Q J Med 2006; 99:431–436

doi:10.1093/qjmed/hcl059

Review

Antihypertensive treatment with beta-blockers and

the spectrum of glycaemic control
P.A. SARAFIDIS and G.L. BAKRIS
From the Hypertension/Clinical Research Center, Departments of Preventive and Internal Medicine,
Rush University Medical Center, Chicago, USA

Summary
Hypertension and type 2 diabetes mellitus (DM)
are major cardiovascular risk factors, and often
cluster in the same individual in the context of
the metabolic syndrome. Management of hyper-
tension in the diabetic patient is extremely impor-
tant, and agents from all major antihypertensive
classes are effective towards this goal. Conventional
b-blockers are associated with detrimental
effects on insulin sensitivity, glycaemic control,
and the incidence of type 2 DM and thus are
less often used in hypertensive patients with DM.
In contrast, the newer vasodilating b-blockers
appear to be free of adverse effects on the above
metabolic parameters, and could be a valuable
tool for hypertension treatment in patients with DM
or the metabolic syndrome. This review summarizes
the evidence on the effects of antihypertensive
treatment with both traditional and vasodilating
b-blockers on parameters related to carbohydrate
metabolism, and discuss the pathophysiological
mechanisms that may be responsible.

Introduction
Hypertension and diabetes mellitus (DM) represent
two of the major risk factors for cardiovascular
disease (CVD).1 In many individuals, hypertension
and type 2 DM accompany other CVD risk factors
such as visceral adiposity and dyslipidaemia, in the
so-called Metabolic or Insulin Resistance Syndrome,
for which insulin resistance and compensatory
hyperinsulinaemia have been proposed as the
underlying disorders.2 This combination appears
to accelerate the development of atherosclerosis,
adding substantial cardiovascular risk beyond that of
the individual risk factors.3
Treatment of CVD risk factors such as hyper-
tension aims primarily to reduce cardiovascular
morbidity and mortality.4,5 In diabetic patients,
management of hypertension is of great impor-
tance,6 and current guidelines recommend that
to achieve a goal of 130/80 mmHg, agents from
all antihypertensive classes can be used, usually
in combination.4,5 However, previous studies
have suggested that antihypertensive agents from
different classes may exert different effects on
glucose tolerance. In general, angiotensin-
converting-enzyme (ACE) inhibitors and calcium-
channel blockers (CCBs) were associated with
neutral or beneficial effects on carbohydrate and
lipid metabolism, but thiazide diuretics and
b-blockers with adverse effects.7,8 Therefore, although

Address correspondence to Dr P.A. Sarafidis, Hypertension/Clinical Research Center, Department of Preventive

Medicine, Rush University Medical Center, 1700 West Van Buren, Suite 470, Chicago, IL 60612, USA.
email: psarafidis11@yahoo.gr
! The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088

by guest
on 02 May 2018
 432 P.A. Sarafidis and G.L. Bakris
conventional b-blockers reduce cardiovascular
risk in diabetic individuals,6,9 they are not recom-
mended as first-line antihypertensive therapy in
patients with DM.4,5 However, there are data
suggesting that newer b-blockers with vasodilating
properties have a different metabolic profile
from traditional ones,10–13 and could therefore be
of particular benefit for patients with type 2 DM.
This review summarizes the clinical evidence on
the effects of antihypertensive treatment with both
conventional and vasodilating b-blockers on param-
eters related to carbohydrate metabolism, such as
glycaemic control, insulin sensitivity and type 2 DM
incidence, providing also some potential patho-
physiological explanations for these effects. For this
purpose, a systematic literature search of MEDLINE/
PubMed database was performed to identify English-
language articles published until October 2005 that
reported data on the effects of antihypertensive
treatment with b-blockers on glycaemic control,
insulin sensitivity and incidence of DM. Search
terms used were: ’b-blocker’, ’antihypertensive
treatment’, ’diabetes’, ’glucose’, ’glycated hemo-
globin’, ’glycemic control’, ’insulin sensitivity’ and
’insulin resistance’. Reference lists of identified
articles were also evaluated for additional relevant
papers and information. Clinical studies providing
adequate information on effects of b-blockers on the
above parameters, as well as background studies
providing mechanistic explanations for these effects,
were included.
