How can we get more beta cells?

Inada, Akira; Bonner-Weir, Susan; Toschi, Elena

doi:10.1007/s11892-006-0018-7

Cited by 8 publications

(6 citation statements)

References 49 publications

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“…The ability of beta cells to undergo mitosis has been demonstrated in rodents [2][3][4]. In response to insulin resistance, beta cells proliferate significantly to compensate for the increased demand for insulin [5,6].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of beta cell growth and function by bone morphogenetic proteins

Bruun¹,

Christensen

Jacobsen

et al. 2014

Diabetologia

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Aims/hypothesis Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the development of diabetes, there is an increase in the expression of inhibitory factors that prevent the beta cells from adapting to the increased need for insulin. We evaluated the effects of bone morphogenetic protein (BMP) 2 and -4 on beta cells. Methods The effects of BMP2 and -4 on beta cell proliferation, apoptosis, gene expression and insulin release were studied in isolated islets of Langerhans from rats, mice and humans. The expression of BMPs was analysed by immunocytochemistry and real-time PCR. The role of endogenous BMP was investigated using a soluble and neutralising form of the BMP receptor 1A.Results BMP2 and -4 were found to inhibit basal as well as growth factor-stimulated proliferation of primary beta cells from rats and mice. Bmp2 and Bmp4 mRNA and protein were expressed in islets and regulated by inflammatory cytokines. Neutralisation of endogenous BMP activity resulted in enhanced proliferation of rodent beta cells. The expression of Id mRNAs was induced by BMP4 in rat and human islets. Finally, glucose-induced insulin secretion was significantly impaired in rodent and human islets pre-treated with BMP4, and inhibition of BMP activity resulted in enhanced insulin release. Conclusions/interpretation These data show that BMP2 and -4 exert inhibitory actions on beta cells in vitro and suggest that BMPs exert regulatory roles of beta cell growth and function.

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Section: Introductionmentioning

confidence: 99%

Inhibition of beta cell growth and function by bone morphogenetic proteins

Bruun¹,

Christensen

Jacobsen

et al. 2014

Diabetologia

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“…The changes observed in the early periods of our juvenile porcine islet culture system closely resemble the budding of islet cells from the ducts and reorganization to form clusters during the process of islet morphogenesis seen both in vitro and in vivo (8,12,23). Bonner-Weir et al among others have reviewed the plasticity of adult pancreatic cells and the ultimate feasibility of in vivo neogenesis (6,20,23). In vitro differentiation of stem/progenitor cells into β-cells is being pursued as an important approach to generate a reliable and replenishable source of β-cells.…”

Section: Discussionmentioning

confidence: 99%

“…The source of the islets remains a primary concern, and isolation from donor pancreata demands resolution of questions concerning the source, supply, and condition of the donor organs. Reliance upon an adequate supply of human organs for this purpose is considered limited, such that alternative sources are actively being sought (6,20).…”

Section: Introductionmentioning

confidence: 99%

Plasticity and Aggregation of Juvenile Porcine Islets in Modified Culture: Preliminary Observations

et al. 2016

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Diabetes is a major health problem worldwide, and there is substantial interest in developing xenogeneic islet transplantation as a potential treatment. The potential to relieve the demand on an inadequate supply of human pancreata is dependent upon the efficiency of techniques for isolating and culturing islets from the source pancreata. Porcine islets are favored for xenotransplantation, but mature pigs (>2 years) present logistic and economic challenges, and young pigs (3-6 months) have not yet proven to be an adequate source. In this study, islets were isolated from 20 juvenile porcine pancreata (~3 months; 25 kg Yorkshire pigs) immediately following procurement or after 24 h of hypothermic machine perfusion (HMP) preservation. The resulting islet preparations were characterized using a battery of tests during culture in silicone rubber membrane flasks. Islet biology assessment included oxygen consumption, insulin secretion, histopathology, and in vivo function. Islet yields were highest from HMP-preserved pancreata (2,242 ± 449 IEQ/g). All preparations comprised a high proportion (>90%) of small islets (<100 μm), and purity was on average 63 ± 6%. Morphologically, islets appeared as clusters on day 0, loosely disaggregated structures at day 1, and transitioned to aggregated structures comprising both exocrine and endocrine cells by day 6. Histopathology confirmed both insulin and glucagon staining in cultures and grafts excised after transplantation in mice. Nuclear staining (Ki-67) confirmed mitotic activity consistent with the observed plasticity of these structures. Metabolic integrity was demonstrated by oxygen consumption rates = 175 ± 16 nmol/min/mg DNA, and physiological function was intact by glucose stimulation after 6-8 days in culture. In vivo function was confirmed with blood glucose control achieved in nearly 50% (8/17) of transplants. Preparation and culture of juvenile porcine islets as a source for islet transplantation require specialized conditions. These immature islets undergo plasticity in culture and form fully functional multicellular structures. Further development of this method for culturing immature porcine islets is expected to generate small pancreatic tissue-derived organoids termed "pancreatites," as a therapeutic product from juvenile pigs for xenotransplantation and diabetes research.

