Increase Functional β-Cell Mass in Subcutaneous Alginate Capsules With Porcine Prenatal Islet Cells but Loss With Human Adult Islet Cells

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

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Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells

Endocrinology ◽

10.1210/en.2008-1009 ◽

2009 ◽

Vol 150 (2) ◽

pp. 570-579 ◽

Cited By ~ 10

Author(s):

Wei Chen ◽

Salma Begum ◽

Lynn Opare-Addo ◽

Justin Garyu ◽

Thomas F. Gibson ◽

...

Keyword(s):

Cell Differentiation ◽

Glucose Transporter ◽

Islet Cells ◽

Precursor Cells ◽

Cell Contact ◽

Β Cells ◽

Β Cell ◽

Glucose Transporter 2 ◽

Adult Islet

It is thought that differentiation of β-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify β-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed β-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or βTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into β-cells was induced by mature islet cells. It was specific for β-cells and not a general feature of endodermal derived cells. β-Cell differentiation required cell-cell contact. The induced cells acquired features of mature β-cells including increased expression of β-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature β-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of β-cells can be affected by other β-cells. Mature β cells affect differentiation of pancreatic anlage cells into functional β cells. The differentiated cells respond to glucose and ameliorate diabetes.

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Maternal Low Protein Isocaloric Diet Suppresses Pancreatic β-Cell Proliferation in Mouse Offspring via miR-15b

Endocrinology ◽

10.1210/en.2016-1167 ◽

2016 ◽

Vol 157 (12) ◽

pp. 4782-4793 ◽

Cited By ~ 12

Author(s):

Yutong Su ◽

Xiuli Jiang ◽

Yanli Li ◽

Feng Li ◽

Yulong Cheng ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Islet Cells ◽

Control Diet ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell ◽

Isocaloric Diet ◽

Low Protein ◽

And Control

The mechanism underlying the increased susceptibility of type 2 diabetes in offspring of maternal malnutrition is poorly determined. Here we tested the hypothesis that functional microRNAs (miRNAs) mediated the maternal low-protein (LP) isocaloric diet induced pancreatic β-cell impairment. We performed miRNA profiling in the islets from offspring of LP and control diet mothers to explore the potential functional miRNAs responsible for β-cell dysfunction. We found that LP offspring exhibited impaired glucose tolerance due to decreased β-cell mass and insulin secretion. Reduction in the β-cell proliferation rate and cell size contributed to the decreased β-cell mass. MiR-15b was up-regulated in the islets of LP offspring. The up-regulated miR-15b inhibited pancreatic β-cell proliferation via targeting cyclin D1 and cyclin D2. Inhibition of miR-15b in LP islet cells restored β-cell proliferation and insulin secretion. Our findings demonstrate that miR-15b is critical for the regulation of pancreatic β-cells in offspring of maternal protein restriction, which may provide a further insight for β-cell exhaustion originated from intrauterine growth restriction.

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The Cells of the Islets of Langerhans

Journal of Clinical Medicine ◽

10.3390/jcm7030054 ◽

2018 ◽

Vol 7 (3) ◽

pp. 54 ◽

Cited By ~ 37

Author(s):

Gabriela Da Silva Xavier

Keyword(s):

Islets Of Langerhans ◽

Islet Cell ◽

Islet Cells ◽

Cell Mass ◽

Current Data ◽

Treatment Modalities ◽

Human Pancreas ◽

Β Cells ◽

Β Cell ◽

Islet Mass

Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.

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Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival

Endocrinology ◽

10.1210/en.2010-0233 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3577-3588 ◽

Cited By ~ 38

Author(s):

Jeremy A. Lavine ◽

Philipp W. Raess ◽

Donald S. Stapleton ◽

Mary E. Rabaglia ◽

Joshua I. Suhonen ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Islet Cells ◽

Cell Mass ◽

Obese Mouse ◽

Β Cell ◽

Key Factor ◽

Islet Size ◽

Mouse Islets ◽

Mass Expansion

An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/ob mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance.

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The Plasticity of Pancreatic β-Cells

Metabolites ◽

10.3390/metabo11040218 ◽

2021 ◽

Vol 11 (4) ◽

pp. 218

Author(s):

Norikiyo Honzawa ◽

Kei Fujimoto

Keyword(s):

Insulin Secretion ◽

Progenitor Cells ◽

Islet Cells ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Cell Plasticity ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Impaired Insulin

Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3(Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.

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Effect of prolonged in vitro exposure to high glucose on neonatal porcine pancreatic islets

Journal of Endocrinology ◽

10.1677/joe.1.06812 ◽

2006 ◽

Vol 191 (1) ◽

pp. 37-44 ◽

Cited By ~ 6

Author(s):

George Harb ◽

Gregory S Korbutt

Keyword(s):

High Glucose ◽

Prolonged Exposure ◽

Islet Cells ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Porcine Islets ◽

