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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ex vivo expansion of human beta-cells is an important step toward the development of cell-based insulin delivery systems in type 1 diabetes. Here, we report that human pancreatic endocrine cells can be expanded through 15 cell doublings in vitro for an estimated total 30,000-fold increase in cell number. We believe that the cells resulting from these cultures are of beta-cell origin, since they uniformly express the transcription factor PDX-1 (STF-1, IDX-1, IPF-1), which is initially seen only in cells positive for insulin and negative for the ductal cell marker cytokeratin (CK)-19. To rule out the possibility that PDX-1 expression might be induced by the culture conditions used here, cells from isolated human pancreatic ducts were cultured under the same conditions as the islet cells. Cells in these cultures expressed CK-19 but not PDX-1. Although the expanded beta-cells continued to express PDX-1, insulin expression was lost over time. Whether reexpression of islet-specific genes in vitro is essential for successful cell transplantation remains to be determined.
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PMID:Sustained proliferation of PDX-1+ cells derived from human islets. 1033 5

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.
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PMID:Monogenic diabetes mellitus in youth. The MODY syndromes. 1060 19

Cell therapy offers today important perspectives for the treatment of type 1 diabetes. The current utilization of primary human islets of Langerhans nevertheless forbids all hope of developing this treatment on a large scale. The recent description of the persistence of stem cells capable of proliferating and differentiating in the adult pancreas offers an attractive alternative for the production in vitro of homologous insulin-secreting cells. We first reproduced in vitro from human islet preparations the proliferation of ductal epithelial structures and their progressive organization. Thereafter, we focused on the description of a reproducible source of human ductal cells by the transdifferentiation of exocrine preparations. More recently we described in these exocrine derived ductal cells the the expression the of insulin promoter factor-1 (IPF-1/otherwise known as PDX-1), a transcription factor essential for the differentiation of ductal cells into endocrine cells during both development and pancreatic regeneration. If the proliferation and differentiation of these cells is confirmed, this approach could lead to the description of an abundant source of human pancreatic stem cells for the production ex vivo of human insulin secreting cells and may even allow autologous cell therapy, in the absence of immunosuppression.
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PMID:[Human pancreatic stem cell and diabetes cell therapy]. 1147 Dec 51

This text describes, in an epistemological perspective, the development of the concept of cellular therapy applied to the treatment of type 1 diabetes. Emphasis is put on three recent papers describing the success of islet allograft in diabetic patients, the development of neo-islets from stem cells isolated from the pancreas of adult mice, and the effect of hepatic cell transfection with an adenovirus bearing the gene coding for PDX-1, a transcription factor involved in the maturation of islets of Langerhans. This text tries to delineate some factors which may be involved in the chances for these techniques to reach the real world of human therapeutics.
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PMID:[Towards a cell therapy for diabetes? An epistemiological perspective]. 1153 May 7

Glucagon-like peptide-1 (GLP-1), an intestinal gut hormone, is rapidly emerging as a new therapeutic agent for the treatment of diabetes mellitus. GLP-1, released from intestinal L-cells, is renowned for its potent stimulation of insulin biosynthesis and release from pancreatic b-cells. Exogenous administration of GLP-1 to subjects with type 2 diabetes results in the normalization of plasma glucose concentrations, in part, as a result of augmented glucose-stimulated insulin secretion. However, it is now recognized that GLP-1 has several other anti-diabetic actions that collectively improve the type 2 diabetic phenotype, and may also prove beneficial in the treatment of type 1 diabetes. These effects include the deceleration of gastric emptying and promotion of satiety, thereby reducing the availability of nutrients for absorption and reducing the requirement for insulin secretion. GLP-1 also reduces plasma glucose levels by suppressing glucagon secretion from pancreatic a-cells and potentially by improving insulin sensitivity in peripheral tissues. Further-more, GLP-1 upregulates expression of b-cell genes (GLUT2, glucokinase, insulin, and PDX-1) and promotes b-cell neogenesis and differentiation of ductal cells into insulin secreting cells. Although initial clinical trials indicate GLP-1 has excellent therapeutic potential, its relatively short-lived biological activity and delivery difficulties limit its appeal. Several approaches that are currently being explored to overcome these limitations include mobilizing endogenous GLP-1 release, preserving the biological activity of the native peptide, and developing GLP-1 analogues with extended durations of action.
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PMID:The multifaceted potential of glucagon-like peptide-1 as a therapeutic agent. 1196 1

Several lines of evidence suggest that the aetio-pathogenesis of the common form of type 2 diabetes mellitus and its intrinsically related features of impaired insulin secretion and decreased insulin sensitivity (insulin resistance) includes a strong genetic component. At present, however, little is known about the nature of this genetic component although familial clustering of the disease has been described for decades. Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. Pathophysiological models of insulin resistance in skeletal muscles and impaired glucose-induced insulin secretion in the beta-cells have formed a basis for selecting candidate genes with potential influence on the development of type 2 diabetes ("diabetogenes"). This process of selecting and analyzing genes for mutations that potentially associate with either type 2 diabetes mellitus, insulin resistance or impaired insulin secretion is often described as the "candidate gene approach". The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). Twelve of the genes that encode proteins in the insulin-signalling pathway from the insulin receptor through the phosphatidylinositide-regulated kinases down to the complex of phosphatases that regulate glycogen synthesis in skeletal muscle were analyzed. We could not confirm that a Val985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. Reviewed in context of the existing data our studies support the candidate gene approach as a feasible method for directly either identifying or excluding any gene as a diabetes-susceptibility gene ("diabetogene").
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PMID:Candidate genes and late-onset type 2 diabetes mellitus. Susceptibility genes or common polymorphisms? 1469 50

