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Horm Metab Res 2013; 45(02): 173-180
DOI: 10.1055/s-0032-1327679
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Angiotensin II Impairs Glucose Utilization in Obese Zucker Rats by Increasing HPA Activity via an Adrenal-dependent Mechanism

H. Müller-Fielitz
1   From the Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
,
W. Raasch
1   From the Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
› Author Affiliations
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Publication History

received 02 May 2012

accepted 24 September 2012

Publication Date:
26 October 2012 (online)

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Abstract

Angiotensin II (AngII) increases the activity of the hypothalamus-pituitary-adrenal (HPA) axis. We have previously demonstrated in obese Zucker rats (OZR) that AngII-induced HPA hyperreactivity was associated with impaired glucose utilization. The aim of this study was to specify the potential role of the adrenals in regulating AngII-dependent glucose homeostasis in obesity. Adrenal-specific AngII effects were determined regarding 1) the HPA axis by ACTH tests after treating OZR with AngII (9 μg/h, s.c.) for 3 months and 2) glucose utilization by oral glucose tolerance tests (OGTT) in OZR that were adrenalectomized (adx) or sham operated and treated for 1 month with AngII (9 μg/h, s.c.). AngII increased the corticosterone response after ACTH infusions, clearly indicating the key role of the adrenals for mediating stress reactions. Baseline levels of glucose and corticosterone were not altered by AngII treatment or by adrenalectomy. In contrast, AngII similarly reduced baseline insulin in sham and adxOZR. During OGTT, AngII increased glucose and corticosterone responses in shamOZR, whereas insulin was slightly diminished. This reaction pattern was lost when obese Zucker rats were adrenalectomized. In summary, we verified our hypothesis that the adrenal glands play a key role in worsening glucose homeostasis in obesity in response to AngII, which further supports recent findings that improvement in glucose utilization after AT1 blockade is related to reduced activity of the HPA axis.

Key words

renin-angiotensin II system - obesity - insulin - stress - ACTH test - adrenalectomy
 