The text that follows is divided in four sections:
the effects of conventional b-blockers on insulin
sensitivity and the risk of new onset type 2 DM;
potential mechanisms for these effects of conven-
tional b-blockers; the effects of vasodilating
b-blockers on insulin sensitivity and glycaemic
control; and potential mechanisms for these effects
of vasodilating b-blockers.
Effects of conventional b-blockers
on insulin sensitivity and the risk of
new-onset type 2 diabetes mellitus
In clinical studies that used the euglycaemic
hyperinsulinaemic clamp technique (the most
reliable available method of estimating insulin
sensitivity), treatment with conventional b-blockers
(either non-selective, e.g. propranolol,14 or b1-
selective, e.g. atenolol,15,16 metoprolol,11,16) signifi-
cantly decreased insulin sensitivity in hypertensive
patients. This deterioration of insulin sensitivity with
b-blockers is expected to have a direct negative
effect on glycaemic control in patients with both
Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088
by guest
on 02 May 2018
hypertension and type 2 DM. On the other hand,
in patients without type 2 DM, the concept of the
metabolic syndrome suggests that a decrease in
insulin sensitivity would not result in elevation
of blood glucose levels, as long as the pancreatic
b-cells could secrete the necessary amounts of
insulin. However, after a certain period of time,
b-cells would no longer be able to compensate
for the increasing insulin resistance and type 2 DM
would appear.17
The importance of this detrimental effect of
b-blockers on insulin sensitivity can be seen from
studies examining their effect on the incidence of
DM, which represents a more definite outcome.
Most of these data suggest that use of conventional
b-blockers, such as atenolol or metoprolol,
increases the propensity of patients with hyperten-
sion to develop type 2 DM. For example, in the large
prospective Atherosclerosis Risk in Communities
(ARIC) cohort study, of 3804 hypertensive subjects,
representing a subgroup of the original study cohort,
after appropriate adjustment for all potentially
important confounders those treated with b-blockers
had a 28% higher risk of type 2 DM, compared
to those taking no medication (RR 1.28, 95%CI
1.04–1.57), whereas users of thiazide diuretics, ACE
inhibitors or CCBs were not at significantly higher or
lower risk for subsequent type 2 DM than untreated
hypertensives.18
In the Captopril Prevention Project (CAPPP) trial,
in which 10 985 hypertensive subjects were
randomized to captopril or conventional treatment
consisting of a diuretic, b-blockers or both, the
captopril-based regimen was associated with a
lower incidence of type 2 DM compared to the
conventional regimen, in both intention-to-treat
(RR 0.86, 95%CI 0.74–0.99) and on-treatment
(RR 0.79, 95%CI 0.67–0.94) analyses.19 In the
Losartan Intervention For Endpoint reduction
(LIFE) study, 9193 patients with hypertension and
left ventricular hypertrophy were randomized to
losartan-based or atenolol-based antihypertensive
treatment for at least 4 years. In patients without
diabetes in randomization, the risk of subsequent
DM was 25% lower for those on losartan-based
compared with those on atenolol-based therapy
(RR 0.75, 95%CI 0.63–0.88).20
In the International Verapamil-Trandorapril Study
(INVEST) trial, 22 576 patients with hypertension
and coronary artery disease were randomized to
verapamil-based or atenolol-based antihypertensive
therapy. Among patients without DM at entry, those
in the verapamil group had a 15% lower incidence
of new onset diabetes than subjects in the atenolol
group (RR 0.85, 95%CI 0.77–0.95).21 In contrast
to the above data, in the Swedish Trial in Old
 Beta-blockers and glycaemic control
Patients with Hypertension 2 (STOP-Hypertension 2)
study, there was no difference in diabetes incidence
