Abstract
Hypertension is highly prevalent among people with diabetes, and the presence of diabetes
among those with hypertension portends an increase in cardiovascular risk. In this
review we aim to explore the pathophysiological links between diabetes and hypertension.
Renal sodium handling differs in diabetes because there is an upregulation of sodium
transporters in the kidneys. The renin-angiotensin-aldosterone system may be upregulated
in diabetes, leading to hypertension through a direct effect mediated by angiotensin
II, as well as indirectly through upregulation of sympathetic activity. Renin-angiotensin-aldosterone
system blockade is a mainstay therapy for hypertension, and evidence suggests that
it might also reduce the incidence of diabetes. People with diabetes frequently have
autonomic dysfunction, which could contribute to hypertension through increased sympathetic
tone and through stimulation of renin production in the juxtaglomerular apparatus.
Furthermore, people with diabetes also frequently show an abnormality in their circadian
blood pressure pattern. Another important link between hypertension and diabetes is
the development as well as progression of diabetic kidney disease, the pathophysiology
of which is mediated through several pathways including endothelial dysfunction and
advanced glycation end products. Finally, obesity and the metabolic syndrome, through
their effects on various hormones and inflammation, might also contribute to the pathogenesis
of hypertension and diabetes.
Résumé
L'hypertension est fortement prévalente chez les personnes atteintes de diabète, et
la présence de diabète chez les personnes hypertendues laisse présager une augmentation
du risque cardiovasculaire. L'objet de cette étude est d'explorer les liens physiopathologiques
entre le diabète et l'hypertension. La prise en charge du sodium rénal diffère dans
le diabète en raison de la régulation positive à laquelle sont soumis les transporteurs
de sodium dans le rein. Le système rénine-angiotensine-aldostérone pourrait être régulé
positivement dans le diabète et provoquer de l'hypertension à la fois par un effet
direct médié par l'angiotensine II et indirectement par la régulation positive de
l'activité sympathique. Le blocage du système rénine-angiotensine-aldostérone est
un élément fondamental du traitement de l'hypertension et, d'après des données probantes,
pourrait également réduire l'incidence du diabète. Les personnes atteintes de diabète
présentent aussi souvent un dysfonctionnement du système nerveux autonome qui pourrait
contribuer à l'hypertension par l'intermédiaire de la stimulation de la production
de rénine dans l'appareil juxtaglomérulaire. De surcroît, les personnes atteintes
de diabète présentent souvent une anomalie de leur profil de variation circadienne
de la pression artérielle. Un autre lien important entre l'hypertension et le diabète
est l'apparition et la progression de la néphropathie diabétique par plusieurs voies
physiopathologiques, y compris la dysfonction endothéliale et les produits terminaux
de la glycation. Enfin, par leurs effets sur différentes hormones et sur l'inflammation,
l'obésité et le syndrome métabolique pourraient également jouer un rôle dans la pathogenèse
de l'hypertension et du diabète.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 2016. Global report on diabetes.(Available at:)apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdfDate accessed: October 31, 2017
- Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.Diabetes Care. 2004; 27: 1047-1053
- Type 2 diabetes mellitus and hypertension: an update.Endocrinol Metab Clin North Am. 2014; 43: 103-122
- Prevalence of insulin resistance and related risk factors for cardiovascular disease in patients with essential hypertension.Am J Hypertens. 2009; 22: 106-111
- Joint effects of history of hypertension at baseline and type 2 diabetes at baseline and during follow-up on the risk of coronary heart disease.Eur Heart J. 2007; 28: 3059-3066
- Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure.Hypertension. 2011; 57: 891-897
- Sodium and potassium in the pathogenesis of hypertension.N Engl J Med. 2007; 356: 1966-1978
- Hypertension treated by salt restriction.Lancet. 1978; 1: 227-230
- Association of urinary sodium and potassium excretion with blood pressure.N Engl J Med. 2014; 371: 601-611
- Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion.BMJ. 1988; 297: 319-328
- The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866
- Diabetes and hypertension: a position statement by the American Diabetes Association.Diabetes Care. 2017; 40: 1273-1284
- High sodium and low potassium intake in patients with type 2 diabetes.Diabet Med. 2010; 27: 1401-1408
- A low-sodium diet potentiates the effects of losartan in type 2 diabetes.Diabetes Care. 2002; 25: 663-671
- Salt supplementation blunts the blood pressure response to telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes.Diabetologia. 2010; 53: 1295-1303
- Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type 2 diabetes mellitus.Clin Sci (Lond). 2015; 129: 415-422
- Sodium and its role in cardiovascular disease – the debate continues.Front Endocrinol (Lausanne). 2016; 7: 164
- Dietary salt intake and mortality in patients with type 2 diabetes.Diabetes Care. 2011; 34: 703-709
- Relationship between urinary sodium excretion and serum aldosterone in patients with diabetes in the presence and absence of modifiers of the renin-angiotensin-aldosterone system.Clin Sci (Lond). 2014; 126: 147-154
- Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials.JAMA. 1997; 277: 1624-1632
- Joint effects of sodium and potassium intake on subsequent cardiovascular disease: the Trials of Hypertension Prevention follow-up study.Arch Intern Med. 2009; 169: 32-40
- Relationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus.Clin Exp Pharmacol Physiol. 2018; 45: 94-97
- Body sodium-blood volume state in nonazotemic diabetes mellitus.Miner Electrolyte Metab. 1982; 7: 36-47
- Exchangeable sodium and renin in hypertensive diabetic patients with and without nephropathy.Hypertension. 1985; 7: II43-II48
- Increased prevalence of salt sensitivity of blood pressure in IDDM with and without microalbuminuria.Diabetologia. 1995; 38: 1443-1448
- Salt-sensitive blood pressure and exaggerated vascular reactivity in the hypertension of diabetes mellitus.Am J Med. 1990; 88: 210-216
- Insulin’s impact on renal sodium transport and blood pressure in health, obesity, and diabetes.Am J Physiol Renal Physiol. 2007; 293: F974-F984
- The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man.J Clin Invest. 1975; 55: 845-855
- Changes in blood pressure and plasma catecholamine levels during prolonged hyperinsulinemia.Metabolism. 2005; 54: 391-396
- Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans.Hypertension. 1992; 19: 621-627
- ‘Physiological’ hyperinsulinaemia increases distal artery systolic blood pressure without changing proximal blood pressure.Clin Sci (Lond). 1997; 93: 535-540
- Epithelial sodium channel: Mendelian versus essential hypertension.Hypertension. 2008; 52: 595-600
- Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London.Lancet. 1998; 351: 1388-1392
- Increased renal Na-K-ATPase, NCC, and beta-ENaC abundance in obese Zucker rats.Am J Physiol Renal Physiol. 2001; 281: F639-F648
- Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes.Am J Physiol Renal Physiol. 2003; 285: F1125-F1137
- Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.J Am Soc Hypertens. 2014; 8: 330-339
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128
- Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657
- Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.Diabetes Care. 2015; 38: 420-428
- Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Diabetes Endocrinol. 2016; 4: 211-220
- Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin.Kidney Int. 2018; 93: 231-244
- The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.Cardiovasc Diabetol. 2014; 13: 28
- SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.Diabetes Care. 2016 May; 39: 717-725
- Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management.Adv Chronic Kidney Dis. 2011; 18: 28-41
- Deficiency in angiotensin AT1a receptors prevents diabetes-induced hypertension.Am J Physiol Regul Integr Comp Physiol. 2007; 292: R1184-R1189
- Tissue gene expression of renin-angiotensin system in human type 2 diabetic nephropathy.Diabetes Care. 2006; 29: 848-852
- Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension.J Hypertens. 2002; 20: 965-973
- The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications.Am J Hypertens. 2004; 17: 16S-20S
