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)

The thiazolidinedione compounds are well known hypoglycemic agents via increasing insulin-sensitivity. Herein, we provide the possibility that thiazolidinedione compounds could be useful for renal dysfunction through mechanism dependent or independent of its insulin-sensitizing action. In type 2 diabetes, troglitazone could reduce urinary albumin-creatinine ratio compared to metformin. Furthermore, we have shown that troglitazone was able to prevent diabetic glomerular dysfunction through inhibition of diacylglycerol-protein kinase C-extracellular signal-regulated kinase pathway in type 1 diabetic rats. Thus, thiazolidinediones might be effective agents for treating insulin-resistant diabetes as well as diabetes-induced kidney disease.
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PMID:[Kidney disease and insulin resistance--clinical impact of thiazolidinedione compounds for kidney disease]. 1070 73

Hypertension often complicates type 2 diabetes mellitus, and angiotensin converting enzyme inhibitor treatment has been shown to improve insulin resistance in such cases. However, the effect of angiotensin II type-1 (AT(1)) receptor antagonists on insulin resistance is still controversial. To gain further information on this effect, we examined the effect of losartan on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systolic blood pressure, but did not improve oral glucose tolerance test or insulin resistance in OLETF rats. However, the administration of losartan with exercise significantly improved both systolic blood pressure and insulin resistance relative to control OLETF rats. On the other hand, losartan treatment, regardless of exercise, increased glucose uptake in excised soleus muscle and fat cells. To explore the beneficial effect of losartan on skeletal muscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions were not affected by losartan with or without exercise, extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase activities were increased by both interventions. These results indicate that angiotensin AT(1) receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controversy over the effect of angiotensin AT(1) receptor antagonists on insulin resistance in clinical use. The enhancing effect of angiotensin AT(1) receptor antagonist on skeletal muscle glucose uptake may be attributable to MAP kinase activation or other mechanisms rather than phosphatidylinositol 3-kinase activation.
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PMID:Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long-Evans Tokushima Fatty rats. 1171 Oct 55

Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the beta-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1beta-induced apoptosis and impaired function in human beta-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1beta, or 10 and 100 micromol/l of the sulfonylurea tolbutamide induced beta-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1beta were blocked by 200 micromol/l diazoxide as well as by 3 and 30 micromol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1beta were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta-cell apoptosis, and impaired function. Finally, islet release of IL-1beta in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1beta-induced beta-cell secretory dysfunction and apoptosis are Ca(2+) influx and ERK dependent and can be prevented by the beta-cell selective potassium channel opener NN414.
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PMID:Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. 1522 Jan 94

Autocrine activation of the IGF-I system in mesangial cells (MC) promotes glomerular scarring in a model of type 1 diabetes. Although estrogens protect against progressive nondiabetic glomerulosclerosis (GS), women with diabetes seem to loose the estrogen-mediated protection against cardiovascular disease. However, little is known about the local IGF-I system and its interactions with estrogens in the pathogenesis of type 2 diabetic GS. Therefore, we examined db/db B6 (db/db) mice, a model of type 2 diabetes and diabetic GS. The IGF-I system was activated in the glomeruli and MC of female diabetic db/db mice, but not in nondiabetic db/+ littermates. We found increased IGF-I receptor (IGFR) expression and activation, including activation of MAPK. Surprisingly, estrogens, via an estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and insulin receptor substrate phosphorylation, and extracellular signal-regulated kinase activation in db/db MC. In contrast, ER expression was decreased in MC and glomeruli of db/db mice. Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD98059 increased ER expression and transcriptional activity. This suggests that the local prosclerotic IGF-I system is activated in type 2 diabetes and diminishes ER-mediated protection against GS. Although estrogens may stimulate protective ER signaling, they also activate the IGF-I system via ER-independent mechanisms in db/db MC. The later estrogen effects appear to outweigh the antisclerotic effects of ER activation. This may in part account for loss of estrogen protection against the progression of diabetic GS in women with type 2 diabetes.
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PMID:Autocrine activation of the local insulin-like growth factor I system is up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts for decreased ER expression in type 2 diabetic mesangial cells. 1555 May 5

Recent reports have suggested that PKCepsilon contributes to systemic insulin resistance, and is involved in the pathogenesis of type 2 diabetes, however, the exact mechanism is still unknown. To elucidate the possible involvement of PKCepsilon in the pathogenesis of type 2 diabetes, we examined the role of PKCepsilon in differentiated adipocytes using mouse 3T3-L1 adipocytes. We found that the over-expression of PKCepsilon resulted in the increase of IL-6 expression in differentiated adipocytes. This PKCepsilon-induced IL-6 expression could be completely inhibited by U0126, an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase. We also demonstrated that PKCepsilon increased the transcriptional activity of Est-like transcription factor (Elk-1) as well as the DNA-binding activity of activator protein-1 (AP-1) in differentiated 3T3-L1 adipocytes. These results suggest that PKCepsilon is able to increase IL-6 expression via the ERK-AP-1 pathway in differentiated adipocytes, and that PKCepsilon is involved in systemic insulin resistance by regulating plasma IL-6 concentrations.
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PMID:PKCepsilon induces interleukin-6 expression through the MAPK pathway in 3T3-L1 adipocytes. 1564 4

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-kappaB (NF-kappaB) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-kappaB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappaB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.
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PMID:Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. 1598 26

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
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PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-kappaB ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-alpha to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-alpha. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.
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PMID:An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. 1714 84

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.
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PMID:Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. 1742 53

Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.
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PMID:Identification of novel orally available small molecule insulin mimetics. 1768 71


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