Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 12/2015

Open Access 01-12-2015 | Article

Role of the renal sympathetic nerve in renal glucose metabolism during the development of type 2 diabetes in rats

Authors: Kazi Rafiq, Yoshihide Fujisawa, Shamshad J. Sherajee, Asadur Rahman, Abu Sufiun, Hiroyuki Kobori, Hermann Koepsell, Masaki Mogi, Masatsugu Horiuchi, Akira Nishiyama

Published in: Diabetologia | Issue 12/2015

Login to get access

Abstract

Aims/hypothesis

Recent clinical studies have shown that renal sympathetic denervation (RDX) improves glucose metabolism in patients with resistant hypertension. We aimed to elucidate the potential contribution of the renal sympathetic nervous system to glucose metabolism during the development of type 2 diabetes.

Methods

Uninephrectomised diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats underwent RDX at 25 weeks of age and were followed up to 46 weeks of age.

Results

RDX decreased plasma and renal tissue noradrenaline (norepinephrine) levels and BP. RDX also improved glucose metabolism and insulin sensitivity, which was associated with increased in vivo glucose uptake by peripheral tissues. Furthermore, RDX suppressed overexpression of sodium-glucose cotransporter 2 (Sglt2 [also known as Slc5a2]) in renal tissues, which was followed by an augmentation of glycosuria in type 2 diabetic OLETF rats. Similar improvements in glucose metabolism after RDX were observed in young OLETF rats at the prediabetic stage (21 weeks of age) without changing BP.

