Evaluating the significance of hypoglycemia in promoting insulin induced hypertension by using a glucose clamp model

  • Abstract
  • Keywords
  • References
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  • Abstract

    Background: Hypoglycemia unawareness is a detrimental risk factor in diabetic patients leading to serious complications if left untreated. Previous studies from our group determined that recurrent insulin induced hypoglycemia (RIIH) promotes hypertension.

    Objective: We hypothesize that RIIH not insulin by itself is the source of hypertension and end organ damage in diabetic patients.

    Methods: Male Sprague-Dawley-rats (200-250g, n=18) were provided with glucose food (125g glucose/kg body weight) and glucose water (0.1g glucose/100g body weight/ml). They were treated with subcutaneous insulin injections (7U/Kg) and blood glucose was monitored intermittently. Daily blood pressure was measured using the tail cuff method. Interstitial samples of ATP and angiotensinII (AngII) were collected by renal microdialysis and analyzed using luciferin-luciferase bioluminescent assay and EIA respectively. Reactive oxygen and nitrogen species in hearts and kidneys were analyzed using Electron Paramagnetic Resonance Spectroscopy (EPR).

    Results: Renal interstitial ATP levels increased from 90.2± 4.7ng/µl to 99.6± 8.7ng/µl (not significant) and AngII from 0.15± 0.02ng/ml to 0.13± 0.05ng/ml (not significant) from day 0 to 14. There was no significant change in mean arterial pressure (121.3 ± 1.4 mmHg on day 0 to 127.8 ± 1.4mmHg on day 14). Oxidative stress was reduced compared to RIIH model, which was evident from the EPR spectra.

    Conclusion: We demonstrated that hypertension induced end organ damage in diabetics is due to insulin induced hypoglycemia not insulin alone (by itself).

  • Keywords

    Angiotensin II; ATP; Diabetes; Hypertension; Microdialysis.

  • References

    1. [1] Action to Control Cardiovascular Risk in Diabetes Study, G., Gerstein, H. C., Miller, M. E., Byington, R. P., Goff, D. C., Jr., Bigger, J. T., Friedewald, W. T. (2008). Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 358(24), 2545-2559. https://doi.org/10.1056/NEJMoa0802743.

      [2] Bally, L., Zueger, T., Pasi, N., Carlos, C., Paganini, D., & Stettler, C. (2016). Accuracy of continuous glucose monitoring during differing exercise conditions. Diabetes Res Clin Pract, 112, 1-5. https://doi.org/10.1016/j.diabres.2015.11.012.

      [3] Baltatzi, M., Savopoulos, C., & Hatzitolios, A. (2011). Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results. Hippokratia, 15(Suppl 1), 27-32.

      [4] Chan, C. M., Unwin, R. J., & Burnstock, G. (1998). Potential functional roles of extracellular ATP in kidney and urinary tract. Exp Nephrol, 6(3), 200-207. https://doi.org/10.1159/000020524.

      [5] Choudhary, P., Ramasamy, S., Green, L., Gallen, G., Pender, S., Brackenridge, A., Pickup, J. C. (2013). Real-time continuous glucose monitoring significantly reduces severe hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes. Diabetes Care, 36(12), 4160-4162. https://doi.org/10.2337/dc13-0939.

      [6] Davis, S. N., Shavers, C., Mosqueda-Garcia, R., & Costa, F. (1997). Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes, 46(8), 1328-1335. https://doi.org/10.2337/diab.46.8.1328.

      [7] De Galan, B. E., Schouwenberg, B. J., Tack, C. J., & Smits, P. (2006). Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes. Neth J Med, 64(8), 269-279.

      [8] Dikalov, S., Griendling, K. K., & Harrison, D. G. (2007). Measurement of reactive oxygen species in cardiovascular studies. Hypertension, 49(4), 717-727. https://doi.org/10.1161/01.HYP.0000258594.87211.6b.

      [9] Dikalova, A., Clempus, R., Lassegue, B., Cheng, G., McCoy, J., Dikalov, S., Griendling, K. K. (2005). Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation, 112(17), 2668-2676. https://doi.org/10.1161/CIRCULATIONAHA.105.538934.

      [10] Eadington, D. W., Frier, B. M., & Swainson, C. P. (1994). Renal tubular responses to low-dose infusion of angiotensin II in type 1 diabetes mellitus; relation to chronic glycaemic control. Nephrol Dial Transplant, 9(9), 1264-1270.

