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Effect of Antihypertensive Agents on the Development of Type 2 Diabetes Mellitus

  • Craig S. Stump
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Craig S. Stump, MD, PhD, Department of Internal Medicine and Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia, Harry S Truman VA Medical Center, Columbia, MO 65212
    Affiliations
    Department of Internal Medicine and Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia, Harry S Truman VA Medical Center, Columbia
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  • Marc T. Hamilton
    Affiliations
    Department of Veterinary Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia
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  • James R. Sowers
    Affiliations
    Department of Internal Medicine and Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia, Harry S Truman VA Medical Center, Columbia
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      People with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and β-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population.
      ACE (angiotensin-converting enzyme), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial), ARB (angiotensin receptor blocker), CCB (calcium channel blocker), CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity), GLUT4 (insulin-sensitive glucose transporter 4)
      Evidence of a causal relationship between insulin resistance and hypertension is increasing.
      • Sowers JR
      Insulin resistance and hypertension.
      Untreated patients with essential hypertension generally have higher fasting and postprandial insulin levels than normotensive patients regardless of body mass. A direct correlation exists between blood pressure and fasting insulin levels with essential hypertension,
      • Sowers JR
      Insulin resistance and hypertension.
      • Denker PS
      • Pollock VE
      Fasting serum insulin levels in essential hypertension: a meta-analysis.
      • Grunfeld B
      • Balzareti M
      • Romo M
      • Gimenez M
      • Gutman R
      Hyperinsulinemia in normotensive offspring of hypertensive parents.
      • Reaven GM
      • Lithell H
      • Landsberg L
      Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.
      • Steinberg HO
      • Chaker H
      • Leaming R
      • Johnson A
      • Brechtel G
      • Baron AD
      Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance.
      • McFarlane SI
      • Banerji M
      • Sowers JR
      Insulin resistance and cardiovascular disease.
      which does not occur with secondary hypertension.
      • Sowers JR
      Insulin resistance and hypertension.
      Insulin resistance and hyperinsulinemia are found in animal models of genetic hypertension.
      • Sowers JR
      Insulin resistance and hypertension.
      Thus, insulin resistance and hyperinsulinemia are not consequences of hypertension. Rather, they may reflect a genetic predisposition that contributes to and links these disorders.
      • Sowers JR
      Insulin resistance and hypertension.
      • McFarlane SI
      • Banerji M
      • Sowers JR
      Insulin resistance and cardiovascular disease.
      This concept is supported by the finding of altered glucose metabolism in normotensive offspring of parents with hypertension
      • Grunfeld B
      • Balzareti M
      • Romo M
      • Gimenez M
      • Gutman R
      Hyperinsulinemia in normotensive offspring of hypertensive parents.
      and further by the discovery of specific genetic defects in persons with combinations of insulin resistance, dyslipidemia, and hypertension, which has been reviewed previously.
      • Roche HM
      • Phillips C
      • Gibney MJ
      The metabolic syndrome: the crossroads of diet and genetics.
      • Groop L
      Genetics of the metabolic syndrome.
      Likewise, in utero fetal programming has been implicated in predisposing individuals to insulin-resistant metabolic disease.
      • McMillen IC
      • Robinson JS
      Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.
      • Stocker CJ
      • Arch JR
      • Cawthorne MA
      Fetal origins of insulin resistance and obesity.
      However, the relative contributions of genetic, fetal, and postnatal environmental factors to overall risk remain uncertain.
      Evidence exists that insulin resistance and hyperinsulinemia predispose patients to the development of hypertension through cellular abnormalities in insulin signaling and associated hemodynamic and metabolic derangements.
      • Sowers JR
      Insulin resistance and hypertension.
      • Reaven GM
      • Lithell H
      • Landsberg L
      Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.
      • McFarlane SI
      • Banerji M
      • Sowers JR
      Insulin resistance and cardiovascular disease.
      These predisposing abnormalities include cellular cation imbalance, enhanced sympathetic nervous system activity,
      • Reaven GM
      • Lithell H
      • Landsberg L
      Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system.
      enhanced tissue renin-angiotensin system activity,
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      • Lavoie JL
      • Bianco RA
      • Sakai K
      • Keen HL
      • Ryan MJ
      • Sigmund CD
      Transgenic mice for studies of the renin-angiotensin system in hypertension.
      and increased inflammation and oxidative stress.
      • Sowers JR
      Insulin resistance and hypertension.
      It also is becoming increasingly clear that antihypertensive medications have disparate effects on insulin sensitivity in patients with essential hypertension.
      • Perez-Stable E
      • Caralis PV
      Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.
      • Lithell HO
      Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.
      • Harper R
      • Ennis CN
      • Sheridan B
      • Atkinson AB
      • Johnston GD
      • Bell PM
      Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.
      • Fletcher A
      • Amery A
      • Birkenhager W
      • et al.
      Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.
      • Savage PJ
      • Pressel SL
      • Curb JD
      • SHEP Cooperative Research Group
      • et al.
      Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program.
      • Verdecchia P
      • Reboldi G
      • Angeli F, L
      • et al.
      Adverse prognostic significance of new diabetes in treated hypertensive subjects.
      • Pollare T
      • Lithell H
      • Selinus I
      • Berne C
      Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.
      • Lithell H
      • Pollare T
      • Vessby B
      Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.
      • Samuelsson O
      • Hedner T
      • Berglund G
      • Persson B
      • Andersson OK
      • Wilhelmsen L
      Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.
      • Gress TW
      • Nieto FJ
      • Shahar E
      • Wofford MR
      • Brancati FL
      Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.
      • Sowers JR
      • Bakris GL
      Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.