between conventional treatment (b-blockers or
diuretics) and either ACE-inhibitor based or
CCB-based treatment.22
Most of the above studies suggest that type 2 DM
incidence is increased in subjects receiving
b-blockers. However, a number of methodological
issues limit the conclusions that can be drawn
from these studies. For example, none of those
studies,18–22 nor any randomized controlled trial
with antihypertensive agents published so far,
examined diabetes incidence as a primary end-
point. In some of the above mentioned randomized
trials, a large proportion of patients in the various
groups were receiving second-line agents that
could influence glycaemic control in the opposite
direction from the main agent.19,21,22 In some of
these studies, an ACE inhibitor19,22 or a CCB22 was
compared to conventional treatment consisting of
diuretics or b-blockers in various combinations, and
thus the net effect of the latter cannot be easily
assessed. Moreover, as these trials compared active
regimens, the observed differences19–21 could be
attributed either to a negative effect of b-blockers
or to a beneficial effect of the other treatment
compared, a fact not allowing firm conclusions to
be drawn. Detection bias could have occurred in
those of the above studies that were open-label with
blinded end-point evaluation,19,21,22 as diabetes may
have been more intensively sought in patients receiving
b-blockers. Therefore to have a definite answer in
this field, it seems that we still need randomized,
double-blind controlled trials examining diabetes
incidence as a primary end-point, preferably comparing
a b-blocker to placebo and having the same proportion
of second-line agents in the groups compared.
Potential mechanisms of the
effects of conventional b-blockers
on insulin sensitivity and glycaemic
control
Although the actions through which conventional
b-blocking agents influence insulin sensitivity and
glycaemic control are not fully clarified, several
mechanisms have been described that may be
responsible. The most important are the haemo-
dynamic effects of these agents. Under normal
conditions, insulin promotes vasodilatation and
increases blood flow in the skeletal muscles, an
action tightly coupled with an increase of glucose
disposal in the same tissue.23 In contrast, in insulin-
resistant states such as type 2 DM and obesity,
Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088
by guest
on 02 May 2018
433
endothelium-dependent insulin-mediated vasodila-
tation is seriously impaired, and it is considered an
important cause of reduction of insulin-stimulated
glucose uptake in the periphery.23,24 On the other
hand, acute sympathetic nervous system (SNS)
stimulation in normal individuals lowers insulin-
stimulated glucose uptake in muscles through
vasoconstriction and blood flow reduction.25,26
This effect is mediated via a1-adrenergic pathways,
as evident from studies with direct a- and
b-blockade,27 and further supported by the vasodi-
latating and insulin-sensitizing properties of
a-adrenergic blockers.28 During treatment with
conventional b-blockers, unopposed a1-activity
would cause vasoconstriction and decreased blood
flow to muscles.29,30 According to the above logic,
this effect will result in reduced insulin-stimulated
glucose uptake: in other words, insulin resistance.
Treatment with b-blockers can also interfere with
insulin secretion from pancreatic b cells. In par-
ticular, b-blockers may decrease the first phase of
insulin secretion, possibly through an impairment
of b2-mediated insulin release.14–16,31 In general,
attenuation of the first phase of insulin secretion
represents a crucial step in the natural history of type
2 DM, and has been suggested as an important
predictor of this disease.32 Thus, this action of
b-blockers could be another important contributor
towards the development of type 2 DM.
