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

2006 ◽  
Vol 291 (1) ◽  
pp. E50-E58 ◽  
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.

A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes

2008 ◽  
Vol 294 (5) ◽  
pp. E928-E938 ◽  
Author(s):  
Katie Robertson ◽  
Yarong Lu ◽  
Kristine De Jesus ◽  
Bing Li ◽  
Qing Su ◽  
...  
Keyword(s):  
Cell Growth ◽  
Islet Cell ◽  
Receptor Gene ◽  
Elevated Serum ◽  
Somatic Growth ◽  
Β Cell ◽  
Igf I ◽  
Onset Of Diabetes ◽  
I Gene

Insulin-like growth factor I (IGF-I) is normally produced from hepatocytes and various other cells and tissues, including the pancreas, and is known to stimulate islet cell replication in vitro, prevent Fas-mediated β-cell destruction and delay the onset of diabetes in nonobese diabetic mice. Recently, however, the notion that IGF-I stimulates islet cell growth has been challenged by the results of IGF-I and receptor gene targeting. To test the effects of a general, more profound increase in circulating IGF-I on islet cell growth and glucose homeostasis, we have characterized MT-IGF mice, which overexpress the IGF-I gene under the metallothionein I promoter. In early reports, a 1.5-fold-elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. We demonstrated that the transgene expression, although widespread, was highly concentrated in the β-cells of the pancreatic islets. Yet, islet cell percent and pancreatic morphology were unaffected. IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, and improved glucose tolerance but normal insulin secretion and sensitivity. Pyruvate tolerance test indicated significantly suppressed hepatic gluconeogenesis, which might explain the severe hypoglycemia after fasting. Finally, due to a partial prevention of β-cell death against onset of diabetes and/or the insulin-like effects of IGF-I overexpression, MT-IGF mice (which overexpress the IGF-I gene under the metallothionein I promoter) were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia and prevention of weight loss and death. Although IGF-I might not promote islet cell growth, its overexpression is clearly antidiabetic by improving islet cell survival and/or providing insulin-like effects.

scholarly journals The Cells of the Islets of Langerhans

2018 ◽  
Vol 7 (3) ◽  
pp. 54 ◽  
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.

Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice

2006 ◽  
Vol 291 (3) ◽  
pp. E491-E498 ◽  
Author(s):  
Katie Robertson ◽  
John J. Kopchick ◽  
Jun-Li Liu
Keyword(s):  
Growth Hormone ◽  
Insulin Receptor ◽  
Islet Cell ◽  
Skeletal Muscles ◽  
Cell Mass ◽  
Β Cell ◽  
Gene Deficiency ◽  
Ghr Gene ◽  
Igf I ◽  
Insulin Responsiveness

Growth hormone (GH), acting through its receptor (GHR), is essential for somatic growth and development and maintaining metabolic homeostasis. GHR gene-deficient (GHR−/−) mice exhibit drastically diminished insulin-like growth factor-I (IGF-I) levels, proportional growth retardation, elevated insulin sensitivity, and reduced islet β-cell mass. Unlike the liver, which is mostly unaffected by changes in IGF-I level, skeletal muscles express high levels of IGF-I receptor (IGF-IR). The net result of a concurrent deficiency in the actions of both GH and IGF-I, which exert opposite influences on insulin responsiveness, has not been evaluated. We studied insulin-stimulated early responses in the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and p85 subunit of phosphatidylinositol 3-kinase. Upon in vivo insulin stimulation, skeletal muscles of GHR−/− mice exhibit transient delayed responses in IR and IRS-1 phosphorylation but normal levels of p85 association with IRS-1. This is in contrast to normal/elevated insulin responses in hepatocytes and indicates tissue-specific effects of GHR gene deficiency. In addition to stimulating normal islet cell growth, GH may participate in islet cell overgrowth, which compensates for insulin resistance induced by obesity. To determine whether the islet cell overgrowth is dependent on GH signaling, we studied the response of male GHR−/− mice to high-fat diet (HFD)-induced obesity. After 17 wk on a HFD, GHR−/− mice became more significantly obese than wild-type mice and exhibited increased β-cell mass to a slightly higher extent. These data demonstrate that GH signaling is not required for compensatory islet growth. Thus, in both muscle insulin responsiveness and islet growth compensation, normal levels of GH signals do not seem to play a dominant role.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

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.

scholarly journals VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

2017 ◽  
Vol 131 (8) ◽  
pp. 673-687 ◽  
Author(s):  
Bárbara Maiztegui ◽  
Verónica Boggio ◽  
Carolina L. Román ◽  
Luis E. Flores ◽  
Héctor Del Zotto ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cell Function ◽  
Cell Damage ◽  
Cell Mass ◽  
Ultrastructural Changes ◽  
Mrna Levels ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Mrna

