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

We previously reported that nonspecific immunomodulations with a streptococcal preparation (OK-432), an inducer of tumor necrosis factor (TNF), or with recombinant TNF prevented development of insulin-dependent diabetes mellitus (IDDM) in animal models (NOD mice and BB rats). Recently we have further reported that lymphotoxin (LT), a cytokine with functional and structural characteristics similar to those of TNF, also protected NOD mice from diabetes. In this study, we have extended our observation on the LT to BB rats. Male and female BB/Wor rats were treated intraperitoneally with recombinant human LT three times a week from 4 to 11 weeks of age. The cumulative incidence of diabetes by 14 weeks of age was 24/30 (80.0%) in nontreated control rats, whereas it was 10/26 (38.5% vs control, P < 0.01) and 4/29 (13.8% vs control, P < 0.0001) in the rats treated with 1 x 10(3) and 1 x 10(4) of LT, respectively. There was no significant difference in nonfasting blood glucose levels and body weights between nontreated control and LT-treated rats, which were nondiabetic. In the LT-treated rats, intensity of insulitis was significantly reduced in comparison with the nontreated rats. Concanavalin A-stimulated TNF/LT productivity of spleen cells was significantly lower in BB/Wor and BB/Sendai rats than in Wistar rats or other normal rat strains. On the other hand, there was no difference between BB/Sendai and Wistar rats in the in vivo TNF/LT productivity induced with LPS or with IFN-gamma plus LPS, and the TNF/LT productivity of these rats was lower on stimulation with LPS alone, but higher with IFN-gamma plus LPS than the other normal rats. These results indicate that treatment with LT, as well as TNF, modulated autoimmunity and prevented development of IDDM in BB/Wor rats which may be low producers of TNF/LT.
 ...
PMID:Prevention of type I diabetes with lymphotoxin in BB rats. 824 3

As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.
 ...
PMID:Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. 827 42

Chronic exposure of fully differentiated 3T3-L1 adipocytes to 50 microM arachidonic acid (AA) resulted in an inhibition (approximately 91%) in cellular GLUT4 mRNA content after a 48-h exposure, without similarly affecting the mRNA content of the ubiquitous glucose transporter, GLUT1. Subsequent investigations revealed that transcription of the GLUT4 gene was reduced by approximately 50% in response to AA treatment and the half-life of GLUT4 mRNA decreased from 8.0 to 4.6 h. By contrast, AA increased the accumulation of GLUT1 mRNA by 65%, by a mechanism that also involved regulation at both transcriptional and mRNA stability levels. Western blot analysis revealed that AA was specifically reducing the insulin-responsive glucose transporter (GLUT4) in both plasma and intracellular membranes. Subsequently, AA was observed to alter the ability of the GLUT4 transporter to respond to insulin and mediate a significant enhancement of glucose uptake. The results presented in this study indicate that AA can partially mimic the effects of both tumor necrosis factor-alpha and insulin which, when chronically supplied to 3T3-L1 adipocytes, also down-regulate GLUT4 gene expression. Therefore, these data may have relevance to the insulin-resistance associated with non-insulin-dependent diabetes mellitus.
 ...
PMID:Arachidonic acid down-regulates the insulin-dependent glucose transporter gene (GLUT4) in 3T3-L1 adipocytes by inhibiting transcription and enhancing mRNA turnover. 827 64