Weight gain is another proposed mechanism of
insulin sensitivity deterioration with b-blockers, as
those agents have been associated with an impor-
tant increase in body weight in various studies9,33
and weight gain is closely connected to insulin
sensitivity reduction.34 However, this mechanism
does not seem to be of primary importance, since
in the above mentioned studies decreased insulin
sensitivity was also observed in subjects without
weight gain,14–16 and in the ARIC study, weight
increase in patients treated with b-blockers
was identical to that of participants receiving no
medication.18
In addition to the above, in insulin-resistant states,
one of the main problems at the level of the liver is
the inability of insulin to suppress hepatic glucose
production, which leads to elevated hepatic glucose
production after meals, a disorder also contributing
to loss of glycaemic control.32,35 Sympathetic
activation stimulates glyconeogenesis and glyco-
genolysis and inhibits glycogen synthesis in the
liver. Although the relative importance of a- and
b-adrenergic receptors in mediating catecholamine-
induced hepatic glucose production in humans
in vivo remains to be resolved, in rats a2-receptors
are involved.36 If a-receptors play the major role in
humans, unopposed a-activity in the presence of
 434 P.A. Sarafidis and G.L. Bakris
b-blockade, as in the case of haemodynamic effects,
could result in enhanced hepatic glucose output,
increasing the risk for type 2 DM. Other mechanisms
responsible for this detrimental effect of b-blockers
on glycaemic control have been also speculated
upon, but not extensively studied, such as changes
in the capacity of aerobic exercise, or changes in the
cellular actions of insulin.8
Effects of vasodilating b-blockers
on insulin sensitivity and
glycaemic control
In contrast to the effect described above, some
studies suggest that newer b-blockers with vasodi-
lating properties can have beneficial effects on
parameters such as glycaemic control and insulin
sensitivity. Several years ago, delivalol, a
b1-selective b-blocker with a b2-agonistic action
was found to improve insulin sensitivity by about
10% in hypertensive patients,37 but was withdrawn
from the market due to side-effects. In a subsequent
study, another b1-blocker with b2-agonistic effects,
celiprolol, was associated with a 35% increase
in insulin sensitivity after a treatment period of
12 months.10
Carvedilol, a non-selective b-blocker with
a1-blocking properties has been also found to
improve insulin sensitivity. Jacob et al. compared
the effects of carvedilol and metoprolol in 72
hypertensive patients without DM, and observed a
14% increase in insulin sensitivity estimated with
the clamp with carvedilol after 12 weeks of
treatment, whereas metoprolol was associated with
a reduction in this parameter.11 In another study,
Giuglano et al. compared the effects of carvedilol
and atenolol in 45 patients with both hypertension
and type 2 DM. After 24 weeks of treatment, fasting
plasma glucose and HbA1c were decreased and
insulin sensitivity measured with the clamp was
increased with carvedilol, whereas atenolol had the
opposite results.12
Some months ago, the results of the Glycemic
Effects in Diabetes Mellitus: Carvedilol-Metoprolol
Comparison in Hypertensives (GEMINI) trial were
published.13 In this multicentre trial, 1235 subjects
with hypertension and type 2 DM who were already
receiving an ACE inhibitor or an angiotensin-
receptor blocker (ARB) were randomized to receive
6.25–25 mg of carvedilol or 50–200 mg of metopro-
lol twice daily, to compare the effects of these
b-blockers on glycaemic and metabolic control.
After 5 months of maintenance therapy, although
both drugs were well-tolerated and blood
Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088
by guest
on 02 May 2018
pressure control was similar in the two groups,
HbA1c increased in the metoprolol (mean
SD
0.15%
0.04%, p < 0.001) but not in the
carvedilol group (0.02%
0.04%, p ¼ 0.65), result-
ing in a difference between the two groups of
0.13%
0.05% (95%CI –0.22% to –0.04%,
p ¼ 0.004) in the modified intention-to-treat
analysis. Insulin resistance, as assessed by the
Homeostasis Model Assessment-Insulin Resistance
(HOMA-IR) index was significantly decreased with
carvedilol (–9.1%, p ¼ 0.004) but not metoprolol
(–2.0%, p ¼ 0.48) and the between-group difference
was –7.2% (95%CI –13.8% to –0.2%; p ¼ 0.04). In
addition, among patients with normal urine albumin
excretion in baseline, fewer progressed to micro-
albuminuria in the carvedilol than in the metoprolol
group (6.4% vs. 10.3%, respectively; OR 0.60,
95%CI 0.36–0.97, ¼ 0.04). These findings support
a less detrimental effect of vasodilating compared
to older b-blockers on glycaemic control and insulin
sensitivity and suggest that among b-blockers,
vasodilating agents should be preferred in subjects
with type 2 DM or the metabolic syndrome.
Potential mechanisms of the effects
of vasodilating b-blockers on insulin
sensitivity and glycaemic control
These beneficial or at least neutral effects of newer
b-blocking agents on glycaemic control and insulin
sensitivity could be explained in terms of patho-
physiology from positive actions on some of the
above adverse mechanisms of the conventional
b-blockers. For example, as far as the haemo-
dynamic effects are concerned, stimulation of
b2-receptors causes vasodilatation,38 therefore non-
selective b-blockade will also stop this b2-mediated
increase in blood flow. This is probably why insulin
sensitivity is relatively more decreased with propran-
olol than with b1-selective blockers.14–16 In addi-
tion, in a patient receiving a b-blocker that
combines b1-selective and b2-agonistic action,
vasodilatation will predominate and peripheral
blood flow will increase.38 Thus, the observed
increases of insulin sensitivity with delivalol37 and
celiprolol10 could be attributed to the vasodilatation
they cause. Moreover, it seems unlikely these
compounds impair first-phase insulin secretion,
which is b2-mediated31 and therefore they are not
implicated in another important mechanism of
deterioration in glycaemic control.
In the case of carvedilol, the a1-blocking property
would be expected to oppose to the a1-mediated
vasoconstriction. Indeed, carvedilol has been
 Beta-blockers and glycaemic control
known for several years to cause vasodilatation and
increase peripheral blood flow.39 Therefore, the
beneficial effects of carvedilol on glycaemic param-
eters could be also explained by its haemodynamic
properties, at least in part. Further, carvedilol
has an a- to b-blockade ratio of 1:7.6 and has
fewer side-effects associated with vasodilatation,
such as postural hypotension and dizziness, than
for example labetalol, an older combined a- and
b-blocker with an a- to b-blockade ratio of 1:4.9.40
This could be of particular importance for patients
with DM, which is often complicated by autonomic
neuropathy.
Conclusions
Although antihypertensive treatment with traditional
b-blockers reduces cardiovascular risk in diabetic
individuals,6,9 these agents are underused in
patients with type 2 DM and the metabolic syn-
drome, as several studies suggested they exert
detrimental effects on insulin sensitivity11,14–16 and
the incidence of type 2 diabetes.18–21 Studies
comparing newer vasodilating to conventional
b-blocking agents showed positive or at least neutral
effects of the former on glycaemic control and
insulin sensitivity,10–13,37 suggesting that they could
be used in subjects with hypertension with or
without DM, without the fear of deterioration in
these parameters. For a definite answer on the
possible benefits of vasodilating over conventional
b-blockers we need studies not only on these
surrogate metabolic parameters but also on out-
comes such as the incidence of new-onset type
2 DM, cardiovascular events and mortality. The
available evidence suggests, however, that vasodi-
lating b-blockers could be a valuable tool in
managing hypertension in patients with type 2 DM
or the metabolic syndrome.
References
1. Wood D, De Backer G, Faergeman O, Graham I, Mancia G,
Pyörälä K. Prevention of coronary heart disease in clinical
practice. Recommendations of the Second Joint Task Force
of European and other Societies on Coronary Prevention.
Eur Heart J 1998; 19:1434–503.
2. De Fronzo RA, Ferrannini E. Insulin resistance—a multi-
faceted syndrome responsible for NIDDM, obesity, hyper-
tension, dyslipidemia and atherosclerotic cardiovascular
disease. Diabetes Care 1991; 14:173–94.