Conclusions/interpretation

Here, we propose the new concept of a connection between renal glucose metabolism and the renal sympathetic nervous system during the development of type 2 diabetes. Our data demonstrate that RDX exerts beneficial effects on glucose metabolism by an increase in tissue glucose uptake and glycosuria induced by Sglt2 suppression. These data have provided a new insight not only into the treatment of hypertensive type 2 diabetic patients, but also the pathophysiology of insulin resistance manifested by sympathetic hyperactivity.
Appendix
Available only for authorised users
Literature
1.
Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E (2006) Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension 48:787–796CrossRefPubMed
2.
Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP (2010) Sympathetic nervous activation in obesity and the metabolic syndrome—causes, consequences and therapeutic implications. Pharmacol Ther 126:159–172CrossRefPubMed
3.
Scherrer U, Sartori C (1997) Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation 96:4104–4113CrossRefPubMed
4.
Mancia G, Bousquet P, Elghozi JL et al (2007) The sympathetic nervous system and the metabolic syndrome. J Hypertens 25:909–920CrossRefPubMed
5.
Linz D, Hohl M, Schutze J et al (2015) Progression of kidney injury and cardiac remodeling in obese spontaneously hypertensive rats: the role of renal sympathetic innervation. Am J Hypertens 28:256–265CrossRefPubMed
6.
DiBona GF (2005) Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Com Physiol 289:R633–R641CrossRef
7.
Esler M (2010) The 2009 Carl Ludwig lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol (1985) 108:227–237CrossRef
8.
Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DA (2003) Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation 108:3097–3101CrossRefPubMed
9.
Vollenweider P, Tappy L, Randin D et al (1993) Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 92:147–154CrossRefPubMedCentralPubMed
10.
Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73:615–621CrossRefPubMed
11.
Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA (2012) Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 126:2976–2982CrossRefPubMed
12.
Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M (2010) Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 376:1903–1909CrossRefPubMed
13.
Krum H, Schlaich M, Whitbourn R et al (2009) Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373:1275–1281CrossRefPubMed
14.
Brandt MC, Mahfoud F, Reda S et al (2012) Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 59:901–909CrossRefPubMed
15.
Rafiq K, Noma T, Fujisawa Y et al (2012) Renal sympathetic denervation suppresses de novo podocyte injury and albuminuria in rats with aortic regurgitation. Circulation 125:1402–1413CrossRefPubMedCentralPubMed
16.
Bhatt DL, Kandzari DE, O'Neill WW et al (2014) A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370:1393–1401CrossRefPubMed
17.
Mahfoud F, Schlaich M, Kindermann I et al (2011) Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 123:1940–1946CrossRefPubMed
18.
Witkowski A, Prejbisz A, Florczak E et al (2011) Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 58:559–565CrossRefPubMed
19.
Schlaich MP, Straznicky N, Grima M et al (2011) Renal denervation: a potential new treatment modality for polycystic ovary syndrome? J Hypertens 29:991–996CrossRefPubMed
20.
Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T (1992) Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428CrossRefPubMed
21.
Yagi K, Kim S, Wanibuchi H, Yamashita T, Yamamura Y, Iwao H (1997) Characteristics of diabetes, blood pressure, and cardiac and renal complications in Otsuka Long-Evans Tokushima Fatty rats. Hypertension 29:728–735CrossRefPubMed
22.
Recordati G, Genovesi S, Cerati D (1982) Renorenal reflexes in the rat elicited upon stimulation of renal chemoreceptors. J Auton Nerv Syst 6:127–142CrossRefPubMed
23.
Recordati G, Genovesi S, Cerati D, di Cintio R (1980) Reno-renal and reno-adrenal reflexes in the rat. Clin Sci (Lond) 59(Suppl 6):S323–S325CrossRef
24.
Nakashima A, Matsuoka H, Yasukawa H et al (1996) Renal denervation prevents intraglomerular platelet aggregation and glomerular injury induced by chronic inhibition of nitric oxide synthesis. Nephron 73:34–40CrossRefPubMed
25.
Luippold G, Beilharz M, Muhlbauer B (2004) Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 19:342–347CrossRefPubMed
26.
Henriksen EJ, Jacob S, Kinnick TR, Teachey MK, Krekler M (2001) Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension 38:884–890CrossRefPubMed
27.
Rafiq K, Hitomi H, Nakano D, Ichihara A, Nishiyama A (2011) Possible involvement of the (pro)renin receptor-dependent system in the development of insulin resistance. Front Biosci (Schol Ed) 3:1478–1485CrossRef
28.
Kraegen EW, James DE, Bennett SP, Chisholm DJ (1983) In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol 245:E1–E7PubMed
29.
Ogihara T, Asano T, Ando K et al (2002) Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 40:872–879CrossRefPubMed
30.
Prysyazhna O, Rudyk O, Eaton P (2012) Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nat Med 18:286–290CrossRefPubMedCentralPubMed
31.
Zhang YC, Bui JD, Shen L, Phillips MI (2000) Antisense inhibition of beta(1)-adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats. Circulation 101:682–688CrossRefPubMed
