Function and Survival of Macroencapsulated Syngeneic Islets Transplanted Into Streptozocin-Diabetic Mice1

Suzuki, Kazuhisa; Bonner-Weir, Susan; Trivedi, Nitin; Yoon, Kun‐Ho; Hollister-Lock, Jennifer; Colton, Clark K.; Weir, Gordon C.

doi:10.1097/00007890-199807150-00004

Cited by 77 publications

(45 citation statements)

References 25 publications

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“…We noted a similar phenomenon with transplanted encapsulated mouse islets several years ago, finding that an identical number of islets either cured or did not cure diabetic mouse recipients with there being no middle ground (25). In the present Px study, a slight variation in the proportion of pancreas removed may have been responsible for the rats initially having a full range of blood glucose levels from low to middle and high values.…”

Section: ␤-Cell Abnormalities Worsen With Duration Of Hyperglycemiasupporting

confidence: 72%

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Laybutt¹,

Glandt

et al. 2003

Journal of Biological Chemistry

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143

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We have proposed that hyperglycemia-induced dedifferentiation of ␤-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. ␤-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1␣), ␤-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC␤, and sarcoplasmic reticulum Ca 2؉ -ATPase 3). Conversely, genes normally suppressed in ␤-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce ␤-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of ␤-cell phenotype with decreased expression of ␤-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the ␤-cell phenotype found in diabetes.Pancreatic ␤-cells maintain specialized pathways of metabolism that efficiently couple the secretion of insulin to circulating glucose levels (1, 2). With the increased demand of insulin resistance and obesity, an adaptation in ␤-cell mass and secretion can keep glucose levels within a narrow range (3-5). The failure of ␤-cells to adequately adapt to increased demand is fundamental to the pathogenesis of all forms of diabetes. We have hypothesized that abnormal ␤-cell function in diabetes is due to the loss of the unique expression pattern of genes that optimize glucose-induced insulin secretion (GIIS) 1 and insulin synthesis (5).The development of the endocrine pancreas and the maintenance of ␤-cell differentiation is regulated by a network of transcription factors, which includes pancreatic and duodenal homeob...

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Section: ␤-Cell Abnormalities Worsen With Duration Of Hyperglycemiasupporting

confidence: 72%

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Laybutt¹,

Glandt

et al. 2003

Journal of Biological Chemistry

Self Cite

143

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“…Various types of bioartificial pancreas have been proposed and developed, including islet micro-or macroencapsulation (5,6). In the present study, a device, constituted of rat pancreatic islets seeded on the pancreatic acellular matrix (AM) and incapsulated into a PVA/PEG semi-permeable membrane, was developed.…”

Section: Discussionmentioning

confidence: 99%

“…Improving culture techniques and strategies to enhance the in vitro expansion rate of ß-cells, extend in vitro islet cell maintenance and increase survival of grafted cells is essential. Several efforts have focused on the development of a bioartificial pancreas, in which transplanted pancreatic islets are integrated into synthetic, semipermeable membrane (4)(5)(6)(7)(8)(9). However, so far, only a few approaches meet the technical or physiological requirements for application in human beings.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic acellular matrix supports islet survival and function in a synthetic tubular device: In vitro and in vivo studies

Carlo

Baiguera²,

Conconi³

et al. 2009

Int J Mol Med

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Abstract. Increasing pancreatic islet survival and function is a starting point for obtaining a valuable bioartificial pancreas for the treatment of type 1 diabetes. In this context, decellularized matrices, obtained after the removal of tissue cellular part, are known to support in vitro adhesion, growth, and function of several cell types. We demonstrate that a homologous acellular pancreatic matrix is a suitable scaffold for rat islet cultures maintaining their long-term viability and function. Islets adhered to the pancreatic matrix showed a constant glucose-induced insulin release during long-term in vitro incubation, while islets cultured without a matrix or on the liver matrix showed a progressive reduction. In order to obtain implantable devices, acellular matrix/islet cultures were entrapped into poly(vinyl alcohol) (PVA)/ poly(ethylene glycol) (PEG) tubes obtained by the freezing/thawing procedure. Under this condition, an in vitro constant insulin release was detected. The devices were then implanted into diabetic rats where reduced insulin requirement was noted suggesting insulin secretory activity of islets contained in the device. Indeed, immunofluorescence confirmed the presence of insulin-and glucagon-producing cells into the explanted devices. These data show that PVA/PEG semi-permeable membrane can obtain devices that restore, at least in part, insulin secretion.

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“…Capsule fibrosis was the most significant problem encountered when utilizing alginate capsules [23,[49][50][51]. Theoretically, immune isolation is achieved by encapsulation of the cells, but some levels of immune rejection and foreign body response still occur.…”

Section: +mentioning

confidence: 99%

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

Alexander¹,

Nguyen²,

Flores³

et al. 2017

Challenges in Pancreatic Pathology

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Islet transplantation, with the advent of the Edmonton protocol in 2000, has offered a significant alternative for long-lasting treatment of type 1 diabetes. However, the immunosuppression required for transplantation has the cytotoxic effect on pancreatic islets, and thus limiting the long-term efficacy of the transplant. Immediate loss of islets after transplant was also observed because of immediate blood-mediated inflammatory response (IBMIR), which kills islets transplanted in the liver through portal vein. There is also commonly a lack of microvascular blood supply to the transplanted islets. In this chapter, we will review the variety of technologies used to protect transplanted islets against toxicity of immunosuppression, immune rejection, and inflammatory response. We will evaluate the mechanisms of these technologies and their progress in solving the challenges to islet transplantation. The technologies include encapsulation of transplanted islets in various polymers, transplants in sites other than the liver, and creation of new prevascularized transplant site. These technologies offer several mechanisms to prevent immune rejection or immediate contact with cytotoxic inflammatory response, in addition to maintaining islet integrity. New transplant sites are also being developed to support the islets, by allowing establishment of microvasculature and innervation, prior to addition of the islets.

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Function and Survival of Macroencapsulated Syngeneic Islets Transplanted Into Streptozocin-Diabetic Mice1

Cited by 77 publications

References 25 publications

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Pancreatic acellular matrix supports islet survival and function in a synthetic tubular device: In vitro and in vivo studies

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

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