3. Meigs JB, D’Agostino RB Sr, Wilson PW, Cupples LA,
Nathan DM, Singer DE. Risk variable clustering in the insulin
resistance syndrome. The Framingham Offspring Study.
Diabetes 1997; 46:1594–600.
Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088
by guest
on 02 May 2018
435
4. Chobanian A, Bakris GL, Black HR, et al. Seventh report
of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
Hypertension 2003; 42:1206–252.
5. European Society of Hypertension–European Society of
Cardiology guidelines committee.2003 European Society of
Hypertension–European Society of Cardiology guidelines
for the management of arterial hypertension. J Hypertens
2003; 21:1011–53.
6. Bakris GL. The importance of blood pressure control in the
patient with diabetes. Am J Med 2004; 116(Suppl. 5A):
30–8S.
7. Lithell HO. Effect of antihypertensive drugs on insulin,
glucose, and lipid metabolism. Diabetes Care 1991;
14:203–9.
8. Sowers JR, Bakris GL. Antihypertensive therapy and the risk
of type 2 diabetes mellitus. N Engl J Med 2000; 342:969–70.
9. UK Prospective Diabetes Study Group.Efficacy of atenolol
and captopril in reducing risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS
39. Br Med J 1998; 317:713–20.
10. Malminiemi K. Association between serum lipids, glucose
tolerance, and insulin sensitivity during 12 months of
celiprolol treatment. Cardiovasc Drugs Therapy 1995;
9:295–304.
11. Jacob S, Rett K, Wicklmayr M, et al. Differential effect of
chronic treatment with two betablocking agents on insulin
sensitivity: the carvedilol-metoprolol study. J Hypertens
1996; 14:489–94.
12. Giugliano D, Acampora R, Marfella R, et al. Metabolic and
cardiovascular effects of carvedilol and atenolol in non-
insulin-dependent diabetes mellitus and hypertension: a
randomized, controlled trial. Ann Intern Med 1997;
126:955–9.
13. Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of
carvedilol vs metoprolol in patients with type 2 diabetes
mellitus and hypertension: a randomized controlled trial.
JAMA 2004; 292:2227–36.
14. Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol
and propranolol in a double-blind cross-over study in
hypertensive patients. Blood Press 1992; 1:92–101.
15. Pollare T, Lithell H, Mörlin C, et al. Metabolic effects of
diltiazem and atenolol: results from a randomized, double-
blind study with parallel groups. J Hypertens 1989; 7:551–9.
16. Pollare T, Lithell HO, Selinus I, Berne C. Sensitivity to insulin
during treatment with atenolol and metoprolol: a random-
ized, double blind study of effects on carbohydrate and
lipoprotein metabolism in hypertensive patients. Br Med J
1989; 298:1152–7.
17. Turner NC, Clapham JC. Insulin resistance, impaired glucose
tolerance and non-insulin-dependent diabetes, pathologic
mechanisms and treatment: current status and therapeutic
possibilities. Prog Drug Res 1998; 51:33–94.
18. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL.
Hypertension and antihypertensive therapy as risk factors for
type 2 diabetes mellitus. N Engl J Med 2000; 342:905–12.
19. 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. Lancet 1999; 353:611–16.
 436 P.A. Sarafidis and G.L. Bakris
20. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular
morbidity and mortality in the Losartan Intervention For
Endpoint reduction in hypertension study (LIFE): a random-
ised trial against atenolol. Lancet 2002; 359:995–1003.
21. Pepine CJ, Handberg EM, Cooper-DeHoff RM, 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. JAMA 2003; 290:2805–16.
22. Hansson L, Lindholm LH, Ekbom T, et al. Randomized trial
of old and new antihypertensive drugs in elderly patients:
cardiovascular mortality and morbidity the Swedish Trial in
Old Patients with Hypertension-2 study. Lancet 1999;
354:1751–6.
