Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental diabetes in rodents has been successfully treated by implantation of isolated islets using a syngenic system (Lewis rats). It is possible to reverse all diabetic symptoms of the animals and to prevent late complications in kidney, eye and nervous system. Although isolated islets are highly immunogenic in an allogenic system immuno-alteration techniques have been developed and succeeded in longterm survival after culture at low temperature (24 degrees C), UV-irradiation, cryopreservation, pretreatment with Ia-antibodies etc. Islet transplantation in larger animals and in man up to now has been less successful. Although in a few studies longterm survival of canine islets has been observed, other groups were less successful using dogs and pigs in auto- or allo-transplantation. In man there are reports from various institutions during the last fifteen years using adult or fetal islet material. Only in a few instances the patients came off insulin for some weeks or months. The reasons for this failure are probably manifold: low number of islets, impurity, long ischemia time before isolation, transplantation to inappropriate sites, impairment of engraftment in longterm diabetic recipients and recurrence of autoimmunity in transplanted islets. Further studies are necessary to overcome these barriers. Recent observations using a higher number of islets (> 500,000) and new immunosuppressive drugs (FK506) seem to be promising.
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PMID:Islet transplantation: clinical and experimental. 149 Jun 85

This report provides our initial experience in islet isolation and intrahepatic allotransplantation in 21 patients. In group 1, 10 patients underwent combined liver-islet allotransplantation following upper-abdominal exenteration for cancer. In group 2, 4 patients received a combined liver-islet allograft for cirrhosis and diabetes. One patients had plasma C-peptide greater than 3 pM and was therefore excluded from analysis. In group 3, 7 patients received 8 combined cadaveric kidney-islet grafts (one retransplant) for end-stage renal disease secondary to type 1 diabetes mellitus. The islets were separated by a modification of the automated method for human islet isolation and the preparation were infused into the portal vein. Immunosuppression was with FK506 (group 1) plus steroids (groups 2 and 3). Six patients in group 1 did not require insulin treatment for 5 to greater than 16 months. In groups 2 and 3 none of the patients became insulin-independent, although decreased insulin requirement and stabilization of diabetes were observed. Our results indicate that rejection is still a major factor limiting the clinical application of islet transplantation in patients with type 1 diabetes mellitus, although other factors such as steroid treatment may contribute to deteriorate islet engraftment and/or function.
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PMID:Human islet isolation and allotransplantation in 22 consecutive cases. 173 36

Delayed administration of tetrandrine, a novel broad-spectrum anti-inflammatory agent, to BB rats at a dosage schedule of 20 mg kg-1 day-1 from 79 days of age reduced the cumulative incidence of diabetes from 73.1 to 41.7% (p < 0.01). Brief treatment with the potent immunosuppressive agent FK506 at a dosage schedule of 0.5 mg kg-1 day-1 from 79 days of age for 5 days had no significant effect on the cumulative incidence of diabetes (66.7%, p > 0.1). However, the combination of tetrandrine and FK506 in the afore-mentioned dosage schedules reduced the incidence of diabetes to only 3.6% (p < 0.001). These results suggest that the strong synergy between tetrandrine and FK506 may offer a safe and effective therapeutic strategy for the treatment of patients with recent onset or imminent IDDM.
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PMID:Synergy between tetrandrine and FK506 in prevention of diabetes in BB rats. 750 74

Pancreatic islet transplantation may be the most ideal treatment for patients with insulin-dependent diabetes mellitus. However, immunosuppressive agents such as cyclosporine A(CsA) and FK506, used for these transplanted patients have been reported to cause glucose intolerance. In the present study, we have compared the effects of CsA and FK506 on glucose-stimulated insulin release from the isolated dog pancreatic islets, which have been maintained in culture for 3 days after isolation. The isolated dog pancreatic islets, pretreated for 24 hr with either CsA or FK506 (1, 10, and 100 nM), were perifused with 16.7 mM glucose. Pretreatment with both drugs suppressed glucose-stimulated insulin secretion in a dose-dependent fashion. CsA (100 nM), which is a therapeutically relevant concentration, significantly suppressed both the first and second phases of glucose-stimulated insulin release compared with 100 nM FK506. These findings suggest that, with a therapeutically relevant concentration, FK506 may be less toxic than CsA against pancreatic islets in patients with organ or cell transplantation.
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PMID:Effects of FK506 and cyclosporine on dynamic insulin secretion from isolated dog pancreatic islets. 750 54

