Insulin Resistance in HIV Infection: Drugs, Host Responses, or Restoration to Health?
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Insulin Resistance in HIV Infection Volume 16 Issue 2 June/July 2008
Perspective
Insulin Resistance in HIV Infection: Drugs, Host Responses,
or Restoration to Health?
Protease inhibitors (PIs) are widely assumed to be associated with a syn- are rarely used because of the need to
drome of insulin resistance accompanied by hyperlipidemia and fat redis- perform insulin clamp studies to make
tribution. Insulin resistance in HIV infection has numerous other causes, the diagnosis (Kahn et al, Diabetes Care,
however, which include not only the direct effects of antiretroviral drugs 2005). Epidemiologically, insulin resis-
but also factors such as aging and restoration to health accompanied by fat tance is strongly linked with coronary
accumulation. Studies of PIs in HIV-infected and noninfected patients indi- artery disease, and debate exists over
cate that some of these drugs are associated with reduced insulin sensitivity whether it is the prime causal factor or
(greater acute versus chronic effects) that may be due to direct blockade of a risk marker. Factors known to cause
the insulin-sensitive glucose transporter in muscle and fat cells. Other studies insulin resistance outside the setting of
have shown that insulin levels increase over time with antiretroviral therapy, HIV infection include obesity, especially
likely the result of improved health, fat accumulation, and aging, and that visceral obesity; physical inactivity; the
increases in visceral fat and upper trunk fat are associated with a higher use of some drugs (eg, glucocorticoids
risk of insulin resistance in HIV-infected and -uninfected individuals alike. and niacin); and acute bacterial infec-
This article summarizes a presentation on insulin resistance in HIV infection tion. Keep in mind, however, that ap-
made by Carl Grunfeld, MD, PhD, at the 10th Annual Ryan White HIV/AIDS proximately 20% of healthy, thin indi-
Program Clinical Update in Phoenix in June 2007. The original presentation viduals have insulin resistance.
is available as a Webcast at www.iasusa.org.
Insulin Resistance in HIV
Infection: Effects of Protease
Protease inhibitors (PIs) are widely as- (HOMA-IR), which is calculated as fol-
Inhibitors
sumed to induce a syndrome of insulin lows: insulin concentration (µU/mL)
resistance accompanied by hyperlip- multiplied by the result of glucose con- Studies of acute HIV infection usually
idemia and fat redistribution that re- centration (mmol/L) divided by 22.5; a show insulin resistance and hyperglyce-
sembles the metabolic syndrome with score of higher than 4 indicates insulin mia (with hypoglycemia appearing dur-
its increased risk of cardiovascular dis- resistance, which is useful in epide- ing sepsis). Early studies of the insulin
ease. Researchers now believe, how- miologic studies. Note, however, that profile in HIV infection (Hommes et al,
ever, that numerous factors contribute the calculation depends on measuring Metabolism, 1991) were remarkable in
to the metabolic alterations observed insulin level and therefore does not that no insulin resistance or hypergly-
in HIV-infected patients and that some work using clinical laboratory measure- cemia was observed; in fact, patients
of these factors may be overlooked if ments. Similar calculations can be de- were often thin, and clamp studies in-
only a single cause is assumed. rived from results of glucose tolerance dicated increased insulin sensitivity. In
testing. The current gold standards are 2000, Mulligan and colleagues report-
the insulin tolerance test and the eugly- ed findings in a study that assessed
Insulin Resistance
cemic-insulin clamp technique, the lat- changes in glucose and insulin before
Insulin resistance exists, but it cannot be ter of which measures insulin-mediated and approximately 3 months after the
diagnosed accurately in the clinic. Clini- glucose disposal (glucose infusion rate addition of a PI (indinavir, saquinavir,
cal insulin assays are, in short, terrible divided by insulin level, or M/I). Neither or ritonavir) or lamivudine to stable
for providing absolute measurements is appropriate for use in the clinic. The antiretroviral therapy and compared
of insulin; these assays were developed bottom line is that insulin resistance is those results to those in patients main-
as a clinical tool to detect inappropriate inferred rather than accurately mea- tained on a stable regimen that did not
insulin levels during hypoglycemia by sured in a given patient. include a PI or lamivudine (control). As
assessing whether insulin levels change A diagnosis of insulin resistance shown in Figure 1, patients receiving a
during fasting. (Research insulin assays portends an unfavorable outcome. In- PI had a clinically trivial but nonethe-
may work better.) Many studies assess sulin resistance is the first step toward less remarkable increase in glucose
insulin resistance using a homeostasis diabetes, but it must be accompanied concentrations over the short study
model assessment of insulin resistance by a (largely genetically determined) period, as well as a doubling in insu-
reduction in insulin secretion. Insulin lin concentrations; also, no change in
resistance is one of the World Health body fat distribution (limb fat and trunk
Dr Grunfeld is Professor of Medicine at the Organization (WHO) criteria for meta- fat) was evident (Mulligan et al, JAIDS,
University of California San Francisco. bolic syndrome, but the WHO criteria 2000). These findings indicate that
89International AIDS Society–USA Topics in HIV Medicine
P = .009
Pretherapy related to restoration of health or a di-
On therapy 22
rect result of the PI. These studies again
M/I (mg/kg*min/µU/mL)
20
100 * showed no alteration in visceral or sub- 18
Glucose (mg/dL)
16
80 cutaneous fat with PI administration. 14
60 Indinavir, but not lopinavir/ritonavir, 12
40 was associated with statistically signifi- 10
8
20 cant increases in fasting glucose and in- 6
0 sulin concentrations (Figure 2; Noor et 4
2
al, AIDS, 2001; Lee et al, AIDS, 2004).