Maturity onset diabetes of the young (MODY) is characterized by youth-onset diabetes that is inherited in an autosomal dominant (monogenic) pattern. Classic MODY accounts for less than 5% of cases of childhood diabetes in Caucasians, presents prior to age 25 years, is nonketotic, and may not require insulin treatment. A variant form of MODY that lacks a clearly defined genetic basis occurs in African Americans [atypical diabetes mellitus (ADM)] clinically presents more acutely and is initially insulin requiring. To date, five molecular causes of classic MODY have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 alpha; MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha; MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta; MODY5). MODY is studied as a model of beta cell hypofunction and modest insulinopenia. Clinical recognition of ADM is important for patient management to avoid confusion with type 1 diabetes mellitus.
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PMID:Molecular and biochemical analysis of the MODY syndromes. 1501 34

Efforts toward routine islet cell transplantation as a means for reversing type 1 diabetes have been hampered by islet availability as well as allograft rejection. In vitro transdifferentiation of mouse bone marrow (BM)-derived stem (mBMDS) cells into insulin-producing cells could provide an abundant source of autologous cells for this procedure. For this study, we isolated and characterized single cell-derived stem cell lines obtained from mouse BM. In vitro differentiation of these mBMDS cells resulted in populations meeting a number of criteria set forth to define functional insulin-producing cells. Specifically, the mBMDS cells expressed multiple genes related to pancreatic beta-cell development and function (insulin I and II, Glut2, glucose kinase, islet amyloid polypeptide, nestin, pancreatic duodenal homeobox-1 [PDX-1], and Pax6). Insulin and C-peptide production was identified by immunocytochemistry and confirmed by electron microscopy. In vitro studies involving glucose stimulation identified glucose-stimulated insulin release. Finally, these mBMDS cells transplanted into streptozotocin-induced diabetic mice imparted reversal of hyperglycemia and improved metabolic profiles in response to intraperitoneal glucose tolerance testing. These results indicate that mouse BM harbors cells capable of in vitro transdifferentiating into functional insulin-producing cells and support efforts to derive such cells in humans as a means to alleviate limitations surrounding islet cell transplantation.
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PMID:In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. 1522 Jan 96

IL-1beta is an important mediator in the pathogenesis of type 1 diabetes both in vivo and in vitro and it has been shown to induce islet beta-cell apoptosis. Most of the IL-1beta effects seem to be mediated by NF-kappaB transcription factor activation, but its role in the induction of islet beta-cell apoptosis has not yet been clarified. Taking advantage of the protease inhibitor TPCK (N-tosyl-L-phenylalanine chloromethyl ketone), which specifically inhibits the nuclear transcription factor NF-kappaB activation, we studied the role of NF-kappaB in the rIL-1beta treated rat pancreatic islets. Our results show that TPCK blocked rIL-1beta-mediated early increase of MnSOD activity and beta-cell defence/repair protein expression, suggesting a protective role for NF-kappaB at the beginning of IL-1beta treatment; but, in a second phase, NF-kappaB induces a sustained decrease of specific beta-cell proteins like insulin, GLUT-2 and PDX-1 with a concomitant increase of aspecific proteins and iNOS transcription. The appearance of iNOS expression correlates with increased levels of nitrite + nitrate levels and appearance of mitochondrial damage detected either at morphological and biochemical level. After 36 h of IL-1beta treatment islet beta-cells begin to undergo apoptosis. Since IL-1beta induction of apoptosis is completely prevented by TCPK treatment, this finding underscores the central role of NF-kappaB in this process. Thus, our results clearly indicate that NF-kappaB regulates MnSOD genes expression and MnSOD activity, which protects islet beta-cells by IL-1beta damage. Furthermore, when the IL-1beta stress impairs islet beta-cell function, NF-kappaB activation regulates the entrance of islet beta-cell into the cell death program.
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PMID:A biphasic role of nuclear transcription factor (NF)-kappaB in the islet beta-cell apoptosis induced by interleukin (IL)-1beta. 1562 24

beta-Cell replacement therapy via islet transplantation is a promising possibility for the optimal treatment of type 1 diabetes; however, such an approach is severely limited by the shortage of donor organs. This problem could be overcome if it were possible to generate transplantable islets from stem cells. We showed previously that adult beta-cells might originate from duct or duct-associated cells. Ductal progenitor cells in the pancreas would become particularly useful for therapies that target beta-cell replacement in diabetic patients, because duct cell types are abundantly available in the pancreas of these patients and in donor organs. In this study, we examined which embryonic transcription factors in adult mouse and human duct cells could efficiently induce their differentiation into insulin-expressing cells. Infection with the adenovirus expressing PDX-1, Ngn3, NeuroD, or Pax4 induced the insulin gene expression. NeuroD was the most effective inducer of insulin expression in primary duct cells. Surprisingly, adenovirus Pax4 strongly induced Ngn3 expression, while Pax4 is considered the downstream target of Ngn3. These data suggest that the overexpression of transcription factors, especially NeuroD, facilitates pancreatic stem/progenitor cell differentiation into insulin-producing cells.
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PMID:Induction of pancreatic stem/progenitor cells into insulin-producing cells by adenoviral-mediated gene transfer technology. 1729 98


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