Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity

Martín-Pagola, Ainhoa; Sisino, Giorgia; Allende, Gloria; Domínguez‐Bendala, Juan; Gianani, Roberto; Reijonen, Helena; Nepom, Gerald T.; Ricordi, Camillo; Ruiz, Philip; Sageshima, Junichiro; Ciancio, Gaetano; Burke, George W.; Pugliese, Alberto

doi:10.1007/s00125-008-1105-x

Cited by 58 publications

(43 citation statements)

References 44 publications

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“…Histological examination of the pancreas of these two monkeys showed scattered proinsulin-positive cells, mostly organized as single cells or in small clusters, not associated with glucagon-positive cells, but often to ducts, similar to the ones just recently described (8,20). The frequency of small proinsulin-positive cell aggregates was higher in the monkeys with recovered ␤-cell function than in diabetic controls but lower than in nondiabetic monkeys.…”

Section: Discussionsupporting

confidence: 77%

Recovery of Endogenous β-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation

et al. 2009

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OBJECTIVE— To describe the ability of nonhuman primate endocrine pancreata to reestablish endogenous insulin production after chemical β-cell destruction. RESEARCH DESIGN AND METHODS— Eleven monkeys ( Macaca fascicularis ) were rendered diabetic with streptozotocin. Eight diabetic monkeys received intraportal porcine islet transplantation. RESULTS— Two monkeys transplanted after 75 days of type 1 diabetes showed recovery of endogenous C-peptide production a few weeks after transplantation, concomitant with graft failure. Histological analysis of the pancreas of these monkeys showed insulin-positive cells, single or in small aggregates, scattered in the pancreas and adjacent to ducts. Interestingly, numerous CK19 + cells costained with proinsulin and PDX-1 antibodies. Furthermore, the peculiar double phenotype glucagon-positive/GLUT2 + was observed. In these monkeys as well as in all others, the original islets showed no insulin staining. CONCLUSIONS— Our data provide evidence that, in nonhuman primates, the pancreas can reestablish endogenous insulin production after chemical β-cell destruction. This seems to be a nongeneralizable event with only 2 out of 11 monkeys recovering β-cell function. In these two monkeys, younger age and islet graft behavior might have played a role in triggering endogenous β-cell recovery.

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Section: Discussionsupporting

confidence: 77%

Recovery of Endogenous β-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation

et al. 2009

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“…Although insulin-positive duct cells have been detected in humans in association with pregnancy (18) and pancreatic transplantations (36) and have been considered to be ␤-cells resulting from neogenesis, recent lineage tracing studies have indicated that the presence of insulinpositive duct cells seems to be distinct from the neogenesis in mice (37,38). Therefore, the role of insulin-positive cells embedded within duct cells remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Predominance of β-Cell Neogenesis Rather Than Replication in Humans With an Impaired Glucose Tolerance and Newly Diagnosed Diabetes

Yoneda

Uno²,

Iwahashi³

et al. 2013

The Journal of Clinical Endocrinology &Amp; Metabolism

113

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Context: A decrease in pancreatic ␤-cell mass is involved in the development of type 2 diabetes.Objective: The purpose of this study was to evaluate the ␤-cell mass and the incidence of ␤-cell neogenesis, replication, and apoptosis at both the prediabetic and diabetic stages. Methods:We conducted a cross-sectional study of pancreatic tissues obtained from 42 patients undergoing a pancreatectomy who were classified into 4 groups: normal glucose tolerance (n ϭ 11), impaired glucose tolerance (n ϭ 11), newly diagnosed diabetes (n ϭ 10), and long-standing type 2 diabetes (n ϭ 10). Results:The relative ␤-cell area decreased and the ␤-cell apoptosis increased during the development of diabetes. The number of single and clustered ␤-cells, some of which coexpressed nestin, increased in the patients with impaired glucose tolerance and newly diagnosed diabetes. The prevalence of cells positive for both insulin and glucagon or somatostatin also increased in these patients compared with those with normal glucose tolerance. These double-positive cells were mainly localized in single and clustered ␤-cells, rather than large islets, and were also positive for Pdx1 or Ngn3. The percentage of insulin-positive cells embedded within ducts increased in the impaired glucose tolerance group. There were no significant differences in the incidence of cells positive for both insulin and Ki67 among the groups. Conclusions:These results suggest that ␤-cell neogenesis, rather than replication, predominates during impaired glucose tolerance and newly diagnosed diabetes in humans and may serve as a compensatory mechanism for the decreased ␤-cell mass.