0
*
These findings thus suggest that the Mean Pretreat- Indinavir Mean
30 effects of at least some PIs on metabo- Pretreat- ment Indinavir
Insulin (µU/mL)
ment
lism do not depend on antiretroviral
20 P = .026
therapy–related restoration of health
10 and improved immune response or on 200
changes in body composition. This is not 180
0 160
Glucose (mg/dL)
PI Lamivudine Control to say, however, that metabolic changes 140
related to body composition factors do 120
not also occur. Clamp studies in the pa- 100
Figure 1. Changes in plasma glucose and in- tients receiving indinavir showed a sta- 80
sulin levels in HIV-infected patients after add- 60
tistically significant decrease in insulin 40
ing a protease inhibitor (PI) (indinavir, n = 16; sensitivity; results of 2-hour oral glucose 20
saquinavir, n = 2; or ritonavir, n = 2) or lami- tolerance testing showed a statistically 0
vudine (n = 9) to stable treatment containing Mean Pretreat- Indinavir Mean
significant increase in glucose levels, Pretreat- ment Indinavir
neither (control, n = 12). Asterisks indicate with 1 patient meeting the criterion for ment
statistically significant difference. Adapted diabetes and 2 patients meeting the cri-
from Mulligan et al, JAIDS, 2000. terion for impaired glucose tolerance Figure 3. Changes in insulin-mediated glu-
(Figure 3). However, the insulin resis- cose disposal (glucose infusion rate divided
Pretherapy tance observed in these patients was by insulin level [MI]) in clamp studies (top),
4-week therapy
Glucose (mmol/L)
5.6
not classic insulin resistance because and glucose levels in 2-hour oral glucose
P = .05
5.4 no resistance to the effects of insulin on tolerance testing (bottom) in HIV-seronega-
5.2 tive patients receiving 4 weeks of indinavir.
5
lipid metabolism was observed. Mea-
4.8 surement of free fatty acid levels during Top dashed line indicates diabetes thresh-
4.6 oral glucose tolerance testing showed old; bottom dashed line, impaired glucose
4.4
Indinavir Lopinavir/ritonavir that levels were normally suppressed in tolerance threshold. Adapted from Noor et
both indinavir and lopinavir/ritonavir re- al, AIDS, 2001.
Insulin (pmol/L)
cipients (Figure 4); similar findings were
150
100
P = .04 made in clamp studies. hibited insulin resistance (reduced M/I),
50 The findings indicating normal lipid with the reduction in glucose infusion rate
0 kinetics in these subjects are of particu- during the clamp study evident within
Indinavir Lopinavir/ritonavir lar interest given in vitro findings indi- 30 minutes. Glucose disposal during the
cating that PIs bind to and block the hyperinsulinemic clamp is caused by in-
insulin-sensitive glucose transporter sulin increasing glucose transport by in-
Figure 2. Plasma glucose and insulin levels (GLUT4; Hruz, Am J Infect Dis, 2006). creasing the activity of GLUT4 in muscle
before and after 4 weeks of protease inhib- Protease inhibitors decreased insulin- and fat. Studies of other PIs showed that
itor treatment in healthy HIV-seronegative stimulated glucose transport in fat cells single-dose ritonavir—but not amprena-
patients. Adapted from Noor et al, AIDS, with no blockade of any aspect of in- vir—reduced M/I (Figure 6), and that 10
2001, and Lee et al, AIDS, 2004. sulin activation (eg, phosphorylation, days of lopinavir/ritonavir also reduced
lipid metabolism). The direct effect on M/I. The picture that has emerged from
whereas PIs do cause some metabolic GLUT4 was supported by showing that these studies is that the effects caused
changes, the changes are not mediated glucose transport was blocked in non- by some PIs of increasing insulin resis-
by alteration of body composition. insulin-sensitive cells transfected with tance are strong in the short term and
Dr Grunfeld and colleagues thus per- GLUT4. These effects of PIs were evi- reduced with long-term dosing (Lee et
formed studies in which indinavir or dent within minutes of exposure. al, Curr HIV/AIDS Rep, 2000). The great-
lopinavir/ritonavir were administered Dr Grunfeld and colleagues therefore est effects are observed with indinavir
to healthy HIV-seronegative patients to examined the effects of single doses of and full-dose ritonavir, the drugs in use
determine whether the metabolic ef- PIs in healthy HIV-seronegative patients. when diabetes began to appear in HIV-
fects in HIV-infected patients might be As shown in Figure 5, every patient ex- infected patients.
