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

Several lines of evidence suggest that autoimmune processes are involved in the pathogenesis of Type I diabetes mellitus. Monocyte-macrophages are among the first mononuclear cells to invade the islets of Langerhans in various murine diabetic syndromes, and blockade of monocyte-macrophage functions by injection of silica particles in these animals prevents the development of the disease. Monokines such as interleukin 1 (IL-1) are known to mediate tissue lesions by inducing collagenase and prostaglandin E2 (PGE2) production. In addition, IL-1 has been demonstrated to inhibit proinsulin biosynthesis and secretion in pancreatic islet cells. Using 3-d cultured rat islets we have found that (a) the lowering of insulin release induced by human recombinant IL-1 (rIL-1) is dose-dependent with a decrease to 21% of control value at the higher rIL-1 tested concentration (500 pg/ml), and about two times more pronounced than the decrease in cellular insulin content, which reached 44% of control value at the highest rIL-1 concentration; (b) rIL-1 stimulates islets to secrete PGE2 but the addition of indomethacin, which blocks PGE2 production, does not affect the decrease in insulin release and content caused by IL-1, suggesting a limited role of endogenous PGE2 as a mediator in this system; and (c) a specific, noncytotoxic IL-1 inhibitor, shown in other cell systems to block the binding of IL-1 to its receptor, prevents the rIL-1 lowering of insulin content and minimizes the decrease of insulin release.
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PMID:A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets. 252 7

The author describes his findings pertaining to spontaneous diabetes mellitus in BB rats and the method and results in juvenile alloxan diabetes in neonatal and adolescent Wistar rats of his own inbreeding F8-10. The author presents also the results of attempts to treat juvenile alloxan diabetes in rats by intrafamilial renal-subscapular allotransplants of 2-5 neonatal collagenase nondigested pancreases. Six of eleven BB females developed latent or manifest insulin dependent diabetes mellitus during the third to fourth month of life. An intraperitoneal injection of alloxan to 2-5-day-old rats causes, after two months of prediabetes, latent or manifest disease, in particular in males. In one-two-month adolescent fasting F6--10 inbred rats (Wistar strain) intravenous injection of 50 mg/kg alloxan causes diabetes mellitus with hyperglycaemia (20-60 mmol/l), glycosuria, polyuria, arrested growth, development of cataract and early death due to pulmonary or intestinal infection. The author tries to prevent these sequelae and complications by insulin therapy or intrafamilial allotransplantations of 2-5 neonatal, collagenase nondigested pancreases beneath the renal capsule, using two-three--week immunosuppression with Cyclosporin A combined with Azathioprine. The author proves permanent cure, histologically and functionally, by repeated allotransplantation which, however, due to the intense thymolymphatic immunological barrier in adolescent rats is less frequent than cure repeatedly achieved by the author in adult diabetic rats.
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PMID:[Spontaneous and experimental models of human juvenile diabetes mellitus]. 275 53

A quantitative method to measure islet cell surface antibodies in human patients has been developed using 125I-protein A. Isolated, dispersed, viable rat islet cells prepared by collagenase digestion were fixed in 4% paraformaldehyde to allow storage for up to 7 wk at 4 degrees C. Human sera, heat inactivated and adsorbed with rat liver and kidney powder (100 mg/ml), were incubated with the fixed cells (50 x 10(3)) for 60 min at 37 degrees C. Thereafter the cells were washed and exposed to 5 x 10(5) cpm 125I-protein A, which binds to IgG attached to the cell surface. Assay precision (14%) and reproducibility (16%) were established by repeated analysis of pooled sera from healthy individuals and IDDM patients using pooled batches of islet cells. Using this method, islet cell surface antibodies were detected in 35% of insulin-dependent diabetic patients.
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PMID:Quantitative determination of islet cell surface antibodies using 125I-protein A. 634 Nov 29

The aim of this study was to develop techniques to obtain monodispersed, human islet cells in large quantities, since these constitute a potentially transplantable beta cell mass with which to treat established type 1 diabetes, as well as provide the most appropriate substrate for studying the immune pathogenesis of the disease. Human islets were isolated from the pancreas of beating-heart organ donors by collagenase digestion. Enzymatic (collagenase types II, IV, V, and XI, trypsin, DNAse, and hyaluronidase) and chemical (EDTA and EGTA) conditions were then used to find the optimum requirements for digestion of intact human islets into their constituent cells. The combination of trypsin with EDTA provided the highest yield of monodispersed islet cells (963 cells/islet) and highest viability (88%). DNAse with EGTA gave high yields (710 cells/islet) but viability was low (55%). Lower yields and viability were obtained using collagenase types II, IV, V, and XI (47-243 cells/islet; viability 45-62%), hyaluronidase (410 cells/islet; 75% viability), and EDTA alone (253 cells/islet; viability 43%). Human islet cells monodispersed using trypsin 0.125 mg/ml in 0.1 mM EDTA retained an insulin secretory response to glucose, and had intact surface class I MHC molecules when analyzed immediately after digestion by flow cytofluorimetry. Our results indicate that functionally intact, single, human islet cells may be obtained in abundance, and provide a potential substrate for islet cell transplantation in the treatment of patients with type 1 diabetes.
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PMID:Development of techniques for obtaining monodispersed human islet cells. 750 87