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“…The source of the islets remains a primary concern, and isolation from donor pancreases demands resolution of questions concerning the source, supply, and condition of the donor organs. Reliance upon an adequate supply of human organs for this purpose is considered futile, such that alternative sources are actively been sought (6, 18, 19).…”

Section: Discussionmentioning

confidence: 99%

Islet Isolation from Juvenile Porcine Pancreas after 24-h Hypothermic Machine Perfusion Preservation

et al. 2010

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Pancreas procurement for islet isolation and transplantation is limited by concerns for the detrimental effects of postmortem ischemia. Hypothermic machine perfusion (HMP) preservation technology has had a major impact in circumventing ischemic injury in clinical kidney transplantation and is applied here to the preservation and procurement of viable islets after hypothermic perfusion preservation of porcine pancreata because pigs are now considered the donor species of choice for xenogeneic islet transplantation. Pancreases were surgically removed from young (<6 months) domestic Yorkshire pigs (25-32 kg), either before or after 30 min of warm ischemia time (WIT), and cannulated for perfusion. Each pancreas was assigned to one of six preservation treatment groups: fresh controls-processed immediately (cold ischemia <1 h) (G1, n = 7); static cold storage-flushed with cold UW-Viaspan and stored in UW-Viaspan at 2-4°C for 24 h with no prior WIT (G2, n = 9); HMP perfused on a LifePort machine at 4-6°C and low pressure (10 mmHg) for 24 h with either KPS1 solution (G3, n = 7) or Unisol-UHK (G4, n = 7). Additional treatment groups to evaluate the effects of prior warm ischemia examined islet isolation after 30 min WIT in situ without (G5, n = 6) or with subsequent 24-h HMP with KPS1 (G6, n = 7). The pancreas was intraductally distended with Liberase PI enzyme and normothermically digested. The isolated islets were purified by a continuous density-gradient centrifugation. Perfusion-induced glandular edema was G3 = 138 ± 19%, G4 = 160 ± 16%, and G6 = 127 ± 22%. Islet yield (IEQ/g of pancreas) varied between the groups: G1 = 1,425 ± 610, G2 = 1,002 ± 262, G3 = 2,242 ± 449 (p < 0.05 vs. G2), G4 = 1,901 ± 420 (p < 0.05 vs. G2), G5 = 1,756 ± 329, and G6 = 1,396 ± 243. Islet stimulation indices were equivalent between the groups and similar to controls (G1). Insulin content (ng/IE) was different between the treatment groups with the highest insulin content in islets harvested from HMP pancreata. Dithizone staining for islets consistently showed more uniform digestion of the perfused organs, with greater separation of the tissue, less entrapped islets, and higher islet yield and purity. The salutary effects of HMP for 24 h were also manifest after 30-min prior warm ischemia. We conclude that 24 h of HMP is well tolerated, leading to moderate edema but no loss of function of the harvested islets. The edema appears to aid in enzymatic digestion, producing a greater yield and purity of islets compared with pancreas subjected to 24 h of static cold storage.

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How can we get more beta cells?

Cited by 8 publications

References 49 publications

Inhibition of beta cell growth and function by bone morphogenetic proteins

Inhibition of beta cell growth and function by bone morphogenetic proteins

Plasticity and Aggregation of Juvenile Porcine Islets in Modified Culture: Preliminary Observations

Islet Isolation from Juvenile Porcine Pancreas after 24-h Hypothermic Machine Perfusion Preservation

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