In order to evaluate the effect of cyclosporine (CsA) versus FK506 on glucose and lipid metabolism, an oral glucose tolerance test (OGTT) was performed in 101 patients after orthotopic liver transplantation (OLT) (mean interval after OLT: 511 days). The liver graft recipients had been randomized prospectively to two groups prior to OLT to receive either immunosuppression with CsA, azathioprine, and corticosteroids (CsA group) or FK506 and corticosteroids (FK group). Along with the OGTT, serum insulin, insulin C-peptide and glucagon as well as serum lipids were monitored. There was no statistically significant difference in the occurrence of impaired glucose tolerance (IGT) or manifest diabetes mellitus disease between the two groups. In fact, not a single patient developed new-onset diabetes in any group. In male and female patients, serum levels of cholesterol and triglycerides increased significantly under FK506 and CsA treatment after OLT. Cholesterol was significantly higher in the CsA group in men, in women this was marked, but not significant. While triglycerides were significantly higher in women on CsA treatment, there was no such difference in men. In conclusion, both CsA and FK506 proved to have similar effects on glucose metabolism, while there was a different spectrum of serum lipid alterations.
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PMID:The effect of FK506 versus cyclosporine on glucose and lipid metabolism--a randomized trial. 752 3

Diabetes mellitus was induced in 40 male C57BL6 mice by injection of a low dose of streptozocin (45 mg/kg body weight) on 5 consecutive days. Twenty four of the mice were immunosuppressed by administration of 1.5 mg FK506/kg body weight daily for 10, 15, 18 and 24 days. Administration of FK506 almost completely inhibited the streptozocin-induced islet damage, and consequently glycaemia remained normal. In FK506-treated animals any inflammatory infiltrate was very sparse and was limited to the vascular pole of the islets. Immunocytochemical results demonstrated that infiltrating cells were Ia-immunoreactive, but were not activated. Ultrastructural observations confirmed the absence of B cell necrosis and degranulation in FK506-treated mice; the few infiltrating elements encountered did not contain phagocytic vesicles or show other signs of activation.
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PMID:The immunosuppressant FK506 inhibits the damage to mouse pancreatic islets induced by low dose streptozocin. 752 68

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8 +/- 13.7 years (range 17.6-78). The mean donor age was 34.0 +/- 20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 +/- 8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22 +/- 4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P = ns compared with double therapy), and a one-year actual graft survival of 82% (P < 0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P < .07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8 +/- 0.8 mg/dl. The mean BUN was 33 +/- 21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192 +/- 49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus--14%; new-onset diabetes--16% (half of which was reversible); and posttransplant lymphoproliferative disorder--1%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A prospective randomized trial of FK506-based immunosuppression after renal transplantation. 753 43

We studied seven nondiabetic subjects with the autoimmune diseases psoriasis, multiple sclerosis, and primary biliary sclerosis who were to receive FK506 as experimental immunotherapy. All subjects underwent two standard oral glucose tolerance tests and two 180-min hyperglycemic clamps immediately before and 10 weeks after starting FK506. There was no significant difference in weight or HbA1c pre- vs. post-FK506 treatment. FK506 levels were therapeutic and non-toxic (0.1-1 ng/ml) for all subjects studied. Repeated measures analysis of variance for interaction between time and treatment was performed on insulin (after outlier removed) and glucose values from the OGTT. There was neither time-by-treatment interaction, nor a treatment effect (P > 0.1). There were no significant differences in pre- vs. post-FK506 treatment values of plasma glucose during the hyperglycemic clamp mean acute insulin response to glucose (AIRG) 164 +/- 38 pmol/L vs. 148 +/- 46 pmol/L (P > 0.1); mean incremental area under the insulin curve (IAUC) during the first 10 min of the study, 473 +/- 109 pmol/L vs. 443 +/- 146 pmol/L (P > 0.1); total area under the insulin curve (TAUC) during the first 10 min of the study, 786 +/- 152 pmol/L vs. 781 +/- 18 pmol/L (P > 0.1); mean glucose infusion rate (GIR) 37.7 +/- 5.0 mumol/kg/min vs. 33.3 +/- 4.4 mumol/kg/min (P > 0.1); or mean insulin sensitivity index (ISI), 3.05 +/- 0.4 vs. 3.13 +/- 0.5 (P > 0.1). Mean steady-state insulin secretion (SSI) was significantly lower 244 +/- 43 pmol/L vs. 200 +/- 25.2 pmol/L (P = 0.03). Peak first-phase insulin secretion values of 321 +/- 62 pmol/L vs. 263 +/- 57 pmol/L approached significance (P = 0.07). No patient progressed to diabetes during the study. FK506 decreased steady-state insulin secretion during the last 60 min of the clamp, regardless of initial glucose tolerance. Insulin sensitivity and glucose infusion rate did not change in the group as a whole with FK506 treatment.
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PMID:The effect of FK506 on glycemic response as assessed by the hyperglycemic clamp technique. 754 15