- Improved islet morphology after blockade of the renin- angiotensin system in the ZDF rat.Diabetes. 2004; 53: 989-997
- Hypertension and diabetes.Curr Opin Nephrol Hypertens. 2002; 11: 221-228
- Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.N Engl J Med. 2000; 342: 145-153
- Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860
- Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869
- Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031
- Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.Lancet. 2003; 362: 759-766
- Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes.J Hypertens. 2005; 23: 463-473
- Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors.Hypertension. 1993; 22: 699-704
- Angiotensin converting enzyme inhibition improves cardiac neuronal uptake of noradrenaline in spontaneously hypertensive rats.J Hypertens. 2001; 19: 1827-1833
- ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure.Am J Physiol. 1999; 277: H1609-H1617
- Autonomic dysfunction in essential hypertension: a systematic review.Ann Med Surg (Lond). 2013; 3: 2-7
- β-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects.Am J Hypertens. 1999; 12: 451-459
- Sympathetic nervous system, diabetes, and hypertension.Clin Exp Hypertens. 2001; 23: 45-55
- Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.J Clin Invest. 1991; 87: 2246-2252
- Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.J Clin Invest. 1994; 93: 2365-2371
- Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension.Circulation. 2003; 108: 3097-3101
- Renal denervation reverses hepatic insulin resistance induced by high-fat diet.Diabetes. 2016; 65: 3453-3463
- Effect of renal sympathetic denervation on hepatic glucose metabolism and blood pressure in a rat model of insulin resistance.J Hypertens. 2016; 34: 2465-2474
- Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study.Circulation. 2011; 123: 1940-1946
- Renal denervation for resistant hypertension.Cochrane Database Syst Rev. 2017; 2: CD011499
- Predictors of mortality in patients with type 2 diabetes with or without diabetic nephropathy: a follow-up study.J Hypertens. 2007; 25: 2479-2485
- Non-dipping circadian blood pressure and renal impairment are associated with increased mortality in diabetes mellitus.Diabet Med. 2000; 17: 360-364
- Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes.N Engl J Med. 2002; 347: 797-805
- Increased blood pressure variability during 24h blood pressure monitoring as an early sign of autonomic dysfunction in non-insulin-dependent diabetics.J Hum Hypertens. 1994; 8: 887-890
- Evening versus morning dosing regimen drug therapy for hypertension.Cochrane Database Syst Rev. 2011; 10: CD004184
- Influence of time of day of blood pressure–lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes.Diabetes Care. 2011; 34: 1270-1276
- Spectrum of renal disease in diabetes.Nephrology (Carlton). 2014; 19: 528-536
- Pathogenetic mechanisms of diabetic nephropathy.J Am Soc Nephrol. 2005; 16: S30-S33
- Effects of glycaemic management on diabetic kidney disease.World J Diabetes. 2017; 8: 172-186
- RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes.J Am Soc Nephrol. 2009; 20: 742-752
- Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes.Clin Sci (Lond). 2016; 130: 711-720
- Insulin action and insulin resistance in vascular endothelium.Curr Opin Clin Nutr Metab Care. 2007; 10: 523-530
- Diabetes mellitus increases endothelin-1 gene transcription in rat kidney.Kidney Int. 2000; 58: 1534-1545
- Elevated plasma endothelin in patients with diabetes mellitus.Diabetologia. 1990; 33: 306-310
- Plasma endothelin levels in patients with uraemia.Lancet. 1989; 1: 991-992
- Avosentan for overt diabetic nephropathy.J Am Soc Nephrol. 2010; 21: 527-535
- The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.J Am Soc Nephrol. 2014; 25: 1083-1093
- Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site.J Clin Invest. 2001; 108: 1341-1348
- Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy.J Am Soc Nephrol. 2007; 18: 539-550
- Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin.Circulation. 2000; 101: 676-681
- Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus.Am J Cardiol. 2001; 88: 1201-1203
- Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease.J Am Soc Nephrol. 1999; 10: 594-600
- Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.Lancet. 2001; 358: 2113-2117
- Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.Arterioscler Thromb Vasc Biol. 2003; 23: 1455-1459
- Association between intrarenal arterial resistance and diastolic dysfunction in type 2 diabetes.Cardiovasc Diabetol. 2008; 7: 15
- The metabolic syndrome.Lancet. 2005; 365: 1415-1428
- Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.J Clin Invest. 1994; 94: 1172-1179
- Adverse endothelial function and the insulin resistance syndrome.J Intern Med. 2000; 247: 425-431
- Role of insulin resistance in the genesis of sodium sensitivity in essential hypertension.J Hum Hypertens. 1999; 13: 257-262
- Amylin. Curr Opin Endocrinol Diabetes Obes. 2006; 13: 191-198
- Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.Lancet. 2014; 383: 1068-1083
- Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney.Am J Physiol. 1997; 272: F13-F21
- Amylin binding in rat renal cortex, stimulation of adenylyl cyclase, and activation of plasma renin.Am J Physiol. 1996; 270: F289-F294
- Amylin stimulates plasma renin concentration in humans.Hypertension. 1995; 26: 460-464
- Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N Engl J Med. 1996; 334: 292-295
- The role of leptin in diabetes: metabolic effects.Diabetologia. 2016; 59: 928-932
- Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes.Diabetes. 2011; 60: 1474-1477
- Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance.Diabetes. 2011; 60: 1647-1656
- Leptin mediates the increase in blood pressure associated with obesity.Cell. 2014; 159: 1404-1416
- Leptin and hypertension in obesity.Vasc Health Risk Manag. 2006; 2: 163-169
- The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications.Diabetes Obes Metab. 2014; 16: 9-21
- Liraglutide and Cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322
- Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844
- Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials.Diabetes Obes Metab. 2013; 15: 737-749
- Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis.BMJ Open. 2013; 3e001986
- Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.Clin Sci (Lond). 1999; 96: 335-342
- Peroxisome proliferator–activated receptors as transcriptional nodal points and therapeutic targets.Circulation. 2007; 115: 518-533
- Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation.Endocrinology. 1994; 135: 798-800
- Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension.Nature. 1999; 402: 880-883
- Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus.Curr Med Res Opin. 2003; 19: 532-539
- Pioglitazone decreases ambulatory blood pressure in type 2 diabetics with difficult-to-control hypertension.J Clin Hypertens (Greenwich). 2007; 9: 530-537
- Inflammation, stress, and diabetes.J Clin Invest. 2005; 115: 1111-1119
- Obesity and the role of adipose tissue in inflammation and metabolism.Am J Clin Nutr. 2006; 83: 461S-465S
- Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ agonists.Am J Cardiol. 2007; 99: 27B-40B
- C-reactive protein and the risk of developing hypertension.JAMA. 2003; 290: 2945-2951
- Blood pressure, C-reactive protein, and risk of future cardiovascular events.Circulation. 2003; 108: 2993-2999
- Inflammation and the incidence of type 2 diabetes.Diabetes Care. 2010; 33: 804-810
- Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.JAMA. 2003; 289: 1799-1804
- Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377: 1119-1131
- Metabolic syndrome and insulin resistance as risk factors for development of chronic kidney disease and rapid decline in renal function in elderly.J Clin Endocrinol Metab. 2012; 97: 1268-1276
- Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults.J Am Soc Nephrol. 2005; 16: 2134-2140
- Insulin resistance in patients with chronic kidney disease.J Biomed Biotechnol. 2012; 2012: 691369
- Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568
- Insulin resistance and pancreatic beta-cell function in patients with hypertensive kidney disease.Nephrol Dial Transplant. 2004; 19: 2025-2029
- Insulin resistance in chronic kidney disease: a systematic review.Am J Physiol Renal Physiol. 2016; 311: F1087-F1108
Article info
Publication history
Published online: January 21, 2018
Accepted:
January 8,
2018
Received:
November 1,
2017
Footnotes
See page 591 for disclosure information.
Identification
Copyright
© 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