  • References

  • 1 Bjorntorp P, Rosmond R. The metabolic syndrome – a neuroendocrine disorder?. Br J Nutr 2000; 83 (Suppl. 01) S49-S57
    CrossrefPubMedGoogle Scholar
  • 2 Chan O, Inouye K, Riddell MC, Vranic M, Matthews SG. Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis. Minerva Endocrinol 2003; 28: 87-102
    PubMedGoogle Scholar
  • 3 Walker BR. Cortisol – cause and cure for metabolic syndrome?. Diabet Med 2006; 23: 1281-1288
    CrossrefPubMedGoogle Scholar
  • 4 Karatsoreos IN, Bhagat SM, Bowles NP, Weil ZM, Pfaff DW, McEwen BS. Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse. Endocrinology 2010; 151: 2117-2127
    CrossrefPubMedGoogle Scholar
  • 5 Munir A, Newell-Price J. Management of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology 2010; 92 (Suppl. 01) 82-85
    CrossrefPubMedGoogle Scholar
  • 6 Saavedra JM, Benicky J. Brain and peripheral angiotensin II play a major role in stress. Stress 2007; 10: 185-193
    CrossrefPubMedGoogle Scholar
  • 7 Pavlatou MG, Mastorakos G, Lekakis I, Liatis S, Vamvakou G, Zoumakis E, Papassotiriou I, Rabavilas AD, Katsilambros N, Chrousos GP. Chronic administration of an angiotensin II receptor antagonist resets the hypothalamic-pituitary-adrenal (HPA) axis and improves the affect of patients with diabetes mellitus type 2: preliminary results. Stress 2008; 11: 62-72
    CrossrefPubMedGoogle Scholar
  • 8 Raasch W, Wittmershaus C, Dendorfer A, Voges I, Pahlke F, Dodt C, Dominiak P, Jöhren O. Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats. Endocrinology 2006; 147: 3539-3546
    CrossrefPubMedGoogle Scholar
  • 9 Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005; 45: 356-362
    CrossrefPubMedGoogle Scholar
  • 10 Müller H, Schweitzer N, Jöhren O, Dominiak P, Raasch W. Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization. Am J Physiol Endocrinol Metab 2007; 293: E802-E810
    CrossrefPubMedGoogle Scholar
  • 11 Guillaume-Gentil C, Rohner-Jeanrenaud F, Abramo F, Bestetti GE, Rossi GL, Jeanrenaud B. Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat. Endocrinology 1990; 126: 1873-1879
    CrossrefPubMedGoogle Scholar
  • 12 Plotsky PM, Thrivikraman KV, Watts AG, Hauger RL. Hypothalamic-pituitary-adrenal axis function in the Zucker obese rat. Endocrinology 1992; 130: 1931-1941
    CrossrefPubMedGoogle Scholar
  • 13 Müller-Fielitz H, Lau M, Jöhren O, Stellmacher F, Schwaninger M, Raasch W. Blood Pressure Response to Angiotensin II is Enhanced in Obese Zucker Rats and is Attributed to an Aldosterone-Dependent Mechanism. Br J Pharmacol 2012; 166: 2417-2429
    CrossrefPubMedGoogle Scholar
  • 14 Müller H, Kröger J, Jöhren O, Szymczak S, Bader M, Dominiak P, Raasch W. Stress sensitivity is increased in transgenic rats with low brain angiotensinogen. J Endocrinol 2010; 204: 85-92
    CrossrefPubMedGoogle Scholar
  • 15 Miesel A, Müller-Fielitz H, Jöhren O, Vogt FM, Raasch W. Double blockade of angiotensin II (AT(1) )-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats. Br J Pharmacol 2012; 165: 2721-2735
    CrossrefPubMedGoogle Scholar
  • 16 Raasch W, Bartels T, Schwartz C, Häuser W, Rütten H, Dominiak P. Regression of ventricular and vascular hypertrophy: are there differences between structurally different angiotensin-converting enzyme inhibitors?. J Hypertens 2002; 20: 2495-2504
    CrossrefPubMedGoogle Scholar
  • 17 Pedersen EB, Danielsen H, Jensen T, Madsen M, Sorensen SS, Thomsen OO. Angiotensin II, aldosterone and arginine vasopressin in plasma in congestive heart failure. Eur J Clin Invest 1986; 16: 56-60
    CrossrefPubMedGoogle Scholar
  • 18 Bray GA, Stern JS, Castonguay TW. Effect of adrenalectomy and high-fat diet on the fatty Zucker rat. Am J Physiol 1992; 262: E32-E39
    PubMedGoogle Scholar
  • 19 Cabassi A, Coghi P, Govoni P, Barouhiel E, Speroni E, Cavazzini S, Cantoni AM, Scandroglio R, Fiaccadori E. Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat. J Clin Endocrinol Metab 2005; 90: 2888-2897
    CrossrefPubMedGoogle Scholar
  • 20 Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000; 35: 1270-1277
    CrossrefPubMedGoogle Scholar
  • 21 Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 1998; 78: 583-686
    PubMedGoogle Scholar
  • 22 Clark JB, Palmer CJ, Shaw WN. The diabetic Zucker fatty rat. Proc Soc Exp Biol Med 1983; 173: 68-75
    PubMedGoogle Scholar
  • 23 Jöhren O, Dendorfer A, Dominiak P, Raasch W. Gene expression of mineralocorticoid and glucocorticoid receptors in the limbic system is related to type-2 like diabetes in leptin-resistant rats. Brain Res 2007; 1184: 160-167
    CrossrefPubMedGoogle Scholar
  • 24 Barseghian G, Levine R. Effect of corticosterone on insulin and glucagon secretion by the isolated perfused rat pancreas. Endocrinology 1980; 106: 547-552
    CrossrefPubMedGoogle Scholar
  • 25 Lambillotte C, Gilon P, Henquin JC. Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J Clin Invest 1997; 99: 414-423
    CrossrefPubMedGoogle Scholar
  • 26 Davani B, Portwood N, Bryzgalova G, Reimer MK, Heiden T, Ostenson CG, Okret S, Ahren B, Efendic S, Khan A. Aged transgenic mice with increased glucocorticoid sensitivity in pancreatic beta-cells develop diabetes. Diabetes 2004; 53 (Suppl. 01) S51-S59
    CrossrefPubMedGoogle Scholar
  • 27 Delaunay F, Khan A, Cintra A, Davani B, Ling ZC, Andersson A, Ostenson CG, Gustafsson J, Efendic S, Okret S. Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest 1997; 100: 2094-2098
    CrossrefPubMedGoogle Scholar
  • 28 Chu KY, Lau T, Carlsson PO, Leung PS. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes 2006; 55: 367-374
    CrossrefPubMedGoogle Scholar
  • 29 Lau T, Carlsson PO, Leung PS. Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia 2004; 47: 240-248
    CrossrefPubMedGoogle Scholar
  • 30 Leung KK, Leung PS. Effects of hyperglycemia on angiotensin II receptor type 1 expression and insulin secretion in an INS-1E pancreatic beta-cell line. J Pancreas (Online) 2008; 9: 290-299
    PubMedGoogle Scholar
  • 31 Feldman JM, Lebovitz HE. Mechanism of epinephrine and serotonin inhibition of insulin release in the golden hamster in vitro. Diabetes 1970; 19: 480-486
    PubMedGoogle Scholar
  • 32 Porte Jr D, Williams RH. Inhibition of insulin release by norepinephrine in man. Science 1966; 152: 1248-1250
    CrossrefPubMedGoogle Scholar
  • 33 Juan CC, Chien Y, Wu LY, Yang WM, Chang CL, Lai YH, Ho PH, Kwok CF, Ho LT. Angiotensin II enhances insulin sensitivity in vitro and in vivo. Endocrinology 2005; 146: 2246-2254
    CrossrefPubMedGoogle Scholar
  • 34 Fliser D, Schaefer F, Schmid D, Veldhuis JD, Ritz E. Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans. Hypertension 1997; 30: 1156-1161
    CrossrefPubMedGoogle Scholar
  • 35 Morris AD, Petrie JR, Ueda S, Connell JM, Elliott HL, Small M, Donnelly R. Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects. Diabetes 1994; 43: 1445-1449
    CrossrefPubMedGoogle Scholar
  • 36 Djordjevic J, Cvijic G, Davidovic V. Different activation of ACTH and corticosterone release in response to various stressors in rats. Physiol Res 2003; 52: 67-72
    PubMedGoogle Scholar