      ANTIHYPERTENSIVE AGENTS AND DIABETES

      Clinical Studies

      Both diuretics and β-blockers are reported to accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension.
      • Perez-Stable E
      • Caralis PV
      Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.
      • Lithell HO
      Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.
      • Harper R
      • Ennis CN
      • Sheridan B
      • Atkinson AB
      • Johnston GD
      • Bell PM
      Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.
      • Fletcher A
      • Amery A
      • Birkenhager W
      • et al.
      Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.
      • Savage PJ
      • Pressel SL
      • Curb JD
      • SHEP Cooperative Research Group
      • et al.
      Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program.
      • Verdecchia P
      • Reboldi G
      • Angeli F, L
      • et al.
      Adverse prognostic significance of new diabetes in treated hypertensive subjects.
      • Pollare T
      • Lithell H
      • Selinus I
      • Berne C
      Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.
      • Lithell H
      • Pollare T
      • Vessby B
      Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.
      • Samuelsson O
      • Hedner T
      • Berglund G
      • Persson B
      • Andersson OK
      • Wilhelmsen L
      Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.
      • Gress TW
      • Nieto FJ
      • Shahar E
      • Wofford MR
      • Brancati FL
      Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.
      • Sowers JR
      • Bakris GL
      Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      The greater incidence of diabetes in reports comparing diuretics and β-blockers with angiotensin-converting enzyme (ACE) inhibitors may reflect in part the beneficial effects of ACE inhibitors on glucose metabolism.
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      • Hansson L
      • Lindholm LH
      • Niskanen L
      • et al.
      Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
      • Brown MJ
      • Palmer CR
      • Castaigne A
      • et al.
      Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [published correction appears in Lancet. 2000;356:514].
      • Black HR
      • Elliott WJ
      • Grandits G
      • et al.
      Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.
      • Pepine CJ
      • Handberg EM
      • Cooper-DeHoff RM
      • INVEST Investigators
      • et al.
      A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
      Compared with calcium channel blockers (CCBs), which are generally considered metabolically neutral,
      • McFarlane SI
      • Farag A
      • Sowers J
      Calcium antagonists in patients with type 2 diabetes and hypertension.
      diuretics and β-blockers are associated with new-onset diabetes mellitus.
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      • Brown MJ
      • Palmer CR
      • Castaigne A
      • et al.
      Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [published correction appears in Lancet. 2000;356:514].
      • Black HR
      • Elliott WJ
      • Grandits G
      • et al.
      Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.
      In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial (ALLHAT),
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      the diuretic chlorthalidone was 43% more likely to be associated with diabetes than the ACE inhibitor lisinopril and 18% more likely than the CCB amlodipine. However, these calculations only account for those individuals whose glucose values increased to greater than 126 mg/dL at 4 years not those who started taking the medication for diabetes during follow-up. Nevertheless, diuretics have consistently demonstrated their ability toreduce the cardiovascular mortality in patients with diabetes. ALLHAT concluded that thiazide diuretics comparably reduced all-cause mortality, such as stroke, coronary artery disease, and heart failure.
      • ALLHAT Officers and Coordinators, ALLHAT Collaborative Research Group
      Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published corrections appear in JAMA. 2003;289:178 and 2004;291:2196].
      Therefore, diuretics continue to play an important role in the management of hypertension in patients with diabetes, especially as an adjunct to ACE inhibitors and angiotensin receptor blockers (ARBs).
      Evidence is accumulating that overcoming insulin resistance with antihypertensive agents that interrupt the reninangiotensin system may prevent or delay the emergence of type 2 diabetes mellitus in patients with essential hypertension
      • Sowers JR
      Insulin resistance and hypertension.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      (Table 1). The Captopril Prevention Project was the first controlled clinical trial to show that an ACE inhibitor reduces the development of diabetes in patients with hypertension.
      • Hansson L
      • Lindholm LH
      • Niskanen L
      • et al.
      Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
      This trial was designed to compare the effect of ACE inhibition with conventional antihypertensive therapy (β-blocker, diuretic, or both) on cardiovascular morbidity and mortality. The number of patients with newly diagnosed diabetes was 14% lower in the captopril group than in the group receiving conventional therapy. These data were confirmed in the Heart Outcomes Prevention Evaluation trial in which a fixed dose of ramipril or placebo was added to whatever other therapy was prescribed for patients at high risk of cardiovascular events (including β-blockers, CCBs, and diuretics).
      • Yusuf S
      • Sleight P
      • Pogue J
      • Bosch J
      • Davies R
      • Dagenais G
      • Heart Outcomes Prevention Evaluation Study Investigators
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376 and 2000;342:748].
      During the 4.5-year trial, 35% fewer patients in the ramipril group than in the placebo (control) group developed diabetes (3.6% of the 4645 patients in the ramipril group vs 5.4% of the 4652 patients in the placebo group). The same percentage of patients (39%) in the ramipril and placebo groups were receiving a β-blocker at baseline. In addition, a retrospective analysis of data from one site that followed up 292 patients, the Studies of Left Ventricular Dysfunction, showed a relative risk reduction of 74% for developing diabetes during the 2.9-year study period in patients receiving enalapril compared with those receiving placebo (incidence of diabetes, 5.9% with enalapril vs 22.4% with placebo).
      • Vermes E
      • Ducharme A
      • Bourassa MG
      • Lessard M
      • White M
      • Tardif JC
      Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD).
      It has been suggested that, by blocking both kininase II and ACE, ACE inhibitors may increase not only nitric oxide production but also bradykinin, thus improving blood flow to skeletal muscle, properties that should improve insulin-mediated glucose uptake.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      • Henriksen EJ
      • Jacob S
      • Kinnick TR
      • Youngblood EB
      • Schmit MB
      • Dietze GJ
      ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide.
      TABLE 1Summary of Published Studies of Antihypertensive Agents That May Prevent or Delay Emergence of Type 2 Diabetes Mellitus in Patients With Essential Hypertension
      ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial; ALPINE = Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; CAPPP = Captopril Prevention Project; CHARM = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; HOPE = Heart Outcomes Prevention Evaluation; INVEST = International Verapamil-Trandolapril Study; LIFE = Losartan Intervention for Endpoint Reduction in Hypertension; PEACE = Prevention of Events with Angiotensin Converting Enzyme Inhibition; SOLVD = Studies of Left Ventricular Dysfunction; SR = sustained release; VALUE = Valsartan Antihypertensive Long-term Use Evaluation.
      TreatmentRisk
      ReferenceNo. of patientsPatient groupActiveControlTreated groupControl groupAbsolute risk reduction (%)Relative risk reduction (%)
      CAPPP
      • Hansson L
      • Lindholm LH
      • Niskanen L
      • et al.
      Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.
      10,985Men and women 25–66 y with diastolic hypertensionCaptoprilβ-Blocker, diuretic6.16.90.811
      HOPE
      • Yusuf S
      • Sleight P
      • Pogue J
      • Bosch J
      • Davies R
      • Dagenais G
      • Heart Outcomes Prevention Evaluation Study Investigators
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376 and 2000;342:748].
      9297Men and women >55 y with cardiovascular diseaseRamiprilPlacebo3.65.41.833
      ALLHAT
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      15,573Men and women ≥55 y with hypertension and at risk of cardiovascular diseaseLisinoprilChlorthalidone or amlodipine8.111.6 and 9.83.5 and 1.730 and 17
      SOLVD
      • Vermes E
      • Ducharme A
      • Bourassa MG
      • Lessard M
      • White M
      • Tardif JC
      Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD).
      291Men and women 18–80 y with left ventricular dysfunctionEnalaprilPlacebo5.922.416.574
      LIFE
      • Lindholm LH
      • Ibsen H
      • Borch-Johnsen K
      • LIFE Study Group