Clinical Islet Transplantation ◽

Neonatal Porcine Islets

Prolonged exposure to high glucose can influence the function, growth, and survival of pancreatic β-cells. In this study, we examine the effects of prolonged in vitro exposure to high glucose on neonatal porcine β-cells, a potentially useful source of insulin-producing cells for clinical islet transplantation. Neonatal porcine islets were prepared by culturing collagenase-digested pancreases for 1 week in 5.6 mM glucose, followed by an additional week in either 5.6, 10.0, or 28.0 mM glucose. An additional 2 days of culture in 5.6 mM glucose followed for recovery from high glucose. The 7-day culture period in 28.0 mM glucose failed to irreversibly impair glucose responsiveness and also caused a modest increase in β-cell mass. Immunostaining revealed that precursor cell differentiation was responsible for the increase in β-cell mass rather than β-cell proliferation. Islet cell survival was also assessed by a DNA fragmentation assay (TUNEL stain) to determine β-cell susceptibility to apoptosis after exposure to high glucose. Interestingly, although the total number of apoptotic islet cells did not drastically change after a week of culture in either 5.6, 10.0, or 28.0 mM glucose (25% TUNEL-positive), neither did the percentage of apoptotic β-cells. These encouraging results further support the use of neonatal porcine islets for clinical transplantation because of their ability to resist the cytotoxic effects of high glucose on islet function and survival.

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Acetone Ingestion Mimics a Fasting State to Improve Glucose Tolerance in a Mouse Model of Gestational Hyperglycemia

International Journal of Molecular Sciences ◽

10.3390/ijms222312914 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12914

Author(s):

Sandra Szlapinski ◽

Brenda Strutt ◽

Madeline Deane ◽

Edith Arany ◽

Jamie Bennett ◽

...

Keyword(s):

Glucose Tolerance ◽

Mouse Model ◽

Islet Cells ◽

Post Partum ◽

Cell Mass ◽

Tolerance Test ◽

Transient Effects ◽

Β Cell ◽

Cell Conversion ◽

Pregnant Mice

Gestational diabetes mellitus results, in part, from a sub-optimal β-cell mass (BCM) during pregnancy. Artemisinins were reported to increase BCM in models of diabetes by α- to β-cell conversion leading to enhanced glucose tolerance. We used a mouse model of gestational glucose intolerance to compare the effects of an artemisinin (artesunate) on glycemia of pregnant mice with vehicle treatment (acetone) or no treatment. Animals were treated daily from gestational days (GD) 0.5 to 6.5. An intraperitoneal glucose tolerance test was performed prior to euthanasia at GD18.5 or post-partum. Glucose tolerance was significantly improved in both pregnant and non-pregnant mice with both artesunate and vehicle-alone treatment, suggesting the outcome was primarily due to the acetone vehicle. In non-pregnant, acetone-treated animals, improved glucose tolerance was associated with a higher BCM and a significant increase in bihormonal insulin and glucagon-containing pancreatic islet cells, suggesting α- to β-cell conversion. BCM did not differ with treatment during pregnancy or post-partum. However, placental weight was higher in acetone-treated animals and was associated with an upregulation of apelinergic genes. Acetone-treated animals had reduced weight gain during treatment despite comparable food consumption to non-treated mice, suggesting transient effects on nutrient uptake. The mean duodenal and ileum villus height was reduced following exposure to acetone. We conclude that acetone treatment may mimic transient fasting, resulting in a subsequent improvement in glucose tolerance during pregnancy.

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Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00596.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. E50-E58 ◽

Cited By ~ 34

Author(s):

Yarong Lu ◽

André Ponton ◽

Hiroshi Okamoto ◽

Shin Takasawa ◽

Pedro L. Herrera ◽

...

Keyword(s):

Cell Growth ◽

Islet Cell ◽

Islet Cells ◽

Cell Damage ◽

Cell Mass ◽

Direct Consequence ◽

Β Cell ◽

Igf I ◽

Streptozotocin Induced Diabetes ◽

I Gene

We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased β-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3α, and -3β, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2- to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced β-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas and suggested their potential role in β-cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and islet neogenesis-associated protein) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D.

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EGF receptor in pancreatic β-cell mass regulation

Biochemical Society Transactions ◽

10.1042/bst0360280 ◽

2008 ◽

Vol 36 (3) ◽

pp. 280-285 ◽

Cited By ~ 35

Author(s):

Päivi Miettinen ◽

Päivi Ormio ◽

Elina Hakonen ◽

Meenal Banerjee ◽

Timo Otonkoski

Keyword(s):

Egf Receptor ◽

Islet Cells ◽

Cell Mass ◽

In Vitro Models ◽

Β Cell ◽

Positive Effects ◽

Ductal Cells ◽

Gut Hormone ◽

Glucagon Like Peptide 1

Pancreatic islet development is impaired in mice lacking EGFRs (epidermal growth factor receptors). Even partial tissue-specific attenuation of EGFR signalling in the islets leads to markedly reduced β-cell proliferation and development of diabetes during the first weeks after birth. Out of the many EGFR ligands, betacellulin has been specifically associated with positive effects on β-cell growth, through both increased proliferation and neogenesis. EGFR action is also necessary for the β-cell mitogenic activity of the gut hormone GLP-1 (glucagon-like peptide 1). Finally, in vitro models demonstrate a central role for EGFR in transdifferentiation of pancreatic acinar and ductal cells into endocrine islet cells. EGFR thus plays an essential role in β-cell mass regulation, but its mechanisms of action remain poorly understood.

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