      [11] El-Atat, F. A., Stas, S. N., McFarlane, S. I., & Sowers, J. R. (2004). The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol, 15(11), 2816-2827. https://doi.org/10.1097/01.ASN.0000133698.80390.37.

      [12] Elks, C. M., Mariappan, N., Haque, M., Guggilam, A., Majid, D. S., & Francis, J. (2009). Chronic NF-{kappa} B blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Renal Physiol, 296(2), F298-305. https://doi.org/10.1152/ajprenal.90628.2008.

      [13] Geddes, J., Schopman, J. E., Zammitt, N. N., & Frier, B. M. (2008). Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med, 25(4), 501-504. https://doi.org/10.1111/j.1464-5491.2008.02413.x.

      [14] Harrison-Bernard, L. M., Imig, J. D., & Carmines, P. K. (2002). Renal AT1 receptor protein expression during the early stage of diabetes mellitus. Int J Exp Diabetes Res, 3(2), 97-108. https://doi.org/10.1080/15604280214483.

      [15] Hoar, W., & Hickman, C. (1975). Ovariectomy and the estrous cycle of the rat-General and Comparitive Physiology.

      [16] Kobori, H., Harrison-Bernard, L. M., & Navar, L. G. (2001). Enhancement of angiotensinogen expression in angiotensin II-dependent hypertension. Hypertension, 37(5), 1329-1335. https://doi.org/10.1161/01.HYP.37.5.1329.

      [17] Komlosi, P., Fintha, A., & Bell, P. D. (2005). Renal cell-to-cell communication via extracellular ATP. Physiology (Bethesda), 20, 86-90. https://doi.org/10.1152/physiol.00002.2005.

      [18] Kopkan, L., Castillo, A., Navar, L. G., & Majid, D. S. (2006). Enhanced superoxide generation modulates renal function in ANG II-induced hypertensive rats. Am J Physiol Renal Physiol, 290(1), F80-86. https://doi.org/10.1152/ajprenal.00090.2005.

      [19] Maran, A., Pavan, P., Bonsembiante, B., Brugin, E., Ermolao, A., Avogaro, A., & Zaccaria, M. (2010). Continuous glucose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther, 12(10), 763-768. https://doi.org/10.1089/dia.2010.0038.

      [20] Martin-Timon, I., & Del Canizo-Gomez, F. J. (2015). Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes, 6(7), 912-926. https://doi.org/10.4239/wjd.v6.i7.912.

      [21] Mathers, C. D., & Loncar, D. (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 3(11), e442. https://doi.org/10.1371/journal.pmed.0030442.

      [22] Moghissi, E., Ismail-Beigi, F., & Devine, R. C. (2013). Hypoglycemia: minimizing its impact in type 2 diabetes. Endocr Pract, 19(3), 526-535. https://doi.org/10.4158/EP13005.RA.

      [23] Navar, L. G., Harrison-Bernard, L. M., Nishiyama, A., & Kobori, H. (2002). Regulation of intrarenal angiotensin II in hypertension. Hypertension, 39(2 Pt 2), 316-322. https://doi.org/10.1161/hy0202.103821.

      [24] Nishiyama, A., Jackson, K. E., Majid, D. S., Rahman, M., & Navar, L. G. (2006). Renal interstitial fluid ATP responses to arterial pressure and tubuloglomerular feedback activation during calcium channel blockade. Am J Physiol Heart Circ Physiol, 290(2), H772-777. https://doi.org/10.1152/ajpheart.00242.2005.

      [25] Nishiyama, A., Majid, D. S., Taher, K. A., Miyatake, A., & Navar, L. G. (2000). Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance. Circ Res, 86(6), 656-662. https://doi.org/10.1161/01.RES.86.6.656.

      [26] Nishiyama, A., Majid, D. S., Walker, M., 3rd, Miyatake, A., & Navar, L. G. (2001). Renal interstitial atp responses to changes in arterial pressure during alterations in tubuloglomerular feedback activity. Hypertension, 37(2 Pt 2), 753-759. https://doi.org/10.1161/01.HYP.37.2.753.

      [27] Nishiyama, A., Rahman, M., & Inscho, E. W. (2004). Role of interstitial ATP and adenosine in the regulation of renal hemodynamics and microvascular function. Hypertens Res, 27(11), 791-804. https://doi.org/10.1291/hypres.27.791.