      • et al.
      Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.
      7998Men and women 55–80 y with hypertension and left ventricular hypertrophyLosartanAtenolol6.08.02.025
      CHARM
      • Pfeffer MA
      • Swedberg K
      • Granger CB
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      3023Men and women >18 y with heart failure grade II-IVCandesartanPlacebo3.15.12.039
      ALPINE
      • Lindholm LH
      • Persson M
      • Alaupovic P
      • Carlberg B
      • Svensson A
      • Samuelsson O
      Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
      392Mostly women 18–75 y with newly detected hypertensionCandesartanHydrochloro-thiazide0.54.13.688
      VALUE
      • Julius S
      • Kjeldsen SE
      • Weber M
      • VALUE Trial Group
      • et al.
      Outcomes in hypertensive patients at high cardiovascular risk treated with regi-mens based on valsartan or amlodipine: the VALUE randomised trial.
      10,419Men and women ≥50 y with hypertension and at high risk of cardiovascular diseaseValsartanAmlodipine13.116.43.323
      INVEST
      • Pepine CJ
      • Handberg EM
      • Cooper-DeHoff RM
      • INVEST Investigators
      • et al.
      A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
      16,176Men and women ≥50 y with hypertension and cardiovascular diseaseVerapamil SR, adding in order trandolapril, hydrochloro-thiazideAtenolol, adding in order hydro-chlorothiazide, trandolapril8.27.01.215
      PEACE
      • Braunwald E
      • Domanski MJ
      • Fowler SE
      • PEACE Trial Investigators
      • et al.
      Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
      6904Men and women >50 y with stable coronary artery diseaseTrandolaprilPlacebo9.811.51.717
      * ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial; ALPINE = Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; CAPPP = Captopril Prevention Project; CHARM = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; HOPE = Heart Outcomes Prevention Evaluation; INVEST = International Verapamil-Trandolapril Study; LIFE = Losartan Intervention for Endpoint Reduction in Hypertension; PEACE = Prevention of Events with Angiotensin Converting Enzyme Inhibition; SOLVD = Studies of Left Ventricular Dysfunction; SR = sustained release; VALUE = Valsartan Antihypertensive Long-term Use Evaluation.
      Several clinical trials demonstrate that ARBs also have beneficial effects on glucose metabolism that likely are independent of bradykinin-mediated mechanisms.
      • Lindholm LH
      • Ibsen H
      • Borch-Johnsen K
      • LIFE Study Group
      • et al.
      Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.
      • Pfeffer MA
      • Swedberg K
      • Granger CB
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      • Lindholm LH
      • Persson M
      • Alaupovic P
      • Carlberg B
      • Svensson A
      • Samuelsson O
      Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      The Losartan Intervention for Endpoint Reduction in Hypertension study showed that losartan reduced the relative risk of developing type 2 diabetes mellitus by 25% compared with the β-blocker atenolol.
      • Lindholm LH
      • Ibsen H
      • Borch-Johnsen K
      • LIFE Study Group
      • et al.
      Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.
      However, since the study did not include a placebo control group, it is likely that the reduction in incident diabetes reflects the net result of both increased insulin sensitivity in the losartan group and increased insulin resistance in the atenolol group. Similar findings relative to placebo were reported in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) studies.
      • Pfeffer MA
      • Swedberg K
      • Granger CB
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      In CHARM-Overall,
      • Pfeffer MA
      • Swedberg K
      • Granger CB
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      a study of 7601 patients followed up for a median of 37.7 months, candesartan (32 mg/d) reduced the relative risk of developing diabetes by 22% compared with placebo. In CHARM-Preserved,
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • CHARM Investigators and Committees
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      which included patients with class II to IV heart failure and an ejection fraction greater than 40% who were followed up for a median of 36.6 months, candesartan reduced the relative risk of developing diabetes by 39% compared with placebo. After 1 year, candesartan had reduced the relative rate of incident diabetes by 88% compared with hydrochlorothiazide in patients with newly diagnosed hypertension in the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation study.
      • Lindholm LH
      • Persson M
      • Alaupovic P
      • Carlberg B
      • Svensson A
      • Samuelsson O
      Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
      However, this study followed up relatively few patients (Table 1).
      The Valsartan Antihypertensive Long-term Use Evaluation trial demonstrated the advantage of an ARB, valsartan, over a CCB, amlodipine, in reducing the relative risk of new-onset diabetes by 23% in patients with hypertension 50 years or older at high risk of cardiac events who were treated for a mean of 4.2 years.
      • Julius S
      • Kjeldsen SE
      • Weber M
      • VALUE Trial Group
      • et al.
      Outcomes in hypertensive patients at high cardiovascular risk treated with regi-mens based on valsartan or amlodipine: the VALUE randomised trial.
      Furthermore, the beneficial effect of valsartan in preventing new-onset diabetes in the Valsartan Antihypertensive Long-term Use Evaluation may have been underestimated, since the valsartan treatment arm was more likely to include patients taking hydrochlorothiazide and other antihypertensive drugs that might negatively affect glucose metabolism than the amlodipine treatment arm. Because amlodipine is considered neutral in its effects on insulin sensitivity and was substantially better than a thiazide diuretic in this regard in the ALLHAT study,
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      drugs in the ARB class may independently improve insulin sensitivity and may have a role in protecting high-risk patients with hypertension from developing diabetes.
      • Weber MA
      Hypertension, the metabolic syndrome, and the risk of developing diabetes: is it time to change the guidelines? [editorial].
      The possibility that an ARB can prevent transition from impaired glucose tolerance, which is common in patients with essential hypertension, to type 2 diabetes mellitus is being explored in the Nateglinide and Valsartan on Impaired Glucose Tolerance Outcomes Research study.
      • Califf RM
      • Holman R
      People at increased risk of cardiovascular disease screened for the NAVIGATOR trial frequently have undiagnosed diabetes or impaired glucose tolerance [abstract].
      The objectives of the 2 × 2 factorial design of this large prospective study of more than 9000 patients with impaired glucose tolerance are to determine whether restoration of the early insulin response with nateglinide and/or improvement in insulin sensitivity by blockade of the renin-angiotensin system with valsartan prevents the transition from either impaired glucose tolerance to diabetes or the incidence of cardiovascular disease.
      • Califf RM
      • Holman R
      People at increased risk of cardiovascular disease screened for the NAVIGATOR trial frequently have undiagnosed diabetes or impaired glucose tolerance [abstract].
      In the Diabetes Reduction Approaches With Medication study,
      • Gerstein HC
      • Yusuf S
      • Holman R
      • Bosch J
      • Pogue J
      • DREAM Trial Investigators
      Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial.
      5269 patients with impaired glucose tolerance have been randomized to ramipril or rosiglitazone vs placebo in a 2 × 2 factorial design to determine whether new-onset diabetes can be prevented.
      Other ACE inhibitor and ARB studies are assessing the incidence of type 2 diabetes mellitus as a secondary end point. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial is a double-blind, parallel-group trial with 3 treatment arms—telmisartan, ramipril, and telmisartan plus ramipril—that will include 23,000 persons.
      • Yusuf S
      From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis.
      It is designed to determine the effect of one or both agents on a composite cardiovascular end point of myocardial infarction, stroke, and hospitalization for heart failure during the 5.5-year follow-up period. Patients unable to tolerate an ACE inhibitor will be entered into a parallel study of telmisartan vs placebo, the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease.
      • Teo K
      • Yusuf S
      • Sleight P
      • ONTARGET/TRANSCEND Investigators
      • et al.
      Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials.
      Collectively, these ongoing studies are expected to clarify the extent by which inhibition of the renin-angiotensin system can reduce the incidence of new-onset diabetes in patients with impaired glucose tolerance, a group that includes many of the 65 million Americans with essential hypertension.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.