32.
Shiuchi T, Iwai M, Li HS et al (2004) Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension 43:1003–1010CrossRefPubMed
33.
Shiuchi T, Nakagami H, Iwai M et al (2001) Involvement of bradykinin and nitric oxide in leptin-mediated glucose uptake in skeletal muscle. Endocrinology 142:608–612CrossRefPubMed
34.
Sudo M, Minokoshi Y, Shimazu T (1991) Ventromedial hypothalamic stimulation enhances peripheral glucose uptake in anesthetized rats. Am J Physiol 261:E298–E303PubMed
35.
Rafiq K, Nakano D, Ihara G et al (2011) Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats. J Hypertens 29:290–298CrossRefPubMedCentralPubMed
36.
Sherajee SJ, Fujita Y, Rafiq K et al (2012) Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor. Arterioscler Thromb Vasc Biol 32:257–263CrossRefPubMed
37.
Sabolic I, Vrhovac I, Eror DB et al (2012) Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol 302:C1174–C1188CrossRefPubMedCentralPubMed
38.
Masuo K, Mikami H, Ogihara T, Tuck ML (1997) Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens 10:77–83CrossRefPubMed
39.
Grassi G, Dell'Oro R, Quarti-Trevano F et al (2005) Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia 48:1359–1365CrossRefPubMed
40.
Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO (1993) Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 21:618–623CrossRefPubMed
41.
Grassi G, Dell'Oro R, Facchini A, Quarti Trevano F, Bolla GB, Mancia G (2004) Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives. J Hypertens 22:2363–2369CrossRefPubMed
42.
Wenzel RR, Spieker L, Qui S, Shaw S, Luscher TF, Noll G (1998) I1-imidazoline agonist moxonidine decreases sympathetic nerve activity and blood pressure in hypertensives. Hypertension 32:1022–1027CrossRefPubMed
43.
Yakubu-Madus FE, Johnson WT, Zimmerman KM, Dananberg J, Steinberg MI (1999) Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat model of type 2 diabetes. Diabetes 48:1093–1100CrossRefPubMed
44.
Krupicka J, Soucek M, Chroust K (2011) The efficacy and safety of moxonidine in patients with metabolic syndrome (the O.B.E.Z.I.T.A. trial). Vnitr Lek 57:541–545PubMed
45.
Prichard BN, Jager BA, Luszick JH et al (2002) Placebo-controlled comparison of the efficacy and tolerability of once-daily moxonidine and enalapril in mild to moderate essential hypertension. Blood Press 11:166–172CrossRefPubMed
46.
Helgeland A, Leren P, Foss OP, Hjermann I, Holme I, Lund-Larsen PG (1984) Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study. Am J Med 76:802–805CrossRefPubMed
47.
William-Olsson T, Fellenius E, Bjorntorp P, Smith U (1979) Differences in metabolic responses to beta-adrenergic stimulation after propranolol or metoprolol administration. Acta Med Scand 205:201–206CrossRefPubMed
48.
Gudbjornsdottir S, Fowelin J, Elam M et al (1997) The effect of metoprolol treatment on insulin sensitivity and diurnal plasma hormone levels in hypertensive subjects. Euro J Clin Investig 27:29–35CrossRef
49.
Pollare T, Lithell H, Selinus I, Berne C (1989) Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med J 298:1152–1157CrossRef
50.
Day JL (1975) The metabolic consequences of adrenergic blockade: a review. Metab Clin Exp 24:987–996CrossRefPubMed
51.
Lager I, Blohme G, Smith U (1979) Effect of cardioselective and non-selective beta-blockade on the hypoglycaemic response in insulin-dependent diabetics. Lancet 1:458–462CrossRefPubMed
52.
Cersosimo E, Ajmal M, Naukam RJ, Molina PE, Abumrad NN (1997) Role of the kidney in plasma glucose regulation during hyperglycemia. Am J Physiol 272:E756–E761PubMed
53.
Dominguez JH, Song B, Maianu L, Garvey WT, Qulali M (1994) Gene expression of epithelial glucose transporters: the role of diabetes mellitus. J Am Soc Nephrol 5:S29–S36PubMed
54.
55.
Wright EM, Loo DD, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794CrossRefPubMed
56.
Kanai Y, Lee WS, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Investig 93:397–404CrossRefPubMedCentralPubMed
57.
Pajor AM, Hirayama BA, Wright EM (1992) Molecular evidence for two renal Na+/glucose cotransporters. Biochim Biophys Acta 1106:216–220CrossRefPubMed
58.
Nakagawa T, Hasegawa Y, Uekawa K et al (2013) Renal denervation prevents stroke and brain injury via attenuation of oxidative stress in hypertensive rats. J Am Heart Assoc 2:e000375CrossRefPubMedCentralPubMed
Metadata
Title
Role of the renal sympathetic nerve in renal glucose metabolism during the development of type 2 diabetes in rats
Authors
Kazi Rafiq
Yoshihide Fujisawa
Shamshad J. Sherajee
Asadur Rahman
Abu Sufiun
Hiroyuki Kobori
Hermann Koepsell
Masaki Mogi
Masatsugu Horiuchi
Akira Nishiyama
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 12/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-015-3771-9

Other articles of this Issue 12/2015

Diabetologia 12/2015 Go to the issue

Article

Lipoprotein heterogeneity may help to detect individuals with insulin resistance

Erratum

Erratum to: Turning the page

Article

Pre-pregnancy dietary patterns and risk of gestational diabetes mellitus: results from an Australian population-based prospective cohort study

Article

Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes

Article

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9–16 years (EarlyBird 66)

Article

Weight cycling and the risk of type 2 diabetes in the EPIC-Germany cohort
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits