting IL-1β can lead to improvements in glucose control and β-cell function, we hypothesized that more efficient targeting of IL-1β with a novel monoclonal antibody, XOMA 052, would reveal an effect on additional parameters affecting metabolic disease. In the diet-induced obesity model, XOMA 052 was administered to mice fed either normal or high-fat diet (HFD) for up to 19 wk. XOMA 052 was administered as a prophylactic treatment or as a therapy. Mice were analyzed for glucose tolerance, insulin tolerance, insulin secretion, and lipid profile. In addition, the pancreata were analyzed for β-cell apoptosis, proliferation, and β-cell mass. Mice on HFD exhibited elevated glucose and glycated hemoglobin levels, impaired glucose tolerance and insulin secretion, and elevated lipid profile, which were prevented by XOMA 052. XOMA 052 also reduced β-cell apoptosis and increased β-cell proliferation. XOMA 052 maintained the HFDinduced compensatory increase in β-cell mass, while also preventing the loss in β-cell mass seen with extended HFD feeding. Analysis of fasting insulin and glucose levels suggests that XOMA 052 prevented HFD-induced insulin resistance. These studies provide new evidence that targeting IL-1β in vivo could improve insulin sensitivity and lead to β-cell sparing. This is in addition to previously reported benefits on glycemic control. Taken together, the data presented suggest that XOMA 052 could be effective for treating many aspects of type 2 diabetes mellitus.

scholarly journals Exendin-4 Promotes Survival of Mouse Pancreaticβ-Cell Line in Lipotoxic Conditions, through the Extracellular Signal-Related Kinase 1/2 Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Jianqiu Gu ◽  
Qian Wei ◽  
Hongzhi Zheng ◽  
Xin Meng ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Cell Mass ◽  
Mitochondrial Pathway ◽  
Apoptosis Pathway ◽  
Min6 Cells ◽  
Mitochondrial Apoptosis Pathway ◽  
Extracellular Signal

Type 2 diabetes is a heterogeneous disorder that develops as a result of relatively inappropriate insulin secretion and insulin resistance. Increased levels of free fatty acids (FFAs) are one of the important factors for the pathogenesis of type 2 diabetes and contribute to defectiveβ-cell proliferation and increasedβ-cell apoptosis. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to possess an antiapoptotic effect, by increasingβ-cell mass and improvingβ-cell function. However, their effects onβ-cells in vitro against lipotoxicity have not been elucidated completely. In this study, we investigated whether the GLP-1 receptor agonist exendin-4 displays prosurvival effects in pancreaticβ-cells exposed to chronic elevated FFAs. Results showed that exendin-4 inhibited apoptosis induced by palmitate in MIN6 cells. After 24 h of incubation, exendin-4 caused rapid activation of extracellular signal-related kinase 1/2 (ERK1/2) under lipotoxic conditions. The ERK1/2 inhibitor PD98059 blocked the antilipotoxic effect of exendin-4 on MIN6 cells. Exendin-4 also inhibited the mitochondrial pathway of apoptosis. This inhibition is associated with upregulation of BCL-2. Our findings suggested that exendin-4 may exert cytoprotective effects through activation of ERK1/2 and inhibition of the mitochondrial apoptosis pathway.

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.

β-Cell compensation concomitant with adaptive endoplasmic reticulum stress and β-cell neogenesis in a diet-induced type 2 diabetes model

2019 ◽  
Vol 44 (12) ◽  
pp. 1355-1366 ◽  
Author(s):  
Hui Huang ◽  
Kaiyuan Yang ◽  
Rennian Wang ◽  
Woo Hyun Han ◽  
Sharee Kuny ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Temporal Association ◽  
Adaptive Responses ◽  
Β Cells ◽  
Β Cell

Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of β-cell compensation are not fully understood. Our previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other β-cell adaptive responses, including glucose metabolism and β-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of β-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in β-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative β-cell growth as a mechanism of β-cell mass adaptation. In contrast, decreased neogenesis and β-cell dedifferentiation were observed in β-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of β-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for β-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. β-Cell neogenesis but not proliferation contributes to β-cell mass adaptation.

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