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Diabetes Care 29:469-471, 2006
DOI: 10.2337/diacare.29.02.06.dc05-2048
© 2006 by the American Diabetes Association
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Letters: Observations

Insulin Signaling, Glucose Metabolism, and the Angiotensin II Signaling System

Studies in Bartter’s/Gitelman’s syndromes

Paul A. Davis, PHD1, Elisa Pagnin, PHD2, Andrea Semplicini, MD2, Angelo Avogaro, MD, PHD2 and Lorenzo A. Calò, MD, PHD2

1 Department of Nutrition, University of California, Davis, California
2 Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy

Address correspondence to Lorenzo A Calò, MD, PhD, Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E-mail: renzcalo{at}unipd.it

Taniyama et al. (1) have recently reported that angiotensin II (Ang II) in vitro decreases insulin receptor substrate-1 protein levels via Src, phosphoinositide-dependent kinase-1, and reactive oxygen species–mediated phosphorylation of Ser307. This leads to the targeting of insulin receptor substrate-1 for proteasome-dependent degradation, which then impairs insulin signaling. These findings provide a rationale for understanding the molecular basis of the positive effect of Ang II type 1 receptor antagonists on insulin resistance.

The relationship between Ang II and insulin signaling shown in vitro leads us to assess whether this is operative also in vivo in humans. We analyzed a cohort of patients with Bartter’s/Gitelman’s syndrome (BS/GS), which attract much attention for persistent normo-/hypotension despite biochemical and hormonal abnormalities typical of hypertension. BS/GS, caused by gene defects in specific kidney transporters and ion channels, presents hypokalemia, sodium depletion, activation of the renin-angiotensin-aldosterone system, and increased levels of Ang II, yet normo-/hypotension, reduced peripheral resistance, and hyporesponsiveness to pressors (2, 3). BS/GS is a good human model to explore the mechanisms responsible for Ang II signaling (2, 4). In BS/GS specifically, the short-term Ang II signaling is blunted (increased regulator of G-protein signaling-2 [5], reduced G{alpha}q expression [6, 7], and reduced related downstream cellular events [6, 8, 9]), while the NO system is upregulated (2, 10–12). The long-term signaling of Ang II, which modulates the cell redox state to promote cardiovascular remodeling and atherosclerosis, is also altered in BS/GS (13, 14). In addition, the RhoA/Rho kinase (ROK) pathway, which is activated by Ang II and shown to affect the Akt–phosphatidylinositol 3-kinase pathway (15), which, in turn, is involved in glucose transport and metabolism (16), is downregulated in BS/GS (17, 18). Thus BS/GS’s molecular and biochemical characteristics make it an attractive model to explore whether high Ang II is indeed affecting glucose homeostasis also in vivo in humans.

Six patients with BS/GS (1 with BS, 5 with GS) and 10 normotensive healthy subjects underwent oral glucose tolerance tests to determine not only the glucose tolerance but also, using the oral glucose insulin sensitivity index (19), the glucose clearance as a function of insulin concentration.

All patients showed a normal oral glucose tolerance test at baseline and at 120 min (5.0 ± 0.5 vs. 5.30 ± 0.8 and 6.41 ± 1.9 vs. 5.06 ± 1.2, respectively). Insulin at baseline was significantly reduced compared with control subjects (22.5 ± 9.8 vs. 57.0 ± 26.3, P = 0.008), while it was not different at 120 min (198.3 ± 136.0 vs. 190.4 ± 142.7). Oral glucose insulin sensitivity was markedly higher in BS/GS (694.6 ± 103.6 vs. 446.5 ± 48.04 ml · min–1 · m–2, P = 0.00001).

These results point toward a reduced insulin resistance in BS/GS, therefore not only confirming the blunted nature of Ang II signaling in BS/GS but also supporting in vivo in humans the link between insulin signaling, glucose metabolism, and Ang II signaling demonstrated in vitro (1).

The possible involvement of the RhoA/ROK pathway in glucose metabolism is one more piece of indirect evidence. Ang II, via stimulation of RhoA/ROK activity, inhibits insulin signaling through the inhibition of phosphatidylinositol 3-kinase and its downstream Akt pathway (16), induction of oxidative stress, decreased NO production, increased myosin light-chain activation, vasoconstriction, and reduced glucose transport (16). On the contrary, RhoA/ROK inhibition activates the Akt pathway leading to cardiovascular protection via activation of endothelial NO synthase (15, 20). BS/GS shows an upregulation of the NO system (10–12) and downregulation of RhoA/ROK activity (17, 18), which may induce Akt pathway supported by BS/GS increased expression of hemeoxygenase-1 (13), which is under Akt control (21).

Finally, the increased expression of p22phox mRNA and oxidative stress as well as the increased expression of p66shc we have shown in type 2 diabetic subjects (22, 23) are opposed to the findings in BS/GS (13), in which preliminary results also show reduced p66shc expression (E.P., L.A.C., personal observation).

In conclusion, our data in BS/GS represent the first direct confirmation in humans of the Ang II/glucose metabolism relationship, thereby supporting the positive effect of blocking the renin-angiotensin-aldosterone system not only for blood pressure control but also glucose tolerance, diabetes, and atherogenesis.