      Mechanisms

      A number of mechanisms exist by which antihypertensive agents may affect glucose metabolism. Mechanistic studies support and explain the findings from clinical studies that have evaluated the effects of antihypertensive agents on glucose metabolism.
      Thiazide Diuretics. Thiazide diuretics appear to worsen glycemic control in a dose-dependent fashion by reducing insulin secretion and peripheral insulin sensitivity.
      • Perez-Stable E
      • Caralis PV
      Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.
      • Lithell HO
      Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism.
      • Harper R
      • Ennis CN
      • Sheridan B
      • Atkinson AB
      • Johnston GD
      • Bell PM
      Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.
      • Fletcher A
      • Amery A
      • Birkenhager W
      • et al.
      Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly.
      • Padwal R
      • Laupacis A
      Antihypertensive therapy and incidence of type 2 diabetes: a systematic review.
      Development of hypokalemia (and perhaps hypomagnesemia) appears to be important because the use of potassium supplementation to prevent hypokalemia reduces the occurrence of thiazide-induced glucose intolerance.
      • Padwal R
      • Laupacis A
      Antihypertensive therapy and incidence of type 2 diabetes: a systematic review.
      • Gorden P
      • Sherman BM
      • Simopoulos AP
      Glucose intolerance with hypokalemia: an increased proportion of circulating proinsulin-like component.
      • Helderman JH
      • Elahi D
      • Andersen DK
      • et al.
      Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium.
      Nevertheless, deterioration in glucose metabolism occurs even with minimal reductions in serum potassium levels.
      • Savage PJ
      • Pressel SL
      • Curb JD
      • SHEP Cooperative Research Group
      • et al.
      Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program.
      • Barzilay JI
      • Pressel S
      • Davis BR
      • et al.
      Risk and impact of incident glucose disorder in hypertensive older adults treated with an ACE inhibitor, a diuretic, or a calcium channel blocker: a report from the ALLHAT trial.
      Since ACE inhibitors and ARBs appear to counteract some of the adverse effects associated with the use of thiazide diuretics, including potassium wasting and aldosterone secretion, early combined therapy has been recommended.
      • Kjeldsen SE
      • Os I
      • Hoieggen A
      • Beckey K
      • Gleim GW
      • Oparil S
      Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide.
      • Mimran A
      • Weir MR
      Angiotensin-receptor blockers and diuretics—advantages of combination.
      • Mogensen CE
      New concepts in blood pressure-lowering management in diabetic patients: the case for early ACE inhibitor combination therapy with diuretics.
      Although combination therapy likely leads to better blood pressure control, head-to-head randomized controlled trials are lacking in determining the metabolic outcomes of such combinations.
      β-Blockers. Therapy with β-blockers has been shown to inhibit pancreatic insulin secretion and peripheral glucose utilization.
      • Pollare T
      • Lithell H
      • Selinus I
      • Berne C
      Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.
      • Lithell H
      • Pollare T
      • Vessby B
      Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.
      • Samuelsson O
      • Hedner T
      • Berglund G
      • Persson B
      • Andersson OK
      • Wilhelmsen L
      Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.
      • Gress TW
      • Nieto FJ
      • Shahar E
      • Wofford MR
      • Brancati FL
      Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.
      • Sowers JR
      • Bakris GL
      Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].
      • Wright AD
      • Barber SG
      • Kendall MJ
      • Poole PH
      Beta-adrenoceptor-blocking drugs and blood sugar control in diabetes mellitus.
      • Jacob S
      • Rett K
      • Henriksen EJ
      Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.
      Weight gain, decreased skeletal muscle blood flow, and unopposed stimulation of β2-receptor-mediated glycogenolysis are also potential mechanisms by which β-blockers might exert adverse effects.
      • Pollare T
      • Lithell H
      • Selinus I
      • Berne C
      Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.
      • Lithell H
      • Pollare T
      • Vessby B
      Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients.
      • Samuelsson O
      • Hedner T
      • Berglund G
      • Persson B
      • Andersson OK
      • Wilhelmsen L
      Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden.
      • Gress TW
      • Nieto FJ
      • Shahar E
      • Wofford MR
      • Brancati FL
      Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study.
      • Sowers JR
      • Bakris GL
      Antihypertensive therapy and the risk of type 2 diabetes mellitus [editorial].
      • Wright AD
      • Barber SG
      • Kendall MJ
      • Poole PH
      Beta-adrenoceptor-blocking drugs and blood sugar control in diabetes mellitus.
      • Jacob S
      • Rett K
      • Henriksen EJ
      Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.
      Interestingly, much attention is being paid to third-generation β-blockers, such as carvedilol and nebivolol, that possess vasodilator actions through such proposed mechanisms as nitric oxide release, antioxidant effects, and Ca2+ blockade. Basic and clinical studies suggest that these drugs may improve insulin sensitivity
      • Jacob S
      • Rett K
      • Henriksen EJ
      Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.
      • Toda N
      Vasodilating beta-adrenoceptor blockers as cardiovascular therapeutics.
      • Bell DS
      Advantages of a third-generation beta-blocker in patients with diabetes mellitus.
      • Jacob S
      • Balletshofer B
      • Henriksen EJ
      • et al.
      Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers.
      • Bakris GL
      • Fonseca V
      • Katholi RE
      • GEMINI Investigators
      • et al.
      Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.
      or are at least metabolically neutral in patients with impaired glucose tolerance.
      • Kuroedov A
      • Cosentino F
      • Luscher TF
      Pharmacological mechanisms of clinically favorable properties of a selective beta1-adrenoceptor antagonist, nebivolol.
      • Poirier L
      • Cleroux J
      • Nadeau A
      • Lacourciere Y
      Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients.
      In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives trial,
      • Bakris GL
      • Fonseca V
      • Katholi RE
      • GEMINI Investigators
      • et al.
      Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.
      the comparison of carvedilol to metoprolol in the presence of reninangiotensin system blockade on glycemic control showed that carvedilol was superior in improving insulin sensitivity, preserving hemoglobin A1c levels, and preventing the progression to microalbuminuria, despite similar blood pressure responses in patients with diabetes mellitus and hypertension. Therefore, third-generation β-blockers may become the preferred antiadrenergic blood pressure drugs in patients with insulin resistance.
      Calcium Channel Blockers. Calcium channel blockers have been proven effective as adjunct therapy in diabetic patients with hypertension. Furthermore, CCBs have been shown to reduce insulin resistance or new-onset diabetes among patients with metabolic syndrome, seeming to be intermediate in effectiveness between ACE inhibitors and ARBs (which reduce the incidence of diabetes mellitus) and thiazide diuretics and β-blockers (which increase it).
      • Pepine CJ
      • Handberg EM
      • Cooper-DeHoff RM
      • INVEST Investigators
      • et al.
      A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.
      • Koyama Y
      • Kodama K
      • Suzuki M
      • Harano Y
      Improvement of insulin sensitivity by a long-acting nifedipine preparation (nifedipine-CR) in patients with essential hypertension.
      • Zanella MT
      • Kohlmann Jr, O
      • Ribeiro AB
      Treatment of obesity hypertension and diabetes syndrome.
      • Black HR
      • Elliott WJ
      • Neaton JD
      • et al.
      Baseline Characteristics and Early Blood Pressure Control in the CONVINCE trial.
      • McKeage K
      • Scott LJ
      Manidipine: a review of its use in the management of hypertension.
      Both dihydropyridine and long-acting nondihydropyridine
      • Koyama Y
      • Kodama K
      • Suzuki M
      • Harano Y
      Improvement of insulin sensitivity by a long-acting nifedipine preparation (nifedipine-CR) in patients with essential hypertension.
      • Yagi S
      • Goto S
      • Yamamoto T
      • Kurihara S
      • Katayama S
      Effect of cilnidipine on insulin sensitivity in patients with essential hypertension.
      calcium antagonists have shown metabolic benefits, with effects on insulin sensitivity and insulin secretion. These agents may improve insulin sensitivity by exerting vasodilatory action in insulin-sensitive tissues without stimulating sympathetic nervous activity,
      • Yagi S
      • Goto S
      • Yamamoto T
      • Kurihara S
      • Katayama S
      Effect of cilnidipine on insulin sensitivity in patients with essential hypertension.
      by preventing the inhibition of glucose transporters and glycogen synthase by calcium,
      • Begum N
      • Sussman KE
      • Draznin B
      Calcium-induced inhibition of phosphoserine phosphatase in insulin target cells is mediated by the phosphorylation and activation of inhibitor 1.
      or through antioxidant effects.
      • McKeage K
      • Scott LJ
      Manidipine: a review of its use in the management of hypertension.
      Centrally Acting Agents. Centrally acting antihypertensive agents are not widely used because of a relatively high incidence of adverse effects. Most central adverse effects appear to be through the α2-receptor. The use of an α2-agonist such as clonidine has been limited by adverse effects, including central nervous system effects, sexual dysfunction, and dry mouth.
      • Materson BJ
      • Reda DJ
      • Cushman WC
      • Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents
      • et al.
      Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo [published correction appears in N Engl J Med. 1994;330:1689].
      The α2-agonists appear to have minimal effects on lipid profiles but may inhibit pancreatic β-cell insulin secretion, thereby impairing glucose metabolism.
      • Leclercq-Meyer V
      • Herchuelz A
      • Valverde I
      • Couturier E
      • Marchand J
      • Malaisse WJ
      Mode of action of clonidine upon islet function: dissociated effects upon the time course and magnitude of insulin release.
      Imidazoline receptor agonists such as moxonidine are selective for the I1-imidazoline receptor in the sympathetic vasomotor centers with little effect at the central α2-receptor.
      • Messerli F
      Moxonidine: a new and versatile antihypertensive.
      Therefore, the adverse effect profile is favorable compared with other centrally acting agents. Moxonidine has been shown to diminish sympathetic activity, and it reduces arterial pressure by lowering systemic vascular resistance without affecting heart rate and cardiac output. Furthermore, drugs such as moxonidine may exert favorable metabolic effects, including improved insulin sensitivity.
      • Jacob S
      • Klimm HJ
      • Rett K
      • Helsberg K
      • Haring HU
      • Godicke J
      Effects of moxonidine vs. metoprolol on blood pressure and metabolic control in hypertensive subjects with type 2 diabetes.
      • Haenni A
      • Lithell H
      Moxonidine improves insulin sensitivity in insulin-resistant hypertensives.
      Animal studies have suggested that this may be due to decreased vasoconstriction in insulin-sensitive tissues such as skeletal muscle and improved insulin signaling, which leads to increased glucose uptake.
      • Krentz AJ
      • Evans AJ
      Selective imidazoline receptor agonists for metabolic syndrome.
      The Moxonidine and Ramipril Regarding Insulin and Glucose Evaluation study will compare the effects of moxonidine and the ACE inhibitor ramipril and the combination of both drugs on metabolic and hemodynamic variables in patients with hypertension and impaired fasting glycemia.
      • Rayner B
      Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in hypertensive patients with impaired insulin sensitivity: partners in a successful MARRIAGE?.
      α1-Blockers. α-Adrenergic blockers have also been shown to have beneficial metabolic effects. Indeed, the selective α1-blockers, such as prazosin, terazosin, and doxazosin, are the only class of antihypertensive agents that appear to have the combined effect of improving insulin sensitivity, raising high-density lipoprotein cholesterol levels, and lowering low-density lipoprotein cholesterol levels.
      • Bakris GL
      • Weir MR
      • Sowers JR
      Therapeutic challenges in the obese diabetic patient with hypertension.
      • Khoury AF
      • Kaplan NM
      Alpha-blocker therapy of hypertension: an unfulfilled promise.
      • Andersson PE
      • Lithell H
      Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men: relationship to changes in skeletal muscle blood flow.
      • Lithell HO
      Hyperinsulinemia, insulin resistance, and the treatment of hypertension.
      However, in 2000, use of the α-blocker doxazosin arm of the ALLHAT study was discontinued early (median follow-up, 3.3 years) based on interim comparisons with the diuretic chlorthalidone. Particularly worrisome was a doubling of risk of congestive heart failure.
      • ALLHAT Collaborative Research Group
      Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) [published correction appears in JAMA. 2002;288:2976].
      Furthermore, α-blockers are associated with troublesome adverse effects, including dizziness, headache, and weakness. In a prospective trial in which 6 different antihypertensive drugs were compared, the α-blocker prazosin was found to have the highest incidence of adverse effects.
      • Materson BJ
      • Reda DJ
      • Cushman WC
      • Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents
      • et al.
      Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo [published correction appears in N Engl J Med. 1994;330:1689].
      Therefore, α-blockers are generally not considered first-line therapy in essential hypertension, even in patients with diabetes or metabolic syndrome.

      INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM: METABOLIC AND HEMODYNAMIC EFFECTS

      Insulin Sensitivity

      Patients with essential hypertension frequently have impaired glucose tolerance due to increased insulin resistance.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      This is related in part to alterations in insulin action at the level of skeletal muscle tissue, which comprises 40% of body mass and is the predominant site of insulin-stimulated glucose utilization
      • DeFronzo RA
      • Ferrannini E
      • Hendler R
      • Felig P
      • Wahren J
      Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man.
      (Table 2). With aging and sedentarylifestyles, which are associated with an increased propensity to hypertension, skeletal muscle mass and insulin sensitivity are reduced.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      Furthermore, an association exists between blood pressure and the proportion of type II fibers in skeletal muscle, which are less sensitive to insulin than type I fibers.
      • Sowers JR
      Insulin resistance and hypertension.
      Interestingly, ACE inhibitors
      • Ura N
      • Higashiura K
      • Shimamoto K
      The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor.
      • Higashiura K
      • Ura N
      • Takada T
      • et al.
      The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats.
      and ARBs
      • Higashiura K
      • Ura N
      • Takada T
      • et al.
      The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats.
      may influence skeletal muscle toward a greater percentage of type I fibers.
      TABLE 2Skeletal Muscle Insulin Resistance in Patients With Hypertension: Potential Mechanisms
      eNOS = endothelial nitric oxide synthase; GLUT4 = insulin-sensitive glucose transporter 4; OLETF = Otsuka Long-Evans Tokushima Fatty; PI3K = phosphatidylinositol 3-kinase; SHR = spontaneously hypertensive rat; TG = transgenic.
      MechanismEvidence
      Decreased nonoxidative glucose metabolism by skeletal muscle
       Postinsulin receptor defects
        Decreased signaling PI3K-Akt pathwayTG(mREN2)27 rats,
      • Sloniger JA
      • Saengsirisuwan V
      • Diehl CJ
      • et al.
      Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat.
      • Lemieux AM
      • Diehl CJ
      • Sloniger JA
      • Henriksen EJ
      Voluntary exercise training enhances glucose transport but not insulin signaling capacity in muscle of hypertensive TG(mREN2)27 rats.
      SHR
      • Zecchin HG
      • Bezerra RM
      • Carvalheira JB
      • et al.
      Insulin signalling pathways in aorta and muscle from two animal models of insulin resistance—the obese middle-aged and the spontaneously hypertensive rats.
        Decreased GLUT4 content and translocationTG(mREN2)27,
      • Kinnick TR
      • Youngblood EB
      • O'Keefe MP
      • Saengsirisuwan V
      • Teachey MK
      • Henriksen EJ
      Modulation of insulin resistance and hypertension by voluntary exercise training in the TG(mREN2)27 rat.
      Zucker obese,
      • Henriksen EJ
      • Jacob S
      • Kinnick TR
      • Teachey MK
      • Krekler M
      Selective angiotensin II receptor receptor antagonism reduces insulin resistance in obese Zucker rats.
      • Jacob S
      • Henriksen EJ
      • Fogt DL
      • Dietze GJ
      Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle.
      and Goto-Kakizaki
      • Bitar MS
      • Al-Saleh E
      • Al-Mulla F
      Oxidative stress—mediated alterations in glucose dynamics in a genetic animal model of type II diabetes.
      rats
        Decreased insulin-mediated glucose transportTG(mREN2)27,
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      • Kinnick TR
      • Youngblood EB
      • O'Keefe MP
      • Saengsirisuwan V
      • Teachey MK
      • Henriksen EJ
      Modulation of insulin resistance and hypertension by voluntary exercise training in the TG(mREN2)27 rat.
      Zucker obese,
      • Henriksen EJ
      • Jacob S
      • Kinnick TR
      • Teachey MK
      • Krekler M
      Selective angiotensin II receptor receptor antagonism reduces insulin resistance in obese Zucker rats.
      • Jacob S
      • Henriksen EJ
      • Fogt DL
      • Dietze GJ
      Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle.
      and Goto-Kakizaki
      • Bitar MS
      • Al-Saleh E
      • Al-Mulla F
      Oxidative stress—mediated alterations in glucose dynamics in a genetic animal model of type II diabetes.
      rats, SHR obese
      • Friedman JE
      • Ishizuka T
      • Liu S
      • et al.
      Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat.
        Decreased glycogen synthase activityTG(mREN2)27 rat
      • Sloniger JA
      • Saengsirisuwan V
      • Diehl CJ
      • et al.
      Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat.
        Increased reactive oxygen speciesTG(mREN2)27,
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      Goto-Kakizaki,
      • Bitar MS
      • Al-Saleh E
      • Al-Mulla F
      Oxidative stress—mediated alterations in glucose dynamics in a genetic animal model of type II diabetes.
      Zucker obese,
      • Henriksen EJ
      • Teachey MK
      • Taylor ZC
      • et al.
      Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat.
      and angiotensin II–infused rats
      • Ogihara T
      • Asano T
      • Ando K
      • et al.
      Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling.
       Altered skeletal muscle fiber type
        Decreased proportion of insulin-sensitive type I fibersHuman,
      • Hernandez N
      • Torres SH
      • Vera O
      • De Sanctis JB
      • Flores E
      Muscle fiber composition and capillarization in relation to metabolic alterations in hypertensive men.
      • Houmard JA
      • Weidner ML
      • Koves TR
      • Hickner RC
      • Cortright RL
      Association between muscle fiber composition and blood pressure levels during exercise in men.
      SHR
      • Ben Bachir-Lamrini L
      • Sempore B
      • Mayet MH
      • Favier RJ
      Evidence of a slow-to-fast fiber type transition in skeletal muscle from spontaneously hypertensive rats.
      • Bortolotto SK
      • Stephenson DG
      • Stephenson GM
      Fiber type populations and Ca2+-activation properties of single fibers in soleus muscles from SHR and WKY rats.
        Increased lipid contentFructose-fed,
      • Ura N
      • Higashiura K
      • Shimamoto K
      The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor.
      Zucker obese
      • Henriksen EJ
      • Teachey MK
      • Taylor ZC
      • et al.
      Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat.
      • Lessard SJ
      • Lo Giudice SL
      • Lau W
      • et al.
      Rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle.
      rats
      Decreased skeletal muscle blood flow with reduced delivery of insulin and glucose
       Reduced generation or response to nitric oxideeNOS knockout mouse,
      • Duplain H
      • Burcelin R
      • Sartori C
      • et al.
      Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.
      NOS inhibition OLETF rat,
      • Nakaya Y
      • Ishimura N
      • Takishita E
      • Takahashi A
      Chronic feeding of a nitric oxide synthase inhibitor induces postprandial hypertriglyceridemia in type 2 diabetic model rats, Otsuka Long-Evans Tokushima Fatty rats, but not in nondiabetic rats.
      SHR
      • Huang A
      • Koller A
      Both nitric oxide and prostaglandin-mediated responses are impaired in skeletal muscle arterioles of hypertensive rats.
      and Zucker obese rat
      • Baron AD
      • Zhu JS
      • Marshall S
      • Irsula O
      • Brechtel G
      • Keech C
      Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats.
      • Frisbee JC
      Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome.
      • Frisbee JC
      • Stepp DW
      Impaired NO-dependent dilation of skeletal muscle arterioles in hypertensive diabetic obese Zucker rats.
       Vascular rarefactionHuman,
      • Olsen MH
      • Fossum E
      • Hoieggen A
      • et al.
      Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.
      • Puato M
      • Faggin E
      • Favaretto E
      • et al.
      Prevalence of fetal-type smooth muscle cells in the media of microvessels from hypertensive patients.
      Zucker obese rat,
      • Frisbee JC
      Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome.
      eNOS knockout mouse,
      • Kubis N
      • Richer C
      • Domergue V
      • Giudicelli JF
      • Levy BI
      Role of microvascular rarefaction in the increased arterial pressure in mice lacking for the endothelial nitric oxide synthase gene (eNOS3pt-/-).
      glucocorticoid-induced hypertensive rat
      • Vogt CJ
      • Schmid-Schonbein GW
      Microvascular endothelial cell death and rarefaction in the glucocorticoid-induced hypertensive rat.
       Vascular hypertrophyHuman,
      • Olsen MH
      • Fossum E
      • Hoieggen A
      • et al.
      Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.
      SHR,
      • Herrmann HJ
      • Moritz V
      • Kuhne C
      Structural wall tissue alterations of the microvasculature in the course of spontaneous hypertension of rats.
      2 kidney, 1 clip SHR
      • Friberg P
      • Wahlander H
      • Nordlander M
      Influence of early antihypertensive treatment on vascular and cardiac design in SHR with and without renal hypertension.
       Increased vasoconstrictionHuman,
      • Olsen MH
      • Fossum E
      • Hoieggen A
      • et al.
      Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.
      • Agapitov AV
      • Correia ML
      • Sinkey CA
      • Dopp JM
      • Haynes WG
      Impaired skeletal muscle and skin microcirculatory function in human obesity.
      eNOS knockout mouse,
      • Kubis N
      • Richer C
      • Domergue V
      • Giudicelli JF
      • Levy BI
      Role of microvascular rarefaction in the increased arterial pressure in mice lacking for the endothelial nitric oxide synthase gene (eNOS3pt-/-).
      Zucker obese rat,
      • Stepp DW
      • Frisbee JC
      Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats.
      SHR
      • Falcone JC
      • Granger HJ
      • Meininger GA
      Enhanced myogenic activation in skeletal muscle arterioles from spontaneously hypertensive rats.
      * eNOS = endothelial nitric oxide synthase; GLUT4 = insulin-sensitive glucose transporter 4; OLETF = Otsuka Long-Evans Tokushima Fatty; PI3K = phosphatidylinositol 3-kinase; SHR = spontaneously hypertensive rat; TG = transgenic.
      Insulin resistance in skeletal muscle is associated with increased intracellular lipid and fat interspersed between muscle fibers,
      • Sowers JR
      Insulin resistance and hypertension.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      which is more prevalent with aging and obesity.
      • Cree MG
      • Newcomer BR
      • Katsanos CS
      • et al.
      Intramuscular and liver triglycerides are increased in the elderly.
      • Houmard JA
      • Tanner CJ
      • Yu C
      • et al.
      Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects.
      It has been proposed that angiotensin II has differential effects on the lipid storage capacity of adipose and skeletal muscle tissues such that triglyceride accumulation occurs in muscle.
      • Strazzullo P
      • Galletti F
      Impact of the renin-angiotensin system on lipid and carbohydrate metabolism.
      Interestingly, renin-angiotensin system activity also appears to affect recruitment and differentiation of adipocytes,
      • Furuhashi M
      • Ura N
      • Takizawa H
      • et al.
      Blockade of the reninangiotensin system decreases adipocyte size with improvement in insulin sensitivity.
      • Ailhaud G
      • Fukamizu A
      • Massiera F
      • Negrel R
      • Saint-Marc P
      • Teboul M
      Angiotensinogen, angiotensin II and adipose tissue development.
      • Janke J
      • Engeli S
      • Gorzelniak K
      • Luft FC
      • Sharma AM
      Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors.
      and recent studies suggest that certain ARBs may interact with the nuclear hormone receptor peroxisome proliferator-activated receptor γ independent of angiotensin II receptors.
      • Schupp M
      • Janke J
      • Clasen R
      • Unger T
      • Kintscher U
      Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity.
      • Benson SC
      • Pershadsingh HA
      • Ho CI
      • et al.
      Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.
      • Scheen AJ
      Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system.
      This interaction may represent a potential mechanism by which ARBs improve insulin sensitivity, since peroxisome proliferator-activated receptor γ is the cellular target for the insulin-sensitizing thiazolidinedione drugs.

      Vascular Effects

      Increased skeletal muscle blood flow and resulting improvements in insulin delivery may be important mechanisms by which attenuation of the renin-angiotensin system improves glucose uptake and metabolism in insulin-sensitive tissues.
      • Nawano M
      • Anai M
      • Funaki M
      • et al.
      Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat.
      • Ekelund U
      Effects of angiotensin-converting enzyme inhibition on arterial, venous and capillary functions in cat skeletal muscle in vivo.
      One potential mechanism would be via the inhibiting effects of ACE inhibitors on kininase II, thereby increasing bradykinin and the subsequent enhancement of nitric oxide production.
      • Henriksen EJ
      • Jacob S
      Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition.
      Other potential mechanisms of renin-angiotensin system blockade are improved vascular sensitivity to insulin and improved endothelial function.
      • Sowers JR
      Insulin resistance and hypertension.
      • McFarlane SI
      • Kumar A
      • Sowers JR
      Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease.
      • Feldman RD
      • Schmidt ND
      Quinapril treatment enhances vascular sensitivity to insulin.
      Moreover, both ACE inhibitors and ARBs likely increase skeletal muscle blood flow by diminishing the vasoconstricting effects of angiotensin II, particularly at the level of the small arteriole.
      • Bergstrom G
      • Johansson I
      • Wickman A
      • Gan L
      • Thorup C
      Brief losartan treatment in young spontaneously hypertensive rats abates long-term blood pressure elevation by effects on renal vascular structure.
      Although ACE inhibition and receptor blockade un-doubtedly diminish the effect of angiotensin II on vascular tissues, angiotensin II appears to have direct effects on skeletal muscle tissue. For example, angiotensin II directly infused into the interstitial space of canine muscle causes insulin resistance for glucose uptake that cannot be attributed to hemodynamic changes.
      • Richey JM
      • Ader M
      • Moore D
      • Bergman RN
      Angiotensin II induces insulin resistance independent of changes in interstitial insulin.
      Thus, ACE inhibitors and ARBs likely improve insulin-mediated glucose disposal in hypertensive and insulin-resistant conditions by augmenting blood flow to insulin-sensitive tissues and by having direct effects on skeletal muscle glucose uptake capacity (Table 2).

