Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liquorice extract has been claimed to induce inhibition of the activity of 11 beta-hydroxysteroid dehydrogenase which converts cortisol to cortisone. This enzyme is thought to protect the mineralocorticoid receptor from being occupied by endogeneous glucocorticoids in the kidney. Based on these hypotheses, we investigated the effect of low-dose glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in eight subjects with NIDDM. The mean serum potassium concentration decreased from 5.3 +/- 0.3 (SD) mEq/1 to 4.9 +/- 0.2 mEq/1 when 15 g of calcium polystyrene sulfonate, a potassium-binding resin, was given per day, and it decreased significantly to 4.4 +/- 0.4 mEq/1 with 150 mg/day of glycyrrhizine therapy. Changes in fasting plasma glucose and hemoglobin A1c were not significant. These data support the assumption that liquorice extract can be used safely in the therapy for treating hyperkalemia due to selective hypoaldosteronism in diabetes mellitus subjects.
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PMID:Effect of glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in diabetes mellitus. 833 14

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. 1076 36

Glucocorticoids may underlie the association between low birth weight and adult disorders such as hypertension, type 2 diabetes and affective dysfunction. We investigated the behavioural and molecular consequences of two paradigms of prenatal dexamethasone administration in rats. Rats received dexamethasone (100 microg/kg per day) throughout pregnancy (DEX1-3), in the last third of pregnancy only (DEX3) or vehicle. Both dexamethasone treatments reduced birth weight, only DEX1-3 offspring had reduced body weight in adulthood. In adult offspring, both prenatal dexamethasone paradigms reduced exploratory behaviour in an open field. In contrast, only DEX3 reduced exploration in an elevated plus-maze and impaired behavioural responses and learning in a forced-swim test. This behavioural inhibition may reflect increased baseline corticotrophin-releasing hormone mRNA levels (30% higher) in the central nucleus of the amygdala in both dexamethasone-exposed groups. Adult DEX3 offspring also showed increased corticotrophin-releasing hormone mRNA with unaltered glucocorticoid receptor mRNA in the hypothalamic paraventricular nucleus and reduced hippocampal glucocorticoid- and mineralocorticoid receptor mRNA expression, suggesting reduced hippocampal sensitivity to glucocorticoid suppression of the stress axis. In contrast, DEX1-3 rats had no changes in hippocampal corticosteroid receptors, but showed increased mRNA levels for both receptors in the basolateral nucleus of the amygdala. From this data we suggest that prenatal glucocorticoid exposure programs behavioural inhibition perhaps via increased amygdalar corticotrophin-releasing hormone levels, while DEX3 also impairs coping and learning in aversive situations, possibly via altered hippocampal corticosteroid receptor levels. Overexposure to glucocorticoids, especially late in gestation, may explain the link between reduced early growth and adult affective dysfunction.
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PMID:Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. 1131 32

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.
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PMID:RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease. 1294 34

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.
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PMID:Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. 1690 64

The role of mineralocorticoids in the development of cardiovascular disease (CVD), cardiometabolic syndrome, type 2 diabetes mellitus, chronic kidney disease (CKD), and hypertension is a growing field of interest. Aldosterone, mainly through nongenomic actions that result in proliferation, fibrosis, inflammation, and tissue remodeling, has been linked to CVD and CKD. Increased circulating aldosterone is also associated with insulin resistance and impaired glucose homeostasis that contribute to the development of endothelial dysfunction, atherosclerosis, and kidney disease. Aldosterone-induced oxidative stress and inflammation play a key role in impairing insulin signaling. Mineralocorticoid receptor blockade restores insulin sensitivity, counterbalances the deleterious cardiovascular and renal effects of aldosterone, and emerges as an alternative to improve blockade of the renin-angiotensin-aldosterone system, which potentially could contribute to reduce the burden of CVD and CKD.
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PMID:The role of aldosterone in cardiovascular disease in people with diabetes and hypertension: an update. 1862 17

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4-5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser(473) phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P < 0.05 vs. Cx), whole body insulin resistance (P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser(473) phosphorylation. The ESC treatment normalized corticosterone secretion (P < 0.05 vs. LBW), whole body insulin sensitivity (P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P < 0.05), and red muscle PKB Ser(473) phosphorylation (P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.
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PMID:Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats. 2010 38

Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future.
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PMID:Drug mechanisms to help in managing resistant hypertension in obesity. 2053 98

Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.
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PMID:Salt, aldosterone, and insulin resistance: impact on the cardiovascular system. 2069 11

Aldosterone has emerged as a deleterious hormone in the kidney, for example as a potent inducer of proteinuria. We identified the podocyte, the final filtration barrier in the glomerulus, as a novel target of aldosterone. Activation of the mineralocorticoid receptor (MR) in the podocyte disrupts the filtration barrier and induces proteinuria. Recent clinical and experimental studies have shown the efficacy of MR antagonism in reducing albuminuria in patients or rodent models of type 1 and type 2 diabetes. We assessed the pathogenic role of aldosterone in SHR/NDmcr-cp, a rat model of type 2 diabetes/metabolic syndrome. Podocyte injury and proteinuria were early manifestations of nephropathy in this model, and were exacerbated by high-salt feeding. Inappropriate activation of the aldosterone/MR system, possibly via adipocyte-derived aldosterone releasing factors, underlay the renal damage. Furthermore, we identified Rac1, a Rho family small GTPase, as a novel ligand-independent activator of MR. This alternative pathway of MR activation, indeed, contributed to podocyte injury in proteinuric kidney disease. In conclusion, MR can be activated by several different pathways, both aldosterone-dependently and -independently, leading to podocyte impairment and progression of proteinuric kidney disease. MR antagonists are promising anti-proteinuric drugs in diabetes, although hyperkalemia is a concern.
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PMID:Endocrinological aspects of proteinuria and podocytopathy in diabetes: role of the aldosterone/mineralocorticoid receptor system. 2106 6


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