References

  1. Taniyama Y, Hitomi H, Shah A, Alexander RW, Griendling KK: Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol 25:1142–1147, 2005[Abstract/Free Full Text]
  2. Calò LA, Pessina AC, Semplicini A: Angiotensin II signaling in the Bartter’s and Gitelman’s syndromes, a negative human model of hypertension. High Blood Press Cardiovasc Prev 12:17–26, 2005
  3. Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D: Bartter’s and Gitelman’s syndromes: from gene to clinic (Review). Nephron Physiol 96:65–78, 2004
  4. Calò LA: A mirror instead of a looking glass to understand vascular tone control in humans: the utility of studies in Bartter’s/Gitelmen’s syndromes. Kidney Int. In press
  5. Calò LA, Pagnin E, Davis PA, Sartori M, Ceolotto G, Pessina AC, Semplicini A: Increased expression of regulator of G protein signaling-2 (RGS-2) in Bartter’s/Gitelman’s sydrome: a role in the control of vascular tone and implication for hypertension. J Clin Endocrinol Metab 89:4153–4157, 2004[Abstract/Free Full Text]
  6. Calò L, Ceolotto G, Milani M, Pagnin E, van den Heuvel LP, Sartori M, Davis PA, Costa R, Semplicini A: Abnormalities of Gq-mediated cell signaling in Bartter and Gitelman syndromes. Kidney Int 60:882–889, 2001[Medline]
  7. Calò L, Davis PA, Semplicini A: Reduced content of alpha subunit of Gq protein in monocytes of Bartter and Gitelman syndromes: relationship with vascular hyporeactivity. Kidney Int 61:353–354, 2002
  8. Di Virgilio F, Calò L, Cantaro S, Favaro S, Piccoli A, Borsatti A: Resting and stimulated cytosolic free calcium levels in neutrophils from patients with Bartter’s syndrome. Clin Sci 72:483–488, 1987[Medline]
  9. Calò L, D’Angelo A, Cantaro S, Rizzolo M, Favaro S, Antonello A, Borsatti A: Intracellular calcium signalling and vascular reactivity in Bartter’s syndrome. Nephron 72:570–573, 1996[Medline]
  10. Calò L, Davis PA, Milani M, Cantaro S, Antonello A, Favaro S, D’Angelo A: Increased endothelial nitric oxide synthase mRNA level in Bartter’s and Gitelman’s syndrome: relationship to vascular reactivity. Clin Nephrol 51:12–17, 1999[Medline]
  11. Calò L, D’Angelo A, Cantaro S, Bordin MC, Favaro S, Antonello A, Borsatti A: Increased urinary NO2–/NO3– and cyclic GMP levels in patients with Bartter’s syndrome: relationship to vascular reactivity. Am J Kidney Dis 27:874–879, 1996
  12. Calò L, Cantaro S, Calabro A, Piarulli F, Rizzolo M, Favaro S, Antonello A, Crepaldi G, Borsatti A: Endothelium-derived vasoactive substances in Bartter’s syndrome. Angiology 46:905–913, 1995
  13. Calò LA, Pagnin E, Davis PA, Sartori M, Semplicini A: Oxidative stress related factors in Bartter’s and Gitelman’s syndromes: relevance for angiotensin II signalling. Nephrol Dial Transplant 18:1518–1525, 2003[Abstract/Free Full Text]
  14. Calò L, Sartore G, Bassi A, Basso C, Bertocco S, Marin R, Zambon S, Cantaro S, D’Angelo A, Davis PA, Manzato E, Crepaldi G: Reduced susceptibility of low density lipoprotein to oxidation in patients with overproduction of nitric oxide (Bartter’s and Gitelman’s syndrome). J Hypertens 16:1001–1008, 1998[Medline]
  15. Wolfrum S, Dendorfer A, Rikitake Y, Stalker TJ, Gong Y, Scalia R, Dominiak P, Liao PK: Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3 kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847, 2004[Abstract/Free Full Text]
  16. Sowers JR: Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 286:H1597–H1602, 2004[Abstract/Free Full Text]
  17. Pagnin E, Davis PA, Sartori M, Semplicini A, Pessina AC, Calò LA: Rho kinase and PAI-1 in Bartter’s/Gitelman’s syndromes: relationship to angiotensin II signaling. J Hypertens 22:1963–1969, 2004[Medline]
  18. Pagnin E, Semplicini A, Sartori M, Pessina AC, and Calò LA: Reduced mRNA and protein content of Rho guanine nucleotide exchange factor (RhoGEF) in Bartter’s and Gitelman’s syndromes: relevance for the pathophysiology of hypertension. Am J Hypertens 18:1200–1205, 2005[Medline]
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  20. Mita S, Kobayashi N, Yoshida K, Nakano S, Matsuoka H: Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertens 23:87–96, 2005[Medline]
  21. Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CM, Cuadrado A: Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem 279:8919–8929, 2004[Abstract/Free Full Text]
  22. Avogaro A, Pagnin E, Calo L: Monocyte NADPH oxidase subunit p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in type II diabetic patients: relationship with oxidative stress. J Clin Endocrinol Metab 88:1753–1759, 2003[Abstract/Free Full Text]
  23. Pagnin E, Fadini G, de Toni R, Tiengo A, Calo L, Avogaro A: Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. J Clin Endocrinol Metab 90:1130–1136, 2005[Abstract/Free Full Text]

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 Nephrol Dial TransplantHome page
L. A. Calo, M. Puato, S. Schiavo, M. Zanardo, C. Tirrito, E. Pagnin, G. Balbi, P. A. Davis, P. Palatini, and P. Pauletto
Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways
Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2804 - 2809.
[Abstract] [Full Text] [PDF]

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