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“…In contrast, SPK patients who were normoglycaemic and without β-cell loss, although with clear evidence of ongoing autoimmunity, rarely had cells amongst the ductal cells that stained positive for insulin and Pdx1. Thus, the presence of both hyperglycaemia and autoimmunity may be important for triggering insulin expression in ductal cells [36]. Transplantation models confirmed the differentiation capacity of purified human pancreatic ductal cells from young donors less than 10 years, as evidenced by a low portion of single or small cluster of insulin-positive cells which were also CK19+ and were in close connection with ductal epithelia [37].…”

mentioning

confidence: 67%

β‐Cell differentiation and regeneration in type 1 diabetes

Ding

Gysemans

Mathieu

2013

Diabetes Obesity Metabolism

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Pancreatic insulin-producing β-cells have traditionally been viewed as a quiescent cell population. However, several recent lines of evidence indicated that like most tissues the β-cell mass is dynamically regulated with ongoing β-cell regeneration throughout life to replenish lost or damaged β-cells. In type 1 diabetes (T1D), this fine-tuned balance between β-cell death and β-cell renewal in the endocrine pancreas is lost and the deficit in β-cell mass is largely caused by autoimmune-mediated apoptosis. Currently, the concept that a cure for T1D will require both re-establishment of immunological tolerance along with replacement or regeneration of a functional β-cell mass in T1D patients is generally accepted. In this study our current understanding of the events directing β-cell replication, β-cell reprogramming from different cell types and β-cell regeneration is reviewed, in view of the results of various immunomodulatory strategies aiming at blocking autoimmune responses against pancreatic β-cells and at improving β-cell mass and function in subjects with T1D. Keywords: β-cells, regeneration, reprogramming, replication, type 1 diabetes Date submitted 21 March 2013; date of final acceptance 24 April 2013 IntroductionDiabetes mellitus is an epidemic around the globe that affects nearly 6% of the world's adult population with almost 80% of the totality in undeveloped territories. The World Health Organization estimates that the number of diabetics will increase from 366 million in 2011 to 552 million by 2030 (http://www.idf.org/media-events/pressreleases/2011/diabetes-atlas-5th-edition). Of all diagnosed cases of diabetes, type 1 diabetes (T1D) that results from a selective destruction of the pancreatic insulin-producing β-cells by CD4+ and CD8+ T cells recognizing many islet auto-antigens, accounts for 5-10% [1]. Although its onset is usually during infancy and puberty, it can occur at any age, even during late adulthood. By the time of diagnosis, about 70-80% of the β-cell mass is lost or damaged largely because of β-cell apoptosis. As a result, exogenous insulin supplementation is needed to promote tight glucose control and diminish the majority of chronic diabetic complications. However, insulin is not a cure for this chronic disease. Currently, it is generally accepted that a cure for overt T1D will require shutting off autoimmunity along with replenishment or stimulating regeneration of a functional β-cell mass in T1D subjects in order to improve blood glucose without treatment-derived adverse effects. However, at present it is unknown whether the existing immunotherapies that are able to restore normal glucose homeostasis in the preclinical and clinical setting of T1D act via β-cell regeneration (by β-cell replication, β-cell neogenesis from progenitors or by β-cell reprogramming/transdifferentiation from acinar-or α-cells)Correspondence to: Conny Gysemans, PhD, Laboratory of Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Katholieke Universiteit Leuven (KU LEUVEN), Herestraat 4...

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Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity

Cited by 58 publications

References 44 publications

Recovery of Endogenous β-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation

Recovery of Endogenous β-Cell Function in Nonhuman Primates After Chemical Diabetes Induction and Islet Transplantation

Predominance of β-Cell Neogenesis Rather Than Replication in Humans With an Impaired Glucose Tolerance and Newly Diagnosed Diabetes

β‐Cell differentiation and regeneration in type 1 diabetes

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