Insulin, carboxypeptidase-H (CP-H), and glutamate decarboxylase (GAD) have been identified as potential autoantigens in insulin-dependent diabetes mellitus (IDDM). Previous studies have described immunoreactive insulin as a surface molecule on the plasma membrane of rat islet cells and suggested that cell-surface insulin was derived during exocytosis by the fusion of insulin secretory granules with the beta-cell plasma membrane. These findings predict that insulin and other secretory granule-derived proteins such as the putative autoantigen CP-H may be colocalized with insulin at specific sites of exocytosis on the beta-cell surface. In studies to test this hypothesis, cell-surface staining of dispersed rat islet cells occurred in a granule-like pattern with antibodies for CP-H and insulin. The specificity of the CP-H antiserum was confirmed by immunoblotting and indicated that the antiserum was essentially monospecific for CP-H. Confocal laser microscopy confirmed that immunoreactive staining for CP-H and insulin was confined to the beta-cell surface. Colocalization of CP-H and insulin on the cell surface of beta-cells was demonstrated by double staining with antibodies to CP-H and insulin, and the percentage of beta-cells positive for both of these autoantigens increased twofold with increases in insulin secretion. In contrast, islet cells failed to reveal cell-surface staining for GAD65, another putative autoantigen in IDDM, under either basal or insulin stimulatory conditions or following exposure of islet cells to the cytokines interleukin-1 beta, tumor necrosis factor-alpha, and recombinant human interferon-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Mar
PMID:Potential autoantigens in IDDM. Expression of carboxypeptidase-H and insulin but not glutamate decarboxylase on the beta-cell surface. 831 14

The in vitro production of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by monocytes was examined in patients with insulin-dependent diabetes mellitus (IDDM), in those with noninsulin-dependent diabetes mellitus (NIDDM), and in healthy volunteers. The production of IL-1 and IL-6 by monocytes was significantly lower in IDDM patients than in NIDDM patients and normal subjects whereas the TNF-alpha production by monocytes did not differ between IDDM patients and normal subjects. On the other hand, the TNF-alpha production was significantly higher in NIDDM patients than in IDDM patients and normal subjects. There was a significant correlation between IL-1 and IL-6 concentrations in culture supernatants of monocytes for IDDM patients but not for NIDDM patients and normal subjects. Neither glucose nor insulin showed any stimulatory effect on in vitro production of these monokines. In the serial observation lasting 3-18 months, the monocyte production of IL-1 was found to be consistently reduced in IDDM patients unrelated to the control state of diabetes, suggesting that the reduction of the IL-1 and IL-6 production by monocytes in IDDM patients may be intrinsically affected by immunological defects.
 ...
PMID:In vitro production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha in insulin-dependent diabetes mellitus. 840 55

The effect of in vivo administration of exogenous tumor necrosis factor-alpha on the survival of rat islet xenografts in STZ-induced diabetic mice was examined. Daily subcutaneous injections of purified recombinant murine TNF-alpha (3 micrograms/day) for 7 days after transplantation of islets prolonged the survival of the xenografts (26.7 +/- 4.9 days) compared with controls (11.2 +/- 1.1 days). Extension of the treatment from 0 to 59 days after transplantation produced an even greater prolongation of graft survival (53.7 +/- 8.5 days). After cessation of treatment, an accelerated rejection of the grafts occurred. A most interesting finding was that delaying initiation of treatment until 3 days after transplantation and continuing until 60 days produced a remarkable prolongation of xenograft survival (mean survival time > 89.8 +/- 17.5 days) with 2 recipients still normoglycemic at 124 days. Removal of the grafts at this time returned the 2 mice to a diabetic state. A second islet transplant from the same donor rat strain (Wistar-Furth) had an accelerated rejection, indicating that the long-term survival of the xenografts was not because of induction of tolerance. Delaying initiation of TNF treatment until 6 days after transplantation produced only a slight prolongation of survival (17.5 +/- 1.2 days). Prolongation of islet xenograft survival also was obtained by continuous, subcutaneous delivery of TNF-alpha by a 7-day mini-osmotic pump (3 micrograms/day). Lower daily doses of TNF-alpha (0.003, 0.3, and 1.0 micrograms) had no effect on graft survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 May
PMID:Tumor necrosis factor-alpha prevents rejection of islet xenografts (rat to mouse). 848 22

The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibroblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (> 1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.
 ...
PMID:Long-term reversal of diabetes by the injection of immunoprotected islets. 851 35