90Insulin Resistance in HIV Infection Volume 16 Issue 2 June/July 2008
Free Fatty Acid Level (mmol/L)
.50 Pretreatment that all groups had a statistically sig- P < .001
Indinavir nificant increase in insulin levels over 20
M/I (mg/kg*min/µU/mL)
.40 18
time (Figure 7). Shorter-term follow-
16
.30 up among nonrandomized patients 14
receiving didanosine/stavudine versus 12
.20 abacavir/lamivudine showed a statis- 10
8
tically nonsignificant greater increase
.10 6
in the patients receiving nucleoside 4
0 analogue reverse transcriptase inhibi- 2
0 30 60 90 120 150 180 tors (nRTIs) than in patients receiving 0
Indinavir (minutes) Mean Placebo Indinavir Mean
NNRTIs (nRTIs are themselves associ- Placebo Indinavir
ated with specific effects on metabo-
lism that are not discussed here; Shlay
14 Indinavir
Pretreatment et al, JAIDS, 2005; Shlay et al, JAIDS,
Glucose Infusion Rate
Placebo
(mg/kg*min/µU/mL)
12
Free Fatty Acid Level (mmol/L)
.50 P = .04 4-week treatment 2007).
10
P = .003
The factors causing increased in-
.40 8 P < .05
P = .01
sulin resistance in these treated pa-
tients, which appear to overwhelm the 6
.30
changes produced by PIs, are likely 4
.20 related to changes such as improved 2
health and gaining of body fat, as well
.10 as aging. In the Fat Redistribution and 0 20 40 60 80 100 120 140 160 180 200
Minutes
0
Metabolism (FRAM) study (Grunfeld et
0 30 60 90 120 150 180 al, JAIDS, 2007), Dr Grunfeld and col-
Lopinavir/ritonavir (minutes) leagues assessed metabolic and body Figure 5. Effect of single dose of indinavir in
composition profiles in nondiabetic HIV-seronegative patients on insulin sensi-
HIV-infected patients and healthy con- tivity (M/I; top) and on glucose infusion rate
Figure 4. Comparison of free fatty acid lev-
trols. Glucose levels were similar in over time during clamp study (bottom).
els during oral glucose tolerance testing in
male and female patients and con-
healthy HIV-seronegative patients receiving assessed by HOMA-IR values above 4
trols; HOMA-IR levels were somewhat
4 weeks of indinavir or lopinavir/ritonavir. is stronger in controls than in HIV-in-
higher in HIV-infected women, but not
Adapted from Noor et al, AIDS, 2001, and fected subjects because other factors,
in HIV-infected men, compared with
Lee et al, AIDS, 2004. such as antiretroviral drugs, contribute
controls. Multivariate analysis showed
that being in the upper tertiles for vis- to insulin resistance in patients with
ceral fat and upper trunk fat was asso- HIV infection that are not operative in
Other Factors in Insulin ciated with a markedly increased risk controls. Factors predictive of greater
Resistance: Restoration of of having a HOMA-IR value higher than visceral fat were male sex, white race,
Health, Fat, and Aging 4 (Table 1). The relationship between increasing age, not smoking, and re-
fat deposits and insulin resistance as duced physical activity (Table 2).
The effects of indinavir on insulin re-
sistance are greater in HIV-infected pa-
tients than in noninfected patients, in- P = .007 P = NS
14 14
dicating that factors in addition to the
M/I (mg/kg*min/µU/mL)
M/I (mg/kg*min/µU/mL)
potential blocking of insulin-mediated 12 12
glucose transport are operative in HIV 10 10
infection. That such factors are active 8 8
in addition to the specific drug effect
6 6
of some PIs is supported by long-term
data. In the Flexible Initial Retrovirus 4 4
Suppressive Therapies (FIRST) study, 2 2
patients in whom a PI was added to 0 0
treatment had an early increase in in- Average Placebo Ritonavir Average Average Placebo Amprenavir Average
sulin levels compared with those add- Placebo Ritonavir Placebo Amprenavir
ing a nonnucleoside analogue reverse
transcriptase inhibitor (NNRTI) or PI
plus NNRTI treatment; however, fol- Figure 6. Effect of single doses of ritonavir (left) and amprenavir (right) on insulin sensitivity
low-up of more than 5 years showed (M/I) in HIV-seronegative patients. NS indicates not statistically significant.
91International AIDS Society–USA Topics in HIV Medicine
Change Change
SE P value SE P value
(unit/month) (unit/month)
PI 0.07 0.02Insulin Resistance in HIV Infection Volume 16 Issue 2 June/July 2008
Table 2. Effects of Subject Characteristics on Visceral Adipose Tissue in Fat Redistribution Diabetes Association and the European As-
and Metabolism Study sociation for the Study of Diabetes. Diabetes
Care. 2005;28:2289-2304.
Men Women Lee GA, Rao MN, Grunfeld C. The effects
of HIV protease inhibitors on carbohydrate
Percent Effect P Value Percent Effect P Value