      [28] Prathipati, P., Alanazi, W., Fakhruddin, Jackson, D. W., & Jackson, K. E. (2015). Role of interstitial ATP and angiotensin II in mediating renal injury induced by recurrent insulin induced hypoglycemia. Annual Research and Review in Biology, 6(5), 9. https://doi.org/10.9734/ARRB/2015/16184.

      [29] Prathipati, P., Quadri, S., Jackson, D. W., & Jackson, K. E. (2012). Adaptation of Renal Microdialysis for chronic interstitial collection of Angiotensin II and ATP. International Journal Biology, 4(4). https://doi.org/10.5539/ijb.v4n4p127.

      [30] Prathipati, P., Quadri, S., Jackson, D. W., & Jackson, K. E. (2014). Role of nitric oxide in septal coronary arteries of obese zucker rats International Journal of Medicine, 2(1), 5. https://doi.org/10.14419/ijm.v2i1.1941.

      [31] Purohit, P., & Mathur, R. (2013). Hypertension association with serum lipoproteins, insulin, insulin resistance and C-Peptide: unexplored forte of cardiovascular risk in hypothyroidism. N Am J Med Sci, 5(3), 195-201. https://doi.org/10.4103/1947-2714.109187.

      [32] Quadri, S., Prathipati, P., Jackson, D. W., & Jackson, K. E. (2013). Augmentation of heme oxygenase Promotes acute angiotensin II induced hypertension Clinical and Experimental Medical Sciences, 1, 22. https://doi.org/10.12988/cems.2013.13003.

      [33] Quadri, S., Prathipati, P., Jackson, D. W., & Jackson, K. E. (2014a). Haemodynamic consequences of recurrent insulin-induced hypoglycaemia. Clin Exp Pharmacol Physiol, 41(1), 81-88. https://doi.org/10.1111/1440-1681.12183.

      [34] Quadri, S., Prathipati, P., Jackson, D. W., & Jackson, K. E. (2014b). Inhibition of angiotensin II with captopril in management of hypertension induced by recurrent insulin induced hypoglycemia. International journal of medical sciences.

      [35] Ruiz-Ortega, M., Esteban, V., Ruperez, M., Sanchez-Lopez, E., Rodriguez-Vita, J., Carvajal, G., & Egido, J. (2006). Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens, 15(2), 159-166. https://doi.org/10.1097/01.mnh.0000203190.34643.d4.

      [36] Ruster, C., & Wolf, G. (2006). Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol, 17(11), 2985-2991. https://doi.org/10.1681/ASN.2006040356.

      [37] Sauer, H., Klimm, B., Hescheler, J., & Wartenberg, M. (2001). Activation of p90RSK and growth stimulation of multicellular tumor spheroids are dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP. FASEB J, 15(13), 2539-2541. https://doi.org/10.1096/fj.01-0360fje.

      [38] Schopman, J. E., Geddes, J., & Frier, B. M. (2010). Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes. Diabetes Res Clin Pract, 87(1), 64-68. https://doi.org/10.1016/j.diabres.2009.10.013.

      [39] Touyz, R. M., & Schiffrin, E. L. (1999). Ang II-stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension, 34(4 Pt 2), 976-982. https://doi.org/10.1161/01.HYP.34.4.976.

      [40] Van Beers, C. A., Kleijer, S. J., Serne, E. H., Geelhoed-Duijvestijn, P. H., Snoek, F. J., Kramer, M. H., & Diamant, M. (2015). Design and rationale of the IN CONTROL trial: the effects of real-time continuous glucose monitoring on glycemia and quality of life in patients with type 1 diabetes mellitus and impaired awareness of hypoglycemia. BMC Endocr Disord, 15, 42. https://doi.org/10.1186/s12902-015-0040-3.

      [41] Wolf, G., Butzmann, U., & Wenzel, U. O. (2003). The renin-angiotensin system and progression of renal disease: from hemodynamics to cell biology. Nephron Physiol, 93(1), P3-13. https://doi.org/10.1159/000066656.

      [42] Zoungas, S., Patel, A., Chalmers, J., de Galan, B. E., Li, Q., Billot, L., Group, A. C. (2010). Severe hypoglycemia and risks of vascular events and death. N Engl J Med, 363(15), 1410-1418. https://doi.org/10.1056/NEJMoa1003795.




Article ID: 6813
DOI: 10.14419/ijm.v5i1.6813

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