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

scholarly journals Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

2009 ◽  
Vol 44 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Laura de Miguel-Santos ◽  
Elisa Fernández-Millán ◽  
María Ángeles Martín ◽  
Fernando Escrivá ◽  
Carmen Álvarez
Keyword(s):  
Cell Growth ◽  
Cell Apoptosis ◽  
Endocrine Pancreas ◽  
Glycogen Synthase ◽  
Cell Mass ◽  
Main Role ◽  
Β Cell ◽  
Adult Age ◽  
Maternal Undernutrition ◽  
The Impact

Replication, neogenesis, and apoptosis play a main role in neonatal endocrine pancreas remodeling. IGFs are major contributors to β-cell growth and function and are highly sensitive to nutritional status. We previously showed that maternal malnutrition caused an increase in β-cell mass in fetuses related to the stimulation of β-cell proliferation due to increased pancreatic IGF-1. At 4 days of life, the β-cell mass was decreased in undernourished neonates and persisted until adult age. To clarify whether undernutrition disrupts islet remodeling, we quantified β-cell mass, neogenesis, replication, and apoptosis on days 4, 14, and 23. To determine the impact of food restriction on IGF ontogeny and the consequences for β-cell growth, we measured IGF-1/-2 protein content in pancreas and liver and pancreatic IGF-1 receptor (IGF-1R)-signaling pathway at the same days. Our results indicate that undernutrition alters the timing and intensity of neonatal β-cell ontogeny. However, although malnutrition causes β-cell deficiency in neonates, an active process of β-cell neogenesis and a lower incidence of β-cell apoptosis maintain the regenerative capacity of the endocrine pancreas. Interestingly, our data provide evidence that local production of IGFs seems to be instrumental in these processes. In particular, increased pancreatic IGF-2 in undernourished rats may contribute to the partial suppression of the developmental wave of β-cell apoptosis probably through the inhibition of glycogen synthase kinase-3. In addition, decreased pancreatic levels of IGFBP-1/-2/-3 in undernourished neonates could enhance IGF availability for interacting with IGF-1R/IR.

scholarly journals Selective Deletion of Pten in Pancreatic β Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes

2006 ◽  
Vol 26 (7) ◽  
pp. 2772-2781 ◽  
Author(s):  
Bangyan L. Stiles ◽  
Christine Kuralwalla-Martinez ◽  
Wei Guo ◽  
Caroline Gregorian ◽  
Ying Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass ◽  
Pten Loss ◽  
Lipid Phosphatase ◽  
Streptozotocin Induced Diabetes ◽  
Phosphatase And Tensin Homologue

ABSTRACT Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing β cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of β-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total β-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in β cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for β-cell protection and regeneration therapies.

In Vivo Cell Transformation: Neogenesis of Beta Cells from Pancreatic Ductal Cells

1995 ◽  
Vol 4 (4) ◽  
pp. 371-383 ◽  
Author(s):  
Lawrence Rosenberg
Keyword(s):  
Endocrine Cell ◽  
Islet Cell ◽  
Cell Transformation ◽  
Islet Cells ◽  
Cell Mass ◽  
Postnatal Period ◽  
Islet Neogenesis ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

During embryogenesis, islet cells differentiate from primitive duct-like cells. This process leads to the formation of islets in the mesenchyme adjacent to the ducts. In the postnatal period, any further expansion of the pancreatic endocrine cell mass will manifest itself either by a limited proliferation of the existing islet cells, or by a reiteration of ontogenetic development. It is the latter, cell transformation by a process of differentiation from a multipotential cell, that will be referred to in this review as islet neogenesis. To better appreciate the mechanisms underlying islet cell neogenesis, some of the basic concepts of developmental biology will be reviewed. Considerable discussion is devoted to the subject of transdifferentiation, a change in a cell or in its progeny from one differentiated phenotype to another, where the change includes both morphological and functional phenotypic markers. While in vitro studies with fetal and neonatal pancreata strongly suggest that new islet tissue is derived from ductal epithelium, what is not established is whether the primary cell is a committed endocrine cell or duct-like cell capable of transdifferentiation. Next, research in the field of β-cell neogenesis is surveyed, in preparation for the examination of whether there is a physiological means of inducing islet cell regeneration, and whether the new islet mass will function in a regulated manner to reverse or stabilize a diabetic state? Our belief is that the pancreas retains the ability to regenerate a functioning islet cell mass in the postnatal period, and that the process of cell transformation leading to islet neogenesis is mediated by growth factors that are intrinsic to the gland. Furthermore, it is our contention that these factors act directly or indirectly on a multipotential cell, probably associated with the ductular epithelium, to induce endocrine cell differentiation. In other words, new islet formation in the postnatal period reiterates the normal ontogeny of islet cell development. These ideas will be fully developed in a discussion of the Partial Duct Obstruction (PDO) Model.

scholarly journals Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

2010 ◽  
Vol 42 (9) ◽  
pp. 628 ◽  
Author(s):  
Mi-Young Song ◽  
Gil-Saeng Jeong ◽  
Kang-Beom Kwon ◽  
Sun-O Ka ◽  
Hyun-Young Jang ◽  
...  
Keyword(s):  
Cell Damage ◽  
Β Cell ◽  
Streptozotocin Induced Diabetes

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

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4782-4793 ◽  
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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