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)

The subcutaneous injection of 5'-bromo-2' deoxyuridine (BrdU) was found to raise the plasma concentrations of ACTH, aldosterone and corticosterone in rats. The aldosterone response was observed at a lower dose of BrdU and lasted for a longer period than those of ACTH and corticosterone (1.25 versus 2.50 mg/100 g body weight; 48 versus 24 h). Corticosterone response to BrdU was partially reversed by the ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP), and aldosterone response by the arginine vasopressin (AVP) V1-receptor antagonist [amino-Pen1, Val4,D-Arg8]-vasopressin (AVP-A). The angiotensin-II (ANG-II)-receptor antagonist [Sar1, Val5, Ala8]-ANG-II (SAR) was ineffective. CIP, AVP-A and SAR, when administered alone, did not alter basal levels of ACTH, aldosterone and corticosterone. In light of these findings the following conclusions can be drawn: (i) BrdU stimulates the hypothalamo-pituitary-adrenal axis in rats, and this effect may influence the results of cell-kinetics studies carried out with the BrdU-labelling technique, especially in those tissue that are highly responsive to glucocorticoids (e.g. pituitary, adrenal and lymphatic tissues); and (ii) different mechanisms underlie the aldosterone and corticosterone secretagogue effects of BrdU, the former being at least in part dependent on the stimulation of AVP release and the latter on the rise in ACTH secretion.
Exp Clin Endocrinol Diabetes 1997
PMID:Different mechanisms mediate the in vivo aldosterone and corticosterone responses to 5-bromo-2'-deoxyuridine in rats. 935 56

Vascular endothelial growth factor (VEGF), in addition oto its growth-promoting effects on endothelial cells, can also increase vascular permeability and monocyte migration. It has therefore been implicated in the pathogenic neovascularization associated with diabetic retinopathy and atherosclerosis. However, the factors regulating VEGF expression in the vascular wall are not fully understood. In this study, we examined the regulation of VEGF expression in vascular smooth muscle cells (VSMC) by hyperglycemia as well as by angiotensin II (ANG II). We also examined whether the 12-lipoxygenase (12-LO) product 12-hydroxyeicosatetraenoic acid (12-HETE) can alter VEGF expression, since 12-LO products of arachidonic acid have angiogenic properties, and ANG II as well as high glucose (HG, 25 mM) can increase 12-LO activity and expression in VSMC. Studies were carried out in human (HSMC) or porcine VSMC (PSMC), which were cultured for at least two passages under normal glucose (NG, 5.5 mM) or HG conditions. HG culture alone increased the expression of VEGF mRNA and protein in both HSMC and PSMC. Furthermore, ANG II treatment significantly induced VEGF mRNA and protein expression only in VSMC cultured in HG and not NG. In addition, 12-HETE significantly increased VEGF mRNA and protein expression in HSMC cultured in NG as well as in HG. Cells cultured in HG also secreted significantly greater amounts of VEGF into the culture medium. These results suggest that elevated VEGF production under HG conditions may play a role in the accelerated vascular disease observed in diabetes.
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PMID:Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. 937 57

Insulin initiates its metabolic and growth-promoting effects by binding to the alpha subunit of its receptor, thereby activating the kinase in the beta subunit. This event leads to tyrosyl phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1), which in turn associates with and activates phosphatidylinositol (PI) 3-kinase. The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. However, the exact molecular mechanism is unknown. In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin.
Diabetes 1997 12
PMID:Effect of captopril, losartan, and bradykinin on early steps of insulin action. 2720 26

In the rat, the glucagon-like peptide 1 (GLP-1)(7-36) amide inhibits neurones in the central nervous system responsible for food and water intake. GLP-1-induced inhibition of food intake may involve the hypothalamic arcuate nucleus, whereas rostral sensory circumventricular organs may be responsible for the inhibitory action of GLP-1 on drinking. To further investigate the role of these blood-brain-barrier-free areas in GLP-1-induced inhibition of ingestive behavior, neonatal Wistar rats were subjected to monosodium glutamate (MSG) treatment, which causes extensive damage to the arcuate nucleus as well as to parts of the sensory circumventricular organs. The inhibitory effect of GLP-1 on feeding induced by food deprivation was completely abolished in MSG-lesioned rats. This effect was not due to either a loss of sensitivity to anorectic agents or a loss of taste aversion because MSG-treated animals displayed normal anorectic responses to central administration of corticotropin-releasing factor and normal aversive responses to peripheral administration of both lithium chloride and D-amphetamine. In non-lesioned rats, neuropeptide Y (NPY)-induced feeding was significantly reduced by concomitant GLP-1 administration. In contrast, GLP-1 had no effect on NPY-induced feeding in MSG-lesioned rats, suggesting that the GLP-1 receptors that mediate inhibition of feeding are localized upstream to the NPY-sensitive neurones inducing feeding behavior. The inhibitory effect of GLP-1 on water intake was tested using an ANG II-elicited drinking paradigm. Central administration of GLP-1 inhibited ANG II drinking in both MSG-treated rats and their nontreated littermates. In contrast, peripheral administration of GLP-1 did not inhibit ANG II-induced drinking behavior in MSG-treated rats. Thus it is evident that centrally acting GLP-1 modulates feeding and drinking behavior via neurones sensitive to MSG lesioning in the arcuate nucleus and circumventricular organs, respectively.
Diabetes 1998 Apr
PMID:Glucagon-like peptide 1(7-36) amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment. 956 83

