Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eighteen cases of invading pituitary adenoma were removed via the approach of transsphenoidal microscopical operation. Among them 4 cases had insulin dependent diabetes. The pituitary adenoma were near-totally removed in 15 cases, partially removed in 3, and 10 cases were treated by supplement radiotherapy postoperatively and 5 cases by oral bromocriptin postoperatively. The average time of follow-up was 3.8 years. There were 3 cases(16.6%) had postoperative recurrence of the tumor which were finally cured by transfrontal craniotomy. The feasibility of the transsphenoidal microscopic approach for the invading pituitaty adenoma was discussed.
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PMID:[Transsphenoidal microscopic removal of invading pituitary adenoma]. 1074 40

Duct cell adenocarcinomas may produce neuroendocrine markers such as pancreatic polypeptide, gastrin and gastrin releasing hormones. A 53 year old patient, with a history of insulin dependent diabetes, was found to have a pancreatic mass which was later pathologically demonstrated to be a duct cell adenocarcinoma. The tumor produced elevated circulating neuroendocrine markers specifically gastrin and pancreatic polypeptides. An 111In Octreotide imaging showed definite uptake of Octreotide by the tumor. The patient was subsequently treated with Somatostatin analog which resulted in the reduction of some of the circulating endocrine markers. The patient had essentially six months of asymptomatic clinical remission but then she relapsed. Octreotide scanning could be useful for selected patients with pathologic diagnosis of duct cell adenocarcinoma, because some tumors may have neuroendocrine features and can be imaged, and might even respond to Somatostatin analog therapy.
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PMID:Pancreatic duct cell carcinoma with positive 111In Octreotide uptake. 1096 25

An i.v. formulation of rubitecan (9-nitrocamptothecin) was evaluated in five human solid tumor xenograft models. Rubitecan in IDD-P, a particulate suspension of the insoluble analog, produced significant tumor growth delay in athymic nude mice bearing A375 melanoma, and MX-1 breast, SKMES non-small-cell lung, Panc-1 pancreatic and HT29 colon carcinomas. The activity of i.v. rubitecan was similar or somewhat superior to those of i.p. regimens with the reference drugs, irinotecan and topotecan. Tumor sensitivity to rubitecan in IDD-P was MX-1>A375>SKMES >Panc-1>HT29. Some complete regression responses were seen with MX-1, A375 and SKMES tumors treated with 2.5 mg/kg on a schedule of two 5-day dosing cycles separated by 2 drug-free days. In nude mice, the MTD of rubitecan in IDD-P lies between 2 and 2.5 mg/kg on this schedule; antitumor efficacy was achieved with doses between 2.5 and 1.25 mg/kg. Dosing with 6.6 mg/kg rubitecan in IDD-P on intermittent schedules (4- or 7-day intervals) was tolerated, but less efficacious, when tested in the A375 model. The good responses obtained with rubitecan in IDD-P suggest it could be used clinically in circumstances where an i.v. formulation offers advantages to oral or aerosol formulations.
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PMID:Preclinical activity of an i.v. formulation of rubitecan in IDD-P against human solid tumor xenografts. 1239 60

The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA-307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF-class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA-307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.
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PMID:TNFA-TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population. 1262 77

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.
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PMID:Diabetic autonomic neuropathy. 1271 21

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet beta-cells activated by TNF-alpha + interferon-gamma. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD.Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27(kip1). Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes.
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PMID:Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice. 1288 12

Cell cycle progression requires the co-ordinated activation of several kinases, some of which are activated upon the binding of a cyclin subunit. At least four of these so-called cyclin-dependent kinases, namely Cdk4, Cdk6, Cdk2 and Cdk1, have specific roles at particular stages of the cell cycle, including passage through the various cell cycle transitions and the response to specific checkpoints. Not surprisingly, most human tumors carry mutations that deregulate at least one of these kinases. To analyze their specific role in vivo, we are generating strains of gene-targeted mice carrying either activated or defective alleles of these Cdks. As an example, Cdk4 expression appears to be expendable in most cell types since mice lacking Cdk4 are viable. Yet, Cdk4 mutant mice are smaller in size and infertile (only partial infertility in males). In addition, Cdk4 defective mice develop insulin dependent diabetes early in life. However, the importance of these Cdks in tumor cell cycles is underscored by the phenotype of knock in mice where the normal Cdk4 gene has been replaced by a Cdk4 R24C (insensitive to INK inhibitors) mutant. These animals develop a wide spectrum of spontaneous tumors and are highly susceptible to specific carcinogenic treatments. These models are being used now to understand how deregulation of these Cdks leads to cancer development and will be a valuable tool to design and validate new therapeutic strategies against tumour development.
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PMID:Driving the cell cycle to cancer. 1290 44