Immunosuppression is currently used for allotransplantation, and is being evaluated for the treatment of insulin-dependent diabetes mellitus and other autoimmune diseases. However, most available agents have a number of side effects that limit their use in clinical situations. It has been shown previously, for example, that cyclosporine may inhibit insulin release from islet tumor cells and rat islets. We have studied the effects of an analog of a newer agent (FK506) termed L-683,590 on insulin secretion by an islet tumor line, beta TC3, and rat islets, and compared the effects of this drug to those of cyclosporine, since both cause similar immunosuppression. L-683,590 and cyclosporine inhibited insulin release by beta TC3 cells by about 50% and 80%, respectively, at doses that inhibit lymphokine production by T cells. The inhibition by L-683,590 and cyclosporine was more pronounced at higher glucose levels, and was not simply attributable to a general toxic effect of the drugs on the cells. Insulin release during long-term (> 48 hr) cultures of isolated rat islets was also inhibited by the drugs. However, there was no effect of either agent on insulin release by islets during the first 4 hr following a glucose stimulus. Both drugs caused reduced levels of insulin mRNA (by 56 +/- 8.1% and 66 +/- 16% in the presence of L-683,590 and cyclosporine, respectively), accounting for reduced rates of insulin biosynthesis that were also seen. Our studies indicate that: (1) both cyclosporine and L-683,590 inhibit insulin release by beta TC3 cells and cultured rat islets after 48 hr (cyclosporine is a more potent inhibitor); (2) neither drug inhibits the release of insulin during the first 4 hr following a glucose stimulus; and (3) their mechanisms of action appear to be similar--both drugs cause reduced levels of insulin mRNA. Although the toxicity of FK506 on human islets in vivo is still unknown, it may be of particular importance in individuals with impaired beta cell function, such as patients with new-onset insulin-dependent diabetes or patients with non-insulin-dependent diabetes mellitus.
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PMID:Inhibition of glucose-stimulated insulin release from beta TC3 cells and rodent islets by an analog of FK506. 767 56

We investigated the preventive effect of the immunosuppressive agent FK506 on autoimmune insulitis in nonobese diabetic mice. The mice were given FK506 in a dose of 1.0 mg/kg, every other day, from age 2 to 12, 2 to 6, and 4 to 12 weeks, respectively; after which, the incidence of insulitis and overt diabetes was monitored. Effects of FK506 on immune reactions to beta cells were also investigated by using both syngeneic and allogeneic islet transplants. Treatment with FK506 in mice from age 2 weeks prevented completely the onset of overt diabetes, and the incidence of insulitis was reduced to less than 10% at age 30 weeks. Treatment of mice with FK506 from age 4 weeks was less effective in preventing insulitis and the onset of diabetes. In case of islet transplantation, FK506 treatment of NOD mice from age 2 to 6 weeks prevented autoimmune responses both in syngeneic islets and in allogeneic islets, which share the same H-2 antigen with the nonobese diabetic mouse. These results also indicate that the recognition of islet antigens and the generation of autoimmune-reactive T lymphocytes start between 2 and 4 weeks of age, and FK506 prevents an autoimmune reaction.
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PMID:Prevention of insulitis and diabetes in nonobese diabetic mice by administration of FK506. 768 40


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