Excessive production and deposition of extracellular matrix proteins are characteristic features of diabetic nephropathy. This study tests the hypothesis that cells from diabetic patients who develop nephropathy have a disturbance in collagen metabolism compared with cells from diabetic patients without complications. Kinetics of overall collagen metabolism and total protein synthesis were examined in serially passaged, subconfluent, quiescent skin fibroblasts cultured in either normal (5 mM) or high (25 mM) glucose concentrations from 14 insulin-dependent diabetic (IDDM) patients with nephropathy; 14 IDDM patients without nephropathy matched for age, diabetes duration, and body mass index; and 14 healthy subjects. Fibroblasts were incubated in the presence of 2 microCi/ml [3H]proline, and after labeling the incorporation of [3H]proline into total protein, collagen (collagenase-sensitive material), and noncollagen proteins (collagenase-resistant material) was determined at different time points. Collagen degradation was determined in pulse-chase experiments by following the residual collagen-bound radioactivity after incubation for 8 h with 10 microCi/ml [3H]proline. In high glucose concentrations (25 mM), overall collagen synthesis (measured as [3H]proline incorporation into extracellular and intracellular collagenase-sensitive material) was significantly greater in the patients with nephropathy (mean +/- SEM after a 24-h labeling period: 7189 +/- 671 dpm/10(6) cells) than in the patients without (4341 +/- 267 dpm/10(6) cells; P < 0.01) or healthy control subjects (3836 +/- 234 dpm/10(6) cells; P < 0.01). No significant differences were observed in noncollagen protein production or in collagen degradation rates among the three groups of subjects. In the presence of normal glucose concentrations (5 mM), collagen synthesis was lower in all groups studied, but the differences between IDDM patients with nephropathy and those without remained unaltered. These results suggest that long-term cultured fibroblasts derived from diabetic patients with nephropathy exhibit an abnormality in collagen metabolism. Cells from long-standing diabetic patients without nephropathy have normal collagen metabolism. The increased collagen synthesis is likely to be intrinsic to those diabetic patients susceptible to nephropathy and may play an important role in the sclerotic processes that occur in the kidneys, arteries, and heart.
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PMID:Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy. 921 63

A reasonable interpretation of the present evidence indicates that diabetes, when a complication of periodontitis, acts as a modifying and aggravating factor in the severity of periodontal infection. Diabetics with periodontitis who were young and poorly controlled, those who were long-duration diabetics, especially those over 30 years old, demonstrated more attachment loss, bone loss, and deeper probing pocket depths than their nondiabetic controls. It seems that the earlier the onset of diabetes and the longer the duration, especially without consistent control, the more susceptible the individual will be to periodontal disease. Consequently, once a diabetic contracts periodontal disease, it is usually more destructive. Although plaque scores of diabetics may be comparable to or even less than those of nondiabetics, diabetics often exhibit higher gingival index scores. The elevation of this particular clinical parameter is indicative of the microangiopathy associated with diabetes. Diabetic microangiopathy contributes to compromised delivery of nutrients to surrounding tissues and poor elimination of metabolic waste products. The complications associated with diabetes such as macroangiopathy, microangiopathy (i.e., retinopathy), ketoacidosis, and hyperglycemia result in impaired wound healing, immunosuppression, and susceptibility to bacterial infection. Individuals ages 30 to 40 suffering from diabetic retinopathy had significantly more gingival inflammation than controls or diabetics without complications. Collagen metabolism is defective in diabetics and is one component underlying delayed wound healing. Animal studies have been instrumental in elucidating the details of delayed wound healing. Hyperglycemia was associated with increased collagenase and protease activity in the gingiva of rats. Vascular wound healing in rats, particularly new re-endothelialization across vascular anastomoses, was significantly impaired. Diabetic abnormalities in immune response include impaired neutrophil chemotaxis, phagocytosis, and adhesion. Decreased neutrophilic chemotactic response seems to be attributable to protein factors in diabetic serum that competitively bind neutrophil receptors, thereby preventing complement-mediated phagocytosis. Because diabetics are not able to eliminate circulating immune complexes (CIC) effectively, serum CIC levels are elevated. There are microbiological differences in the characteristic flora of NIDDM patients and IDDM patients with periodontitis. These differences are not associated with diabetic impaired immune response. Ultimately, bacterial plaque is the primary etiology of periodontal diseases. Evidently, the host's response to bacterial plaque and ability to heal following surgery is altered by diabetic disease. Therefore, a thorough history regarding onset of diabetes, duration, and diabetic control would prove useful in the clinical management of diabetics presenting for treatment of periodontal disease.
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PMID:Periodontal disease, diabetes, and immune response: a review of current concepts. 947 64

