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)

To define the mechanism of vitamin A action at the beta-cell level, we tested for the presence of messenger RNA for retinoic acid receptors alpha, beta, and gamma; cytosolic retinol-binding protein; and cytosolic retinoic acid-binding protein in RINm5F cells, an insulin-secreting cell line, and determined whether cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein are present in isolated purified normal rat beta-cells. Northern blot analyses showed two transcripts of retinoic acid receptor alpha messenger RNA (3.8 and 2.4 kb), one transcript of retinoic acid receptor messenger RNA (3.8 kb), and one transcript of cytosolic retinol-binding protein (0.9 kb) in RINm5F cells. Ribonuclease protection assays also showed the presence of cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein in RINm5F cells. Quantitatively, cytosolic retinol-binding protein levels were 0.10 +/- 0.02 pg/micrograms total RNA. Using specific radioimmunoassays, normal isolated purified rat beta-cells contained CRBP (19.2 +/- 2.38) and cytosolic retinoic acid-binding protein (16 +/- 0.53 ng/10(6) cells). The presence of message for retinoic acid receptors alpha and gamma, cytosolic retinol-binding protein, cytosolic retinoic acid-binding protein, and the gene products of cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein in insulin-secreting cells support a mechanism of vitamin A action and role for cytosolic and nuclear receptors at the beta-cell level similar to that suggested in nonendocrine cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Aug
PMID:Retinoic acid receptor, cytosolic retinol-binding and retinoic acid-binding protein mRNA transcripts and proteins in rat insulin-secreting cells. 839 9

There has been some evidence suggesting an important role of mononuclear cells at bone remodeling sites in the coupling of bone formation to bone resorption. Since cells of the monocyte-macrophage lineage produce important local regulators of bone remodeling, we examined effects of human monocytes-conditioned medium (CM) treated with retinoic acid on [3H] thymidine incorporation (TdR) and alkaline phosphatase (ALP) activity of osteoblastic MC3T3-E1 cells. Treatment of MC3T3-E1 cells with retinoic acid (10(-8) to 10(-6) M) caused an inhibition of TdR in a dose-dependent manner and an inhibition of ALP activity at 10(-6) M. Conditioned medium from monocytes untreated with retinoic acid caused a stimulation of TdR and an inhibition of ALP activity in these cells. In contrast, treatment of monocytes with retinoic acid (10(-8) or 10(-6) M) abolished both stimulation of DNA synthesis and inhibition of ALP activity induced by CM. The present study suggested that retinoic acid modulated osteoblast proliferation and ALP activity not only directly but also indirectly, presumably through modulating the release of local regulators as to bone remodeling from monocytes.
Exp Clin Endocrinol Diabetes 1995
PMID:Effect of retinoic acid on the proliferation and alkaline phosphatase activity of osteoblastic MC3T3-E1 cells by modulating the release of local regulators from monocytes. 853 58

BB/Wor rats develop autoimmune diabetes mellitus with many features in common with human insulin-dependent diabetes mellitus. Since retinoids are known to have effects on insulin secretion and immune function, these studies were designed to investigate the effects of retinoid deficiency on diabetes in BB/Wor rats and to identify a role for retinoid status in the pathogenesis of autoimmune diabetes mellitus. Litters of diabetes-prone (DP) and diabetes-resistant (DR) BB/Wor rats were divided at weaning and fed a diet either (1) devoid of retinoids and leading to clinical deficiency at approximately 60 days of age (A-def diet)-following 10 days of clinical deficiency, rats on the A-def diet were changed to a diet containing 2 microg/g retinoic (A-def/RA diet); (2) containing 2 microg/g retinoic acid but deficient in retinol (RA diet); or (3) replete in retinol with 4 microg/g retinyl palmitate (RP diet). Rats receiving RP or RA diets were pair-fed to rats on the A-def/RA diet. Diabetes by 120 days of age was greatly reduced (P < .01) in DP rats that received the A-def/RA diet (four of 27) or RA diet (four of 29) versus the RP diet (13 of 31). Insulitis progressed with age in nondiabetic DP rats receiving the RP diet (P < .02) or RA diet (P < .05), but not the A-def/RA diet (P > .22). Insulin secretion was measured in perfused pancreas of nondiabetic rats after age 120 days and correlated negatively with insulitis (P < .05). DP rats receiving the RP diet had reduced insulin secretion as compared with other DP and DR rats (P < .05). In DR rats, retinoid status had no effects on insulitis through 120 days of age or on insulin secretion after 120 days of age. In conclusion, retinol deficiency reduces diabetes and insulitis in DP BB/Wor rats, and retinoic acid can at least partly substitute for retinol in the development of insulitis.
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PMID:Vitamin A status affects the development of diabetes and insulitis in BB rats. 859 98

To investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17-83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6%) than in the active ALDH2 group (19.2%) (p < 0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p < 0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding.
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PMID:Association of aldehyde dehydrogenase with inheritance of NIDDM. 887 97

Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2-/- animals failed to express in adipose tissue tumor necrosis factor-alpha (TNF-alpha), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-alpha.
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PMID:Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. 891 Feb 78

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP), retinoic acid, and glucocorticoids stimulate transcription of the PEPCK gene, whereas insulin and phorbol esters have a dominant inhibitory effect. We now show that oxidative and chemical stress (hydrogen peroxide and sodium meta-arsenite, respectively) also produce a dominant inhibitory effect, both on the endogenous PEPCK gene and on a stably transfected PEPCK-chloramphenicol acetyl transferase (CAT) fusion gene. Wortmannin, an inhibitor of 1-phosphatidylinositol 3-kinase (PI 3-kinase), blocks the inhibition of glucocorticoid and cAMP-induced PEPCK gene transcription by insulin; however, it has no effect on the inhibition elicited by oxidative or chemical stress. Thus, the mechanism(s) used by hydrogen peroxide and sodium meta-arsenite to regulate PEPCK gene expression are PI 3-kinase independent. This suggests that these agents operate by a pathway distinct from that used by insulin or that the pathways converge at a point downstream of PI 3-kinase. The reactivating kinase (RK, also known as p38 mitogen activated protein kinase) is induced by insulin, hydrogen peroxide, or sodium meta-arsenite in hepatoma cells, and these effects are blocked by SB203580, a selective inhibitor of RK. However, SB203580 has no effect on the ability of any of these agents to regulate PEPCK-CAT fusion gene expression. Thus, although RK has a role in the regulation of lymphokine gene expression in monocytes, it is not required for the regulation of PEPCK expression by either insulin or oxidative and chemical stress in hepatoma cells.
Diabetes 1997 Jan
PMID:Oxidative and chemical stress mimic insulin by selectively inhibiting the expression of phosphoenolpyruvate carboxykinase in hepatoma cells. 897 Oct 75

Retinoic acids (RA) regulate growth and differentiation of normal epithelial tissue. They have been employed in anticancer treatment and showed positive effects in hematopoetic and various epithelial tumors. Experimental data with follicular thyroid tumor cells showed strong evidence of induction of differentiated cell function and antiproliferative effects. Based on these data a consecutive series of 10 patients with advanced thyroid carcinoma were treated with 13-cis-retinoic acid (Roaccutan) 1.5 mg/kg body weight for six weeks. Follow-up demonstrated renewed uptake of radioiodine in 4 of 10 patients allowing performance of further radioiodine therapy. Reduction in tumor size due to antiproliferative effects of RA could not yet be verified.
Exp Clin Endocrinol Diabetes 1996
PMID:Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: basics and first clinical results. 898 Sep 92

Retinoic acids (RAs), well characterized regulators of proliferation and differentiation, partly re-differentiate follicular thyroid carcinoma cell lines (FTC-133, FTC-238, and HTC-TSHr) as well as SV40-transfected immortalized thyroid cell lines (ori3 and 7751). This is indicated by the stimulation of type I 5'-deiodinase and other differentiation markers. As demonstrated by RT-PCR, electrophoretic mobility shift, and [3H]-retinoic acid binding assays, thyroid carcinoma cell lines express RA receptor mRNAs and functional ligand- and DNA-binding receptor proteins able to mediate RA-dependent signal transduction. Together, these properties make these thyroid-derived cell lines useful in vitro models for studying the effects of an RA re-differentiation therapy of thyroid cancer.
Exp Clin Endocrinol Diabetes 1996
PMID:Effects of retinoids and role of retinoic acid receptors in human thyroid carcinomas and cell lines derived therefrom. 898 Sep 93

We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.
Exp Clin Endocrinol Diabetes 1996
PMID:Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor. 898 Oct 16

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
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PMID:Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. 912 58


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