Previous studies have indicated that rodents are relatively resistant to diet-induced obesity and that this resistance may be mediated in part by the capacity for diet-induced thermogenesis in brown adipose tissue (BAT). To test this hypothesis, we fed UCP-DTA transgenic with toxigene-mediated ablation of BAT and their control littermates a "Western diet" [21% (wt/wt) fat] or normal mouse chow [6.5% (wt/wt) fat]. The diets were begun at weaning (19 days old). At the age of 12 weeks, transgenic mice receiving the Western diet were markedly obese. The increased body weight and total body lipid content were significantly greater in transgenic mice receiving the Western diet than were the additive individual effects of Western diet (in control mice) and decreased BAT (in chow-fed mice), suggesting a synergistic interaction between diminished BAT and diet. A synergistic effect of Western diet and BAT ablation was also observed for morbid metabolic complications, such as insulin resistance, hyperglycemia, and hyperlipidemia. These metabolic changes were accompanied by increased expression of tumor necrosis factor-alpha and decreased expression of GLUT4 and beta 3-adrenergic receptor messenger RNA levels in white adipose tissue of UCP-DTA transgenic mice receiving the Western diet compared to those in the other experimental groups. As previously described, transgenic mice with diminished brown fat are hyperphagic. Of note, the degree of hyperphagia in transgenics compared to controls was similar whether the animals were fed chow or a Western diet. Thus, the synergistic effect of Western diet on obesity in transgenic mice was not mediated by a further stimulation of food intake. Overall, this study demonstrates the existence of a synergistic interaction between decreased BAT and Western diet to cause marked obesity and its accompanying disorders, such as insulin resistance and hyperlipidemia, and gives further support for the view that an important function of BAT is protection from diet-induced obesity, diabetes, and insulin resistance.
 ...
PMID:Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. 853 14

Nitric oxide has been implicated as one possible mediator of interleukin-1 beta (IL-1)-induced inhibition of insulin secretion and islet cell damage. The aim of this study was to define the effects of tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) on nitric oxide production, insulin secretion, and DNA damage in islets from unweaned rats. Treatment of islets with 0.5-500 U/ml of either TNF or IFN on their own inhibited glucose-stimulated insulin secretion in a dose-dependent manner (minimum effective dose 5 U/ml). In combination, the cytokines exerted a pronounced synergistic inhibitory effect on secretion and were equipotent at causing a significant and concentration-dependent increase in culture medium nitrite levels, islet cyclic GMP formation, and DNA damage. Used alone or in combination, TNF and IFN significantly enhanced the activity of inducible nitric oxide synthase as determined by measuring the conversion of 14C-labeled arginine to 14C-labeled citrulline and nitric oxide. Use of arginine-free medium, without or with NG-monomethyl-L-arginine, resulted in inhibition of nitrite formation by 5-1,000 U/ml IFN+TNF and partial restoration of the insulin secretory response to glucose. Treatment of rat islets with increasing doses of TNF+IFN (5, 50, and 500 U/ml) resulted in a progressive increase in DNA damage, as shown by the comet assay, which detects DNA strand breaks in individual islet cells. The DNA damage caused by an intermediate concentration (50 U/ml) of TNF+IFN was comparable to that generated by IL-1 when used at 20 U/ml. We conclude that TNF and IFN induce nitric oxide formation, which partially inhibits glucose-induced insulin secretion and causes significant DNA strand breakage, but that as cytokine concentrations increase, non-nitric-oxide-mediated events predominate.
Diabetes 1996 Feb
PMID:Tumor necrosis factor-alpha and interferon-gamma inhibit insulin secretion and cause DNA damage in unweaned-rat islets. Extent of nitric oxide involvement. 854 63

Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1 alpha (mrIL-1 alpha) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1 alpha (12.5 and 50 micrograms/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1 alpha lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1 alpha had no influence on insulin levels in females, but significantly increased them in males (P < 0.0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1 alpha on insulin secretion. Corticosterone secretion was stimulated by mrIL-1 alpha in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1 alpha in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1 alpha is administered to adrenalectomized animals or when mrIL-1 alpha is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1 alpha, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2.5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance.
 ...
PMID:Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage. 856 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>