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)

The effects of medroxyprogesterone acetate (MPA) and proligestone (PROL) on the hypothalamic-pituitary-adrenocortical axis and glucose homeostasis were studied in two groups of eight ovariohysterectomized beagle bitches. In addition, the binding characteristics of MPA and PROL for the progesterone and glucocorticoid receptor were investigated. The administration of both progestins resulted in suppression of the hypothalamic-pituitary-adrenal axis. Whereas basal plasma concentrations of adrenocorticotrophic hormone (ACTH) were only moderately affected, the basal plasma concentrations of cortisol and the cortisol:creatinine ratio in urine were significantly decreased after the first administration of both progestins. In the group given MPA the increase of ACTH after stimulation with corticotrophin-releasing hormone (CRH) remained normal but it was suppressed in the group treated with PROL. In both treatment groups the increase of cortisol after stimulation with CRH was lower. After cessation of progestin administration both basal and stimulated plasma ACTH concentrations returned to pretreatment concentrations within a few weeks. In contrast, it took 6 month to restore the basal plasma cortisol concentrations and cortisol:creatinine ratios in urine. Paradoxically, the stimulated cortisol concentrations returned to normal shortly after the cessation. Histological examinations revealed a severe atrophy of the zona fasciculata and reticularis of the adrenal gland in all treated dogs and a steroid-induced hepatopathy in 50% of them. During the first half of the progestin treatment, glucose homeostasis was maintained by increased plasma concentrations of insulin in both groups. After prolonged treatment the response to a glucose load became impaired. None of these parameters improved during the 6 month recovery period. Histological changes in the pancreas, characteristics of diabetes mellitus, were found in two dogs of each group. Most probably, the glucocorticoid action of the progestins is not the sole explanation for the insulin resistance since progestin treatment resulted in a concomitant increase in plasma concentrations of growth hormone which has diabetogenic properties. Experiments in vitro confirmed the strong glucocorticoid component of MPA and PROL. The inhibition constants (Ki) of PROL for both the progesterone receptor (PR) and the glucocorticoid receptor (GR) were approximately then times higher than those of MPA. Nonetheless, the ratios of the Ki for the GR and PR indicated that the specificity of MPA and PROL was only slightly different but considerably smaller than that of progesterone. It is long-term treatment with high doses of these progestins may result in a iatrogenic Cushing's syndrome and diabetes mellitus.
 ...
PMID:Effects of progestin administration on the hypothalamic-pituitary-adrenal axis and glucose homeostasis in dogs. 940 5

Hypothalamic neuropeptide Y containing neurones are overactive and may mediate hyperphagia in insulin-deficient diabetic rats, but the factors stimulating them remain uncertain. To determine the possible role of glucocorticoids, we investigated the effects of the glucocorticoid receptor blocker mifepristone (RU486) on food intake and regional hypothalamic neuropeptide Y concentrations in streptozotocin-diabetic rats. RU486 (30 mg/kg) or corn oil vehicle control was given orally for 3 weeks to diabetic rats. Food intake and neuropeptide Y levels in the hypothalamic arcuate and paraventricular nuclei were increased in untreated diabetic rat groups (P < 0.01), and though RU486 did increase plasma corticosterone levels (P < 0.01) it did not have any effect on either feeding or neuropeptide Y levels (P = NS). These negative findings suggest that glucocorticoids may not be responsible for increasing hypothalamic neuropeptide Y or for hyperphagia in insulin-deficient diabetes.
 ...
PMID:Increased hypothalamic neuropeptide Y concentration or hyperphagia in streptozotocin-diabetic rats are not mediated by glucocorticoids. 953 19

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.
 ...
PMID:Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. 959 73

Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release.
 ...
PMID:Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release. 966 43

Although various types of stress induce thymus atrophy and suppress immune functions, the mechanisms involved are unknown. To test the hypothesis that thymocyte apoptosis plays a role in stress-induced atrophy of the thymus, we studied the effects of starvation and hypoglycemia on the thymus in the rat. Administration of insulin caused marked hypoglycemia, increased the plasma corticosterone level, and induced fragmentation of thymocyte DNA in fasted but not in fed rats. Administration of either glucose or RU486, a glucocorticoid receptor antagonist, inhibited the apoptosis of thymocytes elicited by insulin. Available evidence suggest that insulin-induced hypoglycemia causes thymocyte apoptosis by promoting glucocorticoid secretion from the adrenal gland.
Diabetes Res Clin Pract 1998 Apr
PMID:Insulin-induced hypoglycemia elicits thymocyte apoptosis in the rat. 969 84

This review focuses on experiments in humans examining the regulation of the hypothalamo-pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity of this axis is subject to a pronounced and persistent inhibition resulting in minimum concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement (REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures. Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the same hippocampal network appears to be concurrently involved in the formation of declarative memory. Activation of GR after administration of dexamethasone completely blocked the formation of declarative memory during early sleep, indicating that the inhibition of HPA secretory activity is a necessary prerequisite for this memory process. Dysfunction of the described neuro-endocrine mode of regulation during early sleep is present in patients with Cushing's disease, in patients with severe depression and in aged humans. All of these groups show insufficient inhibition of HPA secretory activity particular prominent during early sleep, and reduced SWS in concert with impairments of declarative memory function. First clinical trials suggest that this trias of symptoms may benefit from intranasal treatment with neuropeptides like vasopressin and growth hormone releasing hormone.
Exp Clin Endocrinol Diabetes 1998
PMID:Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. 971 Mar 53

The inheritance of adiposity and related traits has been investigated in the obese, diabetes-prone KK/HlLt (KK) and the lean, normoglycemic C57BL/6J (B6) mouse strains, their F(1) hybrids, and a large intercross generation. Adiposity index (AI) was defined as the sum of four fat depot weights divided by body weight. Both male and female KK mice were obese, but AI values averaged twofold higher in females than in males. In contrast, B6 females were slightly more lean than males. A genome-wide search revealed several qualitative trait loci (QTLs) affecting AI. The proximal region of Chromosome (Chr) 9 has a large effect on AI, with a much stronger effect in females (lod = 6.3) than in males (lod = 2.7). The data for females fit a model in which a dominant allele from KK increases AI by 30%, with the lod score peak falling between markers D9Mit66 and D9Mit328. This QTL has large effects on inguinal and mesenteric fat pad weights, with smaller effects on gonadal and retroperitoneal fat pads. The region of Chr 9 containing this QTL has extensive homology to human Chr 11q. An X-linked QTL affecting AI was evident in males (lod = 3.77), but not females (lod = 0.7). Exclusion of mesenteric fat from male AI resulted in an increased lod score (lod = 5.0) at 8 cM distal to DXMit166. A suggestive AI QTL (lod = 4.2), differentially affecting males, was localized to Chr 18 near the glucocorticoid receptor locus. A region of Chr 7 had a strong effect on body weight (lod = 6.9), a significant effect on inguinal fat% (lod = 4.4), and a suggestive effect on AI in females (lod = 4.1). Plasma leptin levels were associated with genotypes on Chr 9 (lod = 5.9) and Chr 7 (lod = 4.2). A region of Chr 1 had a suggestive effect on fasted blood glucose (lod = 3.6).
 ...
PMID:Gender-influenced obesity QTLs identified in a cross involving the KK type II diabetes-prone mouse strain. 1050 64