      Signaling Pathways

      Insulin-dependent skeletal muscle glucose transport
      • Henriksen EJ
      • Jacob S
      Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition.
      • Zierath JR
      • Krook A
      • Wallberg-Henriksson H
      Insulin action and insulin resistance in human skeletal muscle.
      involves the binding of circulating insulin to the plasma membrane (sarcolemma) receptor, which results in the activation of a cascade of phosphorylation steps. Ultimately, the pathway leads to the translocation of the insulin-sensitive glucose transporter (GLUT4) to the sarcolemma, facilitating glucose uptake into the cell. Evidence is accumulating that angiotensin II interferes with insulin signalingin skeletal muscle. First, studies support the existence of a physiologically functional paracrine skeletal muscle renin-angiotensin system,
      • Strazzullo P
      • Galletti F
      Impact of the renin-angiotensin system on lipid and carbohydrate metabolism.
      • Scheen AJ
      Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system.
      including angiotensin I,
      • Danser AH
      • Koning MM
      • Admiraal PJ
      • Derkx FH
      • Verdouw PD
      • Schalekamp MA
      Metabolism of angiotensin I by different tissues in the intact animal.
      ACE,
      • Dragovic T
      • Minshall R
      • Jackman HL
      • Wang LX
      • Erdos EG
      Kininase II-type enzymes: their putative role in muscle energy metabolism.
      • Reneland R
      • Lithell H
      Angiotensin-converting enzyme in human skeletal muscle: a simple in vitro assay of activity in needle biopsy specimens.
      • Reneland R
      • Haenni A
      • Andersson PE
      • Andren B
      • Lithell H
      Skeletal muscle angiotensin-converting enzyme and its relationship to blood pressure in primary hypertension and healthy elderly men.
      • Ward PE
      • Russell JS
      • Vaghy PL
      Angiotensin and bradykinin metabolism by peptidases identified in skeletal muscle.
      and angiotensin receptors.
      • Linderman JR
      • Greene AS
      Distribution of angiotensin II receptor expression in the microcirculation of striated muscle.
      • Malendowicz SL
      • Ennezat PV
      • Testa M
      • et al.
      Angiotensin II receptor subtypes in the skeletal muscle vasculature of patients with severe congestive heart failure.
      Second, animal
      • Henriksen EJ
      • Jacob S
      • Kinnick TR
      • Teachey MK
      • Krekler M
      Selective angiotensin II receptor receptor antagonism reduces insulin resistance in obese Zucker rats.
      • Navarro-Cid J
      • Maeso R
      • Perez-Vizcaino F
      • et al.
      Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat.
      • Sasaki K
      • Kushiro T
      • Nakagawa S
      • Kanmatsuse K
      Effects of angiotensin II receptor antagonist on insulin sensitivity and sympathetic activity in spontaneously hypertensive rats [in Japanese].
      and human
      • Higashiura K
      • Ura N
      • Miyazaki Y
      • Shimamoto K
      Effect of an angiotensin II receptor antagonist, candesartan, on insulin resistance and pressor mechanisms in essential hypertension.
      studies have shown that long-term ACE inhibition or angiotensin receptor blockade increases whole-body insulin sensitivity under experimental conditions. Moreover, our laboratory
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      and others
      • Kinnick TR
      • Youngblood EB
      • O'Keefe MP
      • Saengsirisuwan V
      • Teachey MK
      • Henriksen EJ
      Modulation of insulin resistance and hypertension by voluntary exercise training in the TG(mREN2)27 rat.
      have shown that skeletal muscle glucose uptake is diminished in transgenic hypertensive rats (Ren-2) that overproduce tissue angiotensin II and that this is prevented with ARB treatment.
      Among the mechanisms by which angiotensin II might inhibit insulin signaling pathways are increases in the generation of reactive oxygen species or alterations in production of nitric oxide. Studies indicate that angiotensin II increases superoxide production in skeletal muscle,
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      which has also been observed in muscle from diabetic mice.
      • Shiuchi T
      • Iwai M
      • Li HS
      • et al.
      Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice.
      In contrast, blockade of the angiotensin II type 1 receptor by ARBs is reported to greatly reduce muscle superoxide production in rodents.
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      • Shiuchi T
      • Iwai M
      • Li HS
      • et al.
      Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice.
      It is well documented that angiotensin II increases generation of reactive oxygen species in vascular cells primarily through the activation of membrane-bound NADPH oxidase.
      • Seshiah PN
      • Weber DS
      • Rocic P
      • Valppu L
      • Taniyama Y
      • Griendling KK
      Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators.
      • Harrison DG
      • Cai H
      • Landmesser U
      • Griendling KK
      Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease.
      • Hanna IR
      • Taniyama Y
      • Szocs K
      • Rocic P
      • Griendling KK
      NAD(P)H oxidase-derived reactive oxygen species as mediators of angiotensin II signaling.
      • Griendling KK
      • Minieri CA
      • Ollerenshaw JD
      • Alexander RW
      Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.
      • Ushio-Fukai M
      • Zafari AM
      • Fukui T
      • Ishizaka N
      • Griendling KK
      p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells.
      However, it remains uncertain whether the angiotensin II-associated increase in skeletal muscle oxidative stress is mediated by NADPH oxidase as depicted in Figure 1 or by other pathways that produce reactive oxygen species.
      Figure thumbnail gr1
      FIGURE 1Potential mechanisms by which the renin-angiotensin system affects insulin sensitivity and glucose transport in skeletal muscle tissue. ACE-I = angiotensin-converting enzyme inhibitor; Akt = protein kinase B; Ang = angiotensin; aPKC = atypical protein kinase C; ARB = angiotensin receptor blocker; AT1R = angiotensin receptor 1; GLUT4 = insulin-sensitive glucose transporter 4; GS = glycogen synthase; GSK3 = glycogen synthase kinase 3; IRS = insulin receptor substrate; NO = nitric oxide; O2 = superoxide anion; PI3K = phosphatidylinositol-3 kinase; PPARγ = peroxisome proliferator-activated receptor γ.
      The effects of oxidative stress on insulin signaling have been demonstrated in insulin-resistant animal models in which increased protein carbonyl levels in skeletal muscle and liver
      • Henriksen EJ
      • Saengsirisuwan V
      Exercise training and antioxidants: relief from oxidative stress and insulin resistance.
      and increased superoxide content in skeletal muscle
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      are evident. Indeed, treatment of these animals with antioxidants such as α-lipoic acid
      • Henriksen EJ
      • Saengsirisuwan V
      Exercise training and antioxidants: relief from oxidative stress and insulin resistance.
      or the superoxide dismutase-catalase mimetic tempol
      • Blendea MC
      • Jacobs D
      • Stump CS
      • et al.
      Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression.
      improved whole-body glucose tolerance and insulin-stimulated skeletal muscle glucose uptake. Interestingly, angiotensin II may act as a negative regulator of GLUT4 gene expression in skeletal muscle,
      • Chan P
      • Wong KL
      • Liu IM
      • Tzeng TF
      • Yang TL
      • Cheng JT
      Anti-hyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats.
      whereas long-term angiotensin II receptor antagonism
      • Henriksen EJ
      • Jacob S
      • Kinnick TR
      • Teachey MK
      • Krekler M
      Selective angiotensin II receptor receptor antagonism reduces insulin resistance in obese Zucker rats.
      or ACE inhibition
      • Steen MS
      • Foianini KR
      • Youngblood EB
      • Kinnick TR
      • Jacob S
      • Henriksen EJ
      Interactions of exercise training and ACE inhibition on insulin action in obese Zucker rats.
      increases GLUT4 protein content in skeletal muscle.
      Alternatively, recent evidence suggests a role for nitric oxide in skeletal muscle glucose metabolism. For example, nitric oxide synthase inhibitors induce insulin resistance,
      • Baron AD
      • Zhu JS
      • Marshall S
      • Irsula O
      • Brechtel G
      • Keech C
      Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats.
      whereas nitric oxide donors stimulate glucose uptake.
      • Henriksen EJ
      • Jacob S
      Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition.
      • Balon TW
      • Nadler JL
      Evidence that nitric oxide increases glucose transport in skeletal muscle.
      • Young ME
      • Radda GK
      • Leighton B
      Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro.
      • Etgen Jr, GJ
      • Fryburg DA
      • Gibbs EM
      Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway.
      Furthermore, endothelial nitric oxide synthase knockout mice exhibit insulin resistance.
      • Duplain H
      • Burcelin R
      • Sartori C
      • et al.
      Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.
      The nitric oxide synthase isoforms neuronal and endothelial are expressed in skeletal muscle.
      • Kobzik L
      • Reid MB
      • Bredt DS
      • Stamler JS
      Nitric oxide in skeletal muscle.
      Moreover, the production of nitric oxide in skeletal muscle can modulate muscle superoxide production.
      • Javesghani D
      • Magder SA
      • Barreiro E
      • Quinn MT
      • Hussain SN
      Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles.
      The potential role of angiotensin II in the generation of reactive oxygen species, impaired insulin signaling, nitric oxide-related mechanisms, and GLUT4 expression and translocation are presented in Figure 1.