23. Steinberg HO, Baron AD. Vascular function, insulin resis-
tance and fatty acids. Diabetologia 2002; 45:623–34.
24. Sartori C, Scherrer U. Insulin, nitric oxide and the sympa-
thetic nervous system: at the crossroads of metabolic and
cardiovascular regulation. J Hypertens 1999; 17:1517–25.
25. Lembo G, Capaldo B, Rendina V, et al. Acute noradrenergic
activation induces insulin resistance in human skeletal
muscle. Am J Physiol 1994; 266:E242–7.
26. Tappy L, Girardet K, Schwaller N, et al. Metabolic effects of
an increase of sympathetic activity in healthy humans. Int J
Obes Relat Metab Disord 1995; 19:419–22.
27. Trueb L, Sartori C, Scherrer U. Insulin resistance
evoked by orthostasis-induced sympathetic activation is
a-adrenergically mediated [Abstract]. Diabetes 1996; 45:97A.
28. Pollare T, Lithell H, Selinus I, Berne C. Application of
prazosin is associated with an increase of insulin sensitivity
in obese patients with hypertension. Diabetologia 1988;
31:415–20.
29. Lund-Johansen P, Omvik P, Nordrehaug JE. Long-term
hemodynamic effects of antihypertensive treatment. Clin
Invest 1992; 70:S58–64.
30. Lithell H, Pollare T, Berne C, Saltin B. The metabolic and
circulatory response to beta-blockade in hypertensive men is
correlated to muscle capillary density. Blood Press 1992;
1:20–6.
Downloaded from https://academic.oup.com/qjmed/article-abstract/99/7/431/2261088
by guest
on 02 May 2018
31. Kaneto A, Miki E, Kosaka K. Effect of beta and beta2
adrenoreceptor stimulants infused intrapancreatically on
glucagons and insulin secretion. Endocrinology 1975;
97:1166–73.
32. DeFronzo RA, Mandarino L, Ferrannini E. Metabolic and
molecular pathogenesis of type 2 diabetes mellitus. In:
DeFronzo RA, Ferrannini E, Keen H, Zimmet P, eds.
International Textbook of Diabetes Mellitus. 3rd edn.
Chichester, John Willey & Sons Ltd, 2004:359–73.
33. Rössner S, Taylor CL, Byington RP, Furberg CD. Long term
propranolol treatment and changes in body weight after
myocardial infarction. Br Med J 1990; 300:902–3.
34. Caro JF. Insulin resistance in obese and non-obese men.
J Clin Endocrinol Metab 1991; 73:691–5.
35. Groop LC, Bonadonna RC, Del Prato S, et al. Glucose and
free fatty acid metabolism in non-insulin-dependent diabetes
mellitus. Evidence for multiple sites of insulin resistance.
J Clin Invest 1989; 84:205–13.
36. Nonogaki K, Iguchi A. Role of central neural mechanisms in
the regulation of hepatic glucose metabolism. Life Sci 1997;
60:797–807.
37. Haenni A, Lithell H. Treatment with a betablocker
with b2-agonism improves glucose and lipid meta-
bolism in essential hypertension. Metabolism 1994;
43:455–61.
38. Reaven GM, Lithell H, Landsberg L. Hypertension and
associated metabolic abnormalities – the role of insulin
resistance and the sympathoadrenal system. N Engl J Med
1996; 334:374–81.
39. Eggertsen R, Sivertsson R, Andren L, Hansson L. Acute and
long term hemodynamic effects of carvedilol, a combined
beta-adrenoreceptor blocking and pre-capillary vasodilating
agent, in hypertensive patients. J Cardiovasc Pharmacol
1987; 10(Suppl.):S76–80.
40. Tomlinson B, Bompart F, Graham BR, Liu JB, Prichard BN.
Vasodilating mechanism and response to physiological
pressor stimuli of acute doses of carvedilol compared with
labetalol, propranolol and hydralazine. Drugs 1988;
36(Suppl. 6):S37–47.