To investigate the effect of medrogestone on bone mineral density (BMD) and bone turnover under conditions of estrogen withdrawal, premenopausal women with endometriosis were treated with goserelin (Zoladex), combined with either placebo (group A, n = 12) or 10 mg medrogestone (Prothil, group B, n = 11) for six months, and followed for an additional six months. Lumbar spine BMD was measured at 0 and 6 month. Markers of bone turnover were serum bone alkaline phosphatase (sBAP) and osteocalcin (sOC) by ELISA, and urinary total pyridinoline (uPYD) and deoxypyridinoline crosslinks (uDPD) by HPLC. Patients in both groups had a similar and significant decrease in BMD after 6 months (4%, p < 0.01). The time course of changes in bone turnover, in contrast, was different in both groups. In group A, crosslink excretion increased from one month onwards, while no changes were seen in group B. In group A, sBAP levels rose during treatment, while in group B, this rise was delayed until treatment was terminated. Additionally, group B showed an initial suppression of sBAP and sOC. In both groups, sOC increased after treatment was discontinued. Medrogestone at 10 mg/d does not prevent lumbar bone loss in premenopausal women under estrogen deprivation. In the medrogestone add back group, the changes in bone turnover are compatible with low turnover bone loss,as ooposed to a state of high turnover seen in the unopposed goserelin group. This effect may be due to glucocorticoid receptor mediated actions of medrogestone on bone.
Exp Clin Endocrinol Diabetes 1999
PMID:Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin. 1054 15

While on the basis of clinical studies glucocorticoids (GC) became the first-line therapy for asthma, the molecular basis of GC action has been extensively studied. Glucocorticoids exert their effects by binding to the glucocorticoid receptor (GR), which then inhibits or increases gene transcription through processes known as transrepression and transactivation, respectively. Transrepression results from the inhibitory interaction between the GR and other transcription factors like AP-1 and NF-kappa B. Since AP-1 and NF-kappa B DNA binding sites have been mapped to the promoter regions of many genes coding for proinflammatory mediators (IL-1, 2, 5, 6, 8, 13, TNF-alpha, RANTES, Eotaxin, GM-CSF, metalloproteinases, ICAM-1 ...), this interaction may be an important aspect of the GC anti-inflammatory properties. Transactivation is mediated through binding of the GC-activated GR to a DNA sequence called glucocorticoid response element (GRE) and may result in some benefits and side effects since GRE has been mapped to the promoter regions of genes coding for lipocortin, beta 2-adrenergic receptor, and for genes involved in the onset of metabolic effects (diabetes, hypokaliemia, hydrosodic retention) and glaucoma. Other molecular mechanisms may also be involved like the binding to the GR to a negative GRE (nGRE), the interaction with the basal transcriptional machinery, and the post transcriptional modulation of mRNA stability. In asthma, the relative importance of each mechanism remains to be studied, but both mechanisms may probably be involved.
 ...
PMID:[Mechanism of action of glucocorticoids in asthma]. 1054 54

Streptozotocin (STZ) -induced diabetic effects were analyzed for glucocorticoid receptor (GR) level and for in vitro activation of GR by specific binding analysis, using [3H]dexamethasone, a synthetic glucocorticoid, and by DNA cellulose and nuclear binding assay, in the liver and kidney of 15- (immature) and 120-day-old (mature) male mice. Comparison of GR level (fmol/mg protein) among the control mice reveals decreased (22-33%) specific binding in the liver and kidney of mature mice compared with immature ones. Scatchard analyses, however, reveal no change in the affinity (K(d)) of receptor at these two ages of mice. STZ-induced diabetes did not alter the level of GR in either of the tissues at both the ages studied. The GR from both the tissues underwent thermal activation, albeit the extent of activation was more pronounced in mature liver compared to immature, with no such difference of activation in the kidney. In diabetic mice, the activation of hepatic GR exhibits reduced DNA cellulose ( approximately 20-23%) and nuclear (24-30%) binding compared to control mice. In contrast, thermal activation of kidney GR does not show marked differences in diabetic mice at either of the ages studied. Cross-mixing experiments (i.e. binding of activated GR from diabetic mice to nuclei of control and vice-versa) performed on the mature liver, indicate receptor specificity. These findings reveal tissue- and age- specific variations in the level of GR that is not influenced under diabetic conditions. However, the activation of hepatic GR is reduced during STZ-induced diabetes that might play a role in controlling glucose homeostasis in diabetic animals.
 ...
PMID:Streptozotocin-induced diabetes and glucocorticoid receptor regulation: tissue- and age-specific variation. 1104 Mar 98


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