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of tumor cells but not most normal cells. Its roles in normal nontransformed tissues are not clear. To explore the potential roles of TRAIL in type 1 diabetes, we examined the consequences of TRAIL blockade or TRAIL deficiency in two animal models of autoimmune diabetes. In the first model, NOD mice received an injection of a soluble TRAIL receptor to block TRAIL function. This significantly accelerated the diabetes and increased the degree of autoimmune inflammation in both pancreatic islets and salivary glands. The GAD65-specific immune responses were also significantly enhanced in animals that received the soluble TRAIL receptor. In the second model, we treated normal and TRAIL-deficient C57BL/6 mice with multiple low-dose streptozotocin to induce diabetes. We found that both the incidence and the degree of islet inflammation were significantly enhanced in TRAIL-deficient animals. On the basis of these observations, we conclude that TRAIL deficiency accelerates autoimmune diabetes and enhances autoimmune responses.
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PMID:Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes. 1294 66

The concept of therapeutic immune regulation aiming to treat autoimmune diseases has been validated in multiple animal models, yet, the development of strategies for treatment of human autoimmune diseases remains problematic. Main obstacles are the contradictory findings in different model systems, as well as the contrasting functions of regulatory lymphocytes and cytokines. By drawing examples primarily from experimental type 1 diabetes, we propose that regulatory cells and cytokines can be classified according to the baseline at which they operate in healthy individuals and disease states that are not accompanied by severe systemic immune deficiency or skewing. Consequently, deletion or neutralization of regulatory cells or cytokines operative at high levels to maintain systemic homeostasis should constitute a therapeutic strategy for immune enhancement (e.g. tumor- and pathogen-specific immunity), whereas boosting these factors will have limited effects if the therapeutic goal is a downmodulation of immune responses (e.g. autoimmunity). Conversely, regulatory cells and cytokines operative at low homeostatic levels should unfold therapeutic capacities by further embellishment but not additional reduction.
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PMID:Introducing baselines for therapeutic use of regulatory T cells and cytokines in autoimmunity. 1455 38

Type 1 diabetes results from the destruction of insulin-producing pancreatic beta-cells by a beta-cell-specific autoimmune process. Although converting other cell types into insulin-producing cells may compensate for the loss of the beta-cell mass while evading beta-cell-specific T-cell responses, proof-of-principle of this approach in large animal models is lacking. This investigation was initiated to determine whether an insulin-producing human hepatocyte line can control diabetes when transplanted into totally pancreatectomized diabetic pigs. We established a reversibly immortalized human hepatocyte line, YOCK-13, by transferring a human telomerase reverse transcriptase cDNA and a drug-inducible Cre recombinase cassette, followed by cDNA for a modified insulin under the control of the L-type pyruvate kinase (L-PK) promoter. YOCK-13 cells produced small amounts of modified insulin and no detectable endogenous L-PK at low glucose concentrations, whereas they produced large amounts of both modified insulin and L-PK in response to high glucose concentrations. Xenotransplantation of YOCK-13 cells via the portal vein into immunosuppressed, totally pancreatectomized pigs decreased hyperglycemia and prolonged survival without adverse effects such as portal thrombosis, liver necrosis, pulmonary embolism, and tumor development. We suggest that this reversibly immortalized, insulin-secreting human hepatocyte line may overcome the shortage of donor pancreata for islet transplantation into patients with type 1 diabetes.
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PMID:Transplantation of reversibly immortalized insulin-secreting human hepatocytes controls diabetes in pancreatectomized pigs. 1469 4


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