The enormous variability of donor factors and organ procurement related variables prevent a constant isolation success, thus reducing the potential number of clinical islet transplants. Since the availability of intact and viable pancreatic donor tissue intended for islet transplantation is limited, the porcine pancreas was selected as a potential source of xenogeneic islets for human recipients. The differences of islet histomorphology between porcine and human pancreas result in a higher intrinsic fragility of porcine islets during collagenase digestion. Nevertheless, if the isolation method is modified to inhibit factors potentially toxic to pig islets, reproducibility of isolation success is higher in the pig as in the human due to a lower variability in donor characteristics and the opportunity of preselection in regard to age and race. If xenograft rejection can be overcome and the risk of xenosis can be minimized, the logistic prerequisites for xenotransplantation of large amounts of viable pig islets into human recipients with insulin dependent diabetes are fulfilled.
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PMID:[Isolation of islands of Langerhans from human and porcine pancreas for transplantation to humans]. 974 81

The fetal porcine pancreas under experimental conditions can be transplanted in the form of explants or islet-like cell clusters (ICCs) to normalize blood glucose levels in diabetic recipients. ICCs are released from the collagenase-digested pancreas and require a 4- to 5-day culture period for their complete formation. In order to maximize insulin producing beta cell differentiation following transplantation, an understanding of ICC development is essential to utilize this alternative treatment for type 1 diabetes. In this study a role is proposed for exocrine cells in the generation of the multipotent pancreatic precursor cells during the culture period. Acinar cells undergo dedifferentiation during the initial stages of the culture period into multipotent pancreatic precursor cells, previously called protodifferentiated cells. The progressive loss of exocrine differentiation appears to involve rapid degranulation of zymogen granules by exocytosis and loss of the prominent secretory apparatus. These processes occur in parallel with a significant reduction in the expression of lipase in the period from day 0 to day 5 and simultaneously there is an increase in the epithelioid/ductal cell marker, cytokeratin 20. Using proliferating cell nuclear antigen, cell proliferation during the culture period does not appear to account for the increase in epithelioid/ductal cells. Further the rates of apoptosis and necrosis which were identified using the TUNEL technique and propidium iodide, respectively, do not appear to account for the reduction in exocrine cell numbers. Exocrine cell dedifferentiation appears to increase the pool of protodifferentiated cells which have the potential to develop into the insulin-producing beta-cell population following transplantation into the diabetic recipient
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PMID:In vitro dedifferentiation of fetal porcine pancreatic tissue prior to transplantation as islet-like cell clusters. 1117 1

New hope for the treatment of type 1 diabetes has recently emerged from the encouraging results of islet cell transplantation in humans during the last few years. Although still facing considerable problems, the challenge to achieving insulin independence has been overcome in some patients who received an islet graft. However, the success of clinical trials is still limited by the inability to transplant enough viable human islets to compensate for the insulin-deficient state, the number of islets that engraft following transplantation, the rejection process, and the recurrence of autoimmunity. The important advances in immunosuppressive regimens, organ procurement techniques, isolation techniques, and availability of defined collagenase blends have contributed to the continuing promise of making islet cell transplantation the treatment of choice for type 1 diabetes mellitus.
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PMID:Human islet transplantation: update. 1134 2

Recent progress in human islet transplantation demonstrates the feasibility of using purified human islets for treatment of type 1 diabetes mellitus; however, a shortage of human pancreata remains a major obstacle. This report describes methods to isolate porcine islets using a modification of the automated chamber method. The pancreata from 2-year-old sows were trimmed and injected intraductally with Sevac, Sigma, or Liberase PI collagenase. The pancreata was placed in the chamber, shaken, and recirculated at 70 ml/min until an adequate number of islets were liberated. The digest was centrifuged and the pellets pooled with University of Wisconsin Solution + 10% horse serum and incubated at 4 degrees C for 1 h. The islets were purified using a continuous gradient of Hypaque Euroficoll on a refrigerated COBE 2991. The islets were collected in fractions, assessed for purity, sized, and then suspended in Medium 199. Collagenase preparations obtained from Sevac (2919 islet equivalents [IE]/g), Sigma (2543 IE/g), and Liberase PI (2901 IE/g) gave similar results with 94%-95% purity. In summary, we report a successful method for efficient isolation and purification of porcine islets, yielding nearly 3000 IE/gm, with different collagenase products.
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PMID:Improved methods for the isolation and purification of porcine islets. 1142 81


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