The effect of 6 weeks' streptozotocin (STZ)-induced (70 mg/kg) diabetes and aminoguanidine (AG) treatment (50 mg/kg s.c. or 250-750 mg/l given in drinking water) on arteriolar reactivity to vasoactive substances was investigated in conscious rats. Studies were performed in untreated control rats (n = 13), STZ-induced diabetic rats (n = 11), AG-treated control rats (n = 12), and AG-treated diabetic rats (n = 12). Rats were provided with a dorsal microcirculatory chamber that allowed intravital microscopy of striated muscle arterioles of varying diameter (A1, large; A2, intermediate; and A3, small arterioles) in conscious animals. The mean arterial pressure (MAP) and arteriolar diameter responses to intravenous infusion of the following drugs were examined: the endothelium-dependent vasodilator acetylcholine (ACh; 3, 10, and 30 microg x kg(-1) x min(-1)), the potassium-channel opener levcromakalim (LC; 30 microg/kg), and the vasoconstrictor agents ANG II (0.1 and 0.3 microg x kg(-1) x min(-1)) and norepinephrine (NE; 0.2, 0.6, and 2.0 microg x kg(-1) x min(-1)). Baseline MAP was lower in both diabetic groups versus the nondiabetic groups (P < 0.05). AG treatment had no influence on baseline MAP. The absolute change in MAP after drug infusion tended to be lower in the diabetic rats than in their nondiabetic littermates. Arteriolar vasodilatory responses to ACh and LC were attenuated in the diabetic animals (1 +/- 7 vs. 19 +/- 7% [P < 0.05] and 7 +/- 3 vs. 34 +/- 8% [P < 0.01] in A2, respectively). AG treatment of diabetic animals did not prevent the development of this disturbance. Vasoconstrictor responses were not influenced by the diabetic state. In the intermediate arterioles of AG-treated control rats, a hyperresponse was observed after ANG II infusion (-10 +/- 2 vs. -2 +/- 2%; P < 0.05) and a hyporesponse was observed after ACh and LC infusion (2 +/- 3 and 15 +/- 6%, respectively; P < 0.05 vs. untreated control rats). These data indicate that 6 weeks of experimental diabetes is associated with a decreased endothelium-dependent and -independent vasodilatation. AG treatment had no beneficial effect on this disturbance.
Diabetes 1998 Jun
PMID:Arteriolar reactivity in conscious diabetic rats: influence of aminoguanidine treatment. 960 69

While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states.
Diabetes 1998 Jun
PMID:Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells. 960 72

A principal, and unique, renal effector site for angiotensin II (ANG II) is the efferent arteriole, and that has generated considerable interest regarding potential benefits of ANG II inhibition in the treatment and prevention of diabetic renal injury. A hallmark complication of long-standing diabetes is glomerular injury, and there is substantial evidence that lowering glomerular hydrostatic pressure attenuates the injury process. One way that has been accomplished is by lowering arterial pressure, but additional evidence suggests that anti-hypertensive treatment with ANG II inhibition provides even greater protection because of the associated efferent arteriolar dilation. Because of that action, ANG II inhibition in diabetes has been advocated even without diagnosis of hypertension, and the benefits of that treatment have been ascribed largely to the effect of decreased efferent arteriolar resistance to lower glomerular hydrostatic pressure. However, that renal vascular action of ANG II, together with powerful direct effects on tubular sodium reabsorption, underlie its dominant influence on chronic arterial pressure control. Moreover, the influence of ANG II on arterial pressure is not limited to hypertension; it contributes significantly to the maintenance of blood pressure when plasma ANG II levels are normal or even reduced. Thus, while acknowledging that efferent arteriolar dilation is a unique intrarenal benefit associated with ANG II inhibition, this review will focus on how and why inhibition of the multiple intrarenal actions of ANG II also protect the kidneys through systemic mechanisms, even when blood pressure and ANG II are not increased.
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PMID:Control of renal function and blood pressure by angiotensin II: implications for diabetic glomerular injury. 993 Mar 76

Changes in activity or expression of transporters may account for alterations in cell behavior in diabetes. We sought to ascertain if mesangial cells (MC) grown in different glucose concentrations exhibit changes in activity and expression of acid-extruding transporters, the Na(+)/H(+) and Na(+)-dependent Cl(-)/HCO(-)(3) exchanger. pH(i) was determined by the use of the fluorescent pH-sensitive dye BCECF. In MCs grown in 5 mM glucose (control), the Na(+)/H(+) exchanger was responsible for 31.8 +/- 5.1% of steady-state pH(i), whereas Na(+)-dependent Cl(-)/HCO(-)(3) contributed 62.9 +/- 4.0% (n = 11). In MCs grown in high glucose for 2 wk, Na(+)/H(+) exchange contribution to acid-extrusion increased as follows: 42.3 +/- 4.6% [n = 8, 10 mM, not significant (NS)], 51.1 +/- 5.1% (n = 8, 20 mM, P < 0.01), and 64.8 +/- 5.5% (n = 7, 30 mM, P < 0.001). The Na(+)-dependent Cl(-)/HCO(-)(3) exchanger contributed less [47.0 +/- 4.6, 38.6 +/- 5.8, and 21.1 +/- 3.8%, for 10, 20, and 30 mM glucose, respectively (n > 7)]. We sought to ascertain if the magnitude of the acute stimulated response to ANG II by the Na(+)/H(+) and Na(+)-dependent Cl(-)/HCO(-)(3) exchanger is changed. Na(+)/H(+) exchanger (1.89-fold increase in 30 vs. 5 mM, P < 0.002), but not Na(+)-dependent Cl(-)/HCO(-)(3) exchange (0. 17-fold, NS), exhibited an enhanced response to ANG II (1 microM). Na(+)/H(+) exchange (NHE1) expression was significantly different (1. 72-fold) after prolonged exposure to high glucose. These results suggest that the Na(+)/H(+) exchanger, but not Na(+)-dependent Cl(-)/HCO(-)(3) exchanger, may play an early role in the response to hyperglycemia in the diabetic state.
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PMID:High glucose induces the activity and expression of Na(+)/H(+) exchange in glomerular mesangial cells. 1064 59

Experiments were performed to test the hypothesis that the impact of endogenous nitric oxide (NO) on ANG II-induced renal arteriolar constriction is reduced in rats with insulin-dependent diabetes mellitus (65 mg/kg streptozotocin; STZ). Arteriolar diameter responses to exogenous ANG II were quantified before and during NO synthase inhibition (100 microM N(omega)-nitro-L-arginine; L-NNA) by using the in vitro blood-perfused juxtamedullary nephron technique. Afferent arteriolar lumen diameter averaged 20.7 +/- 2.0 micrometer in Sham kidneys and 25.9 +/- 1.3 micrometer in STZ kidneys (P < 0.05). Efferent arteriolar diameter did not differ between Sham and STZ rats. In kidneys from Sham rats, afferent and efferent arteriolar responses to ANG II (0.1-10.0 nM) were exaggerated significantly by L-NNA. L-NNA also augmented efferent arteriolar ANG II responses in kidneys from STZ rats (high-glucose bath) but did not alter ANG II responses in afferent arterioles from STZ rats. L-NNA also accentuated efferent, but not afferent, arteriolar ANG II responses in STZ kidneys during acute restoration of bath glucose to normal levels. Superoxide dismutase (150 U/ml) restored the ability of L-NNA to allow exaggerated afferent arteriolar responses to ANG II in kidneys from STZ rats. These observations indicate that superoxide anion suppresses the modulatory influence of endogenous NO on ANG II-induced afferent arteriolar constriction in diabetes mellitus.
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PMID:Superoxide anion curbs nitric oxide modulation of afferent arteriolar ANG II responsiveness in diabetes mellitus. 1066 34

It has been shown that glomerular ANG II receptors are downregulated and protein kinase C (PKC) activity is enhanced in diabetes mellitus. Therefore, we investigated glomerular and preglomerular vascular ANG II receptors and PKC isoform regulation in streptozotocin (STZ)-diabetic rats treated with insulin and/or captopril. Diabetic rats were prepared by injecting STZ (60 mg/kg). Those that developed diabetes after 48 h were treated with low or high doses of insulin, or with a low dose of insulin as well as captopril, and killed 14 days later. Their glomeruli and preglomerular vessels were purified, competitive binding studies were performed by using the ANG II antagonists losartan and PD-123319, and PKC analysis was carried out by Western blotting. Competitive binding studies showed that the AT(1) receptor was the only ANG II receptor detected on both glomeruli and preglomerular vessels of all groups. Preglomerular vascular AT(1) receptor density (B(max)) was significantly upregulated in low insulin-treated STZ rats, whereas glomerular AT(1) B(max) was downregulated. Furthermore, both the captopril- and high insulin-treated groups had less glomerulosclerosis and vascular damage than the low insulin-treated group. PKCalpha, PKCdelta, PKCepsilon, and PKCmu isoforms found in preglomerular vessels were upregulated by captopril and high insulin doses, respectively, whereas no such regulation occurred in glomeruli. We conclude that in STZ-diabetic rats ANG II receptors and PKC isoforms on preglomerular vessels and glomeruli are differentially regulated by treatment with insulin and/or captopril.
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PMID:Renal angiotensin II receptors and protein kinase C in diabetic rats: effects of insulin and ACE inhibition. 1075 Dec 21


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