The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

Machado, Luciana A. C.; Marubayashi, Umeko; Reis, Adelina Martha dos; Coimbra, CC

doi:10.1590/s0100-879x1998001000018

Cited by 10 publications

(9 citation statements)

References 14 publications

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“…In our study, we extended the Ang II infusion to 14 days to determine the therapeutic potential of pancreas-targeted ACE2 gene therapy beyond the 7th day of infusion. Our data are consistent with previous findings (25,27,35) describing Ang II-mediated impairment of glucose tolerance and increased FBG levels. We extended these observations by showing that Ang II increases the expression of components thought to be detrimental to pancreatic and especially ␤-cell function, i.e., AT 1 R and the NAD(P)H oxidase main catalytic subunit gp91…”

Section: E880supporting

confidence: 94%

“…The importance of AT 1 R and ACE2 in the regulation of glycemia has been demonstrated previously by our group (3) and others (11,25,28,35,40).…”

Section: E881supporting

confidence: 63%

“…In the present study, we aimed to study the compensatory role of ACE2 in an overactive RAS model independently of any genetic defect or obesity. Ang II-infused rodent models have been utilized previously to study the effects of RAS overactivity on glycemia (25,27,35). Mitsuishi et al (27) reported impaired glucose tolerance and hyperinsulinemia following a 7-day infusion in mice.…”

Section: E880mentioning

confidence: 99%

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Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

Chhabra

Xia

Pedersen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Chhabra KH, Xia H, Pedersen KB, Speth RC, Lazartigues E. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice. Am J Physiol Endocrinol Metab 304: E874-E884, 2013. First published March 5, 2013; doi:10.1152/ajpendo.00490.2012.-An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7-8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving ␤-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid ␤-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS.angiotensin II; angiotensin-converting enzyme 2; angiotensin II type 1 receptor; type 2 diabetes mellitus; ␤-cell dysfunction; oxidative stress ANGIOTENSIN II (Ang II), a key component of the renin-angiotensin system (RAS), plays a pivotal role in mediating insulin resistance (15,16,18,33) and impaired glucose tolerance (27), thereby contributing to the development of type 2 diabetes mellitus (T2DM). Several clinical trials have explored the benefits of RAS blockade in controlling T2DM. A recent meta-analysis by Tocci et al. (41) showed that angiotensinconverting enzyme (ACE) inhibitors or Ang II type 1 receptor (AT 1 R) blockers reduce the risk for new-onset T2DM in individuals with hypertension or an elevated risk for cardiovascular events. In light of these beneficial effects, agents that counteract or block the RAS may have a potential for treatment of T2DM. ACE2 is a carboxypeptidase that converts Ang II to Ang-(1-7), whose signaling opposes that of Ang II. ACE2 thus provides a compensatory mechanism to counter...

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Section: E880supporting

confidence: 94%

“…The importance of AT 1 R and ACE2 in the regulation of glycemia has been demonstrated previously by our group (3) and others (11,25,28,35,40).…”

Section: E881supporting

confidence: 63%

Section: E880mentioning

confidence: 99%

See 1 more Smart Citation

Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

Chhabra

Xia

Pedersen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Baseline glucose remained unchanged by ANG in LZR and OZR (Table 1). This is in contrast to studies revealing an AT 1 -dependent hyperglycemic response to acute ANG (19,42,45,51). It can be assumed that ANG increases glucose when given acutely, but when given chronically it becomes ineffective.…”

Section: Discussionmentioning

confidence: 70%

Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization

Müller¹,

Schweitzer²,

Dominiak³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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The HPA axis is hyperactive under conditions of leptin and insulin resistance as well as after ANG II administration. We hypothesized that a hyperreactivity of the HPA axis to ANG contributes to an impaired glucose utilization in obesity, since leptin resistance and an overactive renin-angiotensin-aldosterone system are features of obesity. Zucker rats were treated with ANG via subcutaneous minipumps (0, 0.9, and 9.0 g/h; 4 wk). PA axis reactivity and glucose homeostasis were characterized after CRH treatment and during an oral glucose tolerance test (OGTT). The elevated plasma profile of corticosterone after CRH stimulation in saline-treated OZR compared with LZR confirmed that the sensitization of the PA axis depended on leptin resistance. Irrespective of the rat strain, circulating ANG levels and blood pressure were selectively increased after administration of 9 g/h ANG (high ANG). Only high ANG induced an elevation of the corticosterone and glucose response after CRH stimulation in OZR but did not affect the ACTH secretion. During OGTT, corticosterone and consequently glucose increased in OZR after high ANG, whereas the insulin secretion was decreased. In the adrenal glands of OZR, AT1A receptor mRNA levels increased after high ANG. We conclude that the impairment of glucose utilization after ANG stimulation is potentiated in leptin-resistant rats as a result of a hyperreactive PA axis, thereby confirming the functional importance of a dysregulation within the HPA axis in metabolic syndrome or obesity. The ACTHindependent stimulation of corticosterone release and the selective increase of AT 1A receptor mRNA in the adrenals of OZR indicated a sensitization of adrenals toward ANG, causing a stimulation of the PA axis.renin-angiotensin-aldosterone system; obesity; corticosterone; adrenocorticotropic hormone; diabetes IN THE PAST DECADE, symptoms clustering the metabolic syndrome, such as hypertension, insulin resistance, obesity, and dyslipidemia, have all been associated with a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis (8). In this regard, increased plasma levels of corticosterone and ACTH in the morning, stimulated expression of hypothalamic corticotropin-releasing hormone (CRH) mRNA as well as hippocampal mineralocorticoid receptor mRNA, and a decreased glucocorticoid negative feedback sensitivity all indicate a hyperreactivity of the HPA axis in diabetes (15).Visceral fat accumulation is related to a progressive malfunction of the HPA axis with elevations of cortisol levels and failure of central feedback control by glucocorticoid receptors (7,22). The peptide hormone leptin, which is produced by adipocytes, plays an important regulatory role in the body's fat stores by inhibiting food intake and increasing energy expenditure. Leptin has inhibitory effects on the HPA axis, since the release of CRH from isolated hypothalamus is reduced, the stress-or fasting-induced stimulation of corticosterone or adrenocorticotropic hormone (ACTH) is attenuated, and both the secretion and synthesis o...

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“…d. Stimulation of liver glycogenolysis. Ang II infusion leads to an elevation in blood glucose levels (Machado et al 1998) as a consequence of an AT I-receptor dependent action on hepatic glycogen phosphorylase (Keppens et al 1993). Hyperglycaemia becomes useful in fight-or-flight situations, as this condition provides energetic fuel to the skeletal muscles.…”

Section: 13mentioning

confidence: 99%

General Physiology and Pathophysiology of the Renin-Angiotensin System

Montani

Vliet

2004

Angiotensin Vol. I

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The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

Cited by 10 publications

References 14 publications

Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization

General Physiology and Pathophysiology of the Renin-Angiotensin System

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