      Lipoprotein Lipase

      Mechanisms that link hypertension to skeletal muscle insulin resistance remain largely unknown. However, lipoprotein lipase, a secretory enzyme that is highly expressed by skeletal muscle, is one candidate. Wu et al
      • Wu DA
      • Bu X
      • Warden CH
      • et al.
      Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22.
      have estimated that variations within the lipoprotein lipase gene account for 53% to 73% of the total interindividual variation in systolic blood pressure. Interestingly, the ARB losartan has been shown to reverse the diminished lipoprotein lipase activity observed in adipose tissues from hypertensive rats. High lipoprotein lipase activity is also known to increase insulin sensitivity in transgenic rabbits.
      • Liu E
      • Kitajima S
      • Higaki Y
      • et al.
      High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits.
      Moreover, microvascular lipoprotein lipase enzyme activity in skeletal muscle is reduced approximately 50% during aging,
      • Bey L
      • Areiqat E
      • Sano A
      • Hamilton MT
      Reduced lipoprotein lipase activity in postural skeletal muscle during aging.
      is approximately 80% lower in type II compared with type I muscles,
      • Hamilton MT
      • Etienne J
      • McClure WC
      • Pavey BS
      • Holloway AK
      Role of local contractile activity and muscle fiber type on LPL regulation during exercise.
      and is approximately 95% lower in muscles of physically inactive persons,
      • Bey L
      • Hamilton MT
      Suppression of skeletal muscle lipoprotein lipase activity during physical inactivity: a molecular reason to maintain daily low-intensity activity.
      all of which are associated with increases in insulin resistance and hypertension.

      ISLET CELL PROTECTION

      Type 2 diabetes mellitus is associated with both insulin resistance and pancreatic β-cell dysfunction. Therefore, the risk of diabetes developing in patients with hypertension may depend on the preservation of β-cells and insulin-secreting capacity in the pancreas. Evidence suggests that the pancreas has a local renin-angiotensin system.
      • Leung PS
      • Chappell MC
      A local pancreatic renin-angiotensin system: endocrine and exocrine roles.
      • Leung PS
      • Carlsson PO
      Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas.
      • 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.
      Moreover, angiotensin II was shown to suppress insulin secretion in perfused pancreas preparations but not in in vitro systems.
      • Carlsson PO
      The renin-angiotensin system in the endocrine pancreas.
      Thus, it has been proposed that the reninangiotensin system affects pancreatic function primarily by altering islet perfusion.
      • Carlsson PO
      The renin-angiotensin system in the endocrine pancreas.
      Interestingly, animal studies have shown that angiotensin II causes vasoconstriction in the endocrine pancreas,
      • Leung PS
      • Carlsson PO
      Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas.
      • Carlsson PO
      • Berne C
      • Jansson L
      Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats.
      whereas ACE inhibition and angiotensin II receptor blockade preferentially increase islet blood flow.
      • Carlsson PO
      • Berne C
      • Jansson L
      Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats.
      The effects of angiotensin II on perfused pancreas preparations indicate a delayed first phase of insulin release in response to glucose.
      • Carlsson PO
      • Berne C
      • Jansson L
      Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats.
      Similarly, infusion of angiotensin II blunted insulin secretion in healthy humans,
      • Fliser D
      • Schaefer F
      • Schmid D
      • Veldhuis JD
      • Ritz E
      Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans.
      whereas ACE inhibition in patients with hypertension resulted in improved first-phase insulin secretion in response to oral or intravenous glucose.
      • Pollare T
      • Lithell H
      • Berne C
      A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension.

      NONPHARMACOLOGICAL INTERVENTIONS

      The current recommendation of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure
      • Chobanian AV
      • Bakris GL
      • Black HR
      • National High Blood Pressure Education Program Coordinating Committee
      • et al.
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290:197].
      emphasizes the need for the adoption of a healthy lifestyle for the prevention and treatment of hypertension. A diet high in fiber and potassium and low in saturated fat, refined carbohydrates, and salt can improve glycemic control and the lipid profile and significantly lower blood pressure.
      • Sacks FM
      • Svetkey LP
      • Vollmer WM
      • DASH-Sodium Collaborative Research Group
      • et al.
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      In the Dietary Approaches to Stop Hypertension study, a diet abundant in fruits and vegetables, as well as low-fat dairy products, with or without sodium restriction substantially reduced blood pressure in hypertensive patients.
      • Sacks FM
      • Svetkey LP
      • Vollmer WM
      • DASH-Sodium Collaborative Research Group
      • et al.
      Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.
      Indeed, aggressive nonpharmacological interventions are pivotal and indispensable in the therapeutic outcome in all hypertensive populations. What remains to be determined is whether the selection of pharmacological agents for hypertension has a significant impact on metabolic risk factors or progression to diabetes mellitus if patients are adherent to dietary recommendations, maintain a healthy weight, and remain physically active.

      SUMMARY

      Insulin resistance and hyperinsulinemia predispose patients to the development of hypertension through abnormalities in insulin signaling and associated hemodynamic and metabolic effects. Moreover, overcoming insulin resistance by interrupting the renin-angiotensin system may help prevent or delay the emergence of type 2 diabetes mellitus in patients with essential hypertension. This has become particularly relevant in recent years with the emergence of evidence of local tissue renin-angiotensin systems. Among the mechanisms by which angiotensin II might inhibit insulin-signaling pathways are increases in oxidative stress, alterations in nitric oxide signaling, and the activation of low-molecular-weight G proteins. Accordingly, inhibiting renin-angiotensin system activity improves insulin action at the level of skeletal muscle and vascular tissues. In addition, mechanisms that improve blood flow to insulin-sensitive tissues and the endocrine pancreas may be important in preserving insulin sensitivity and β-cell function, respectively, and therefore slowing progression to type 2 diabetes mellitus. This theory is consistent with trial evidence that suggests that treatment with ACE inhibitors or ARBs reduces new-onset diabetes compared with the potentially deleterious effects of β-blockers and diuretics (Table 1). More recently, ARB treatment was shown to provide risk reduction beyond that of metabolically neutral CCB treatment. These observations suggest that the risk of diabetes developing may be an important consideration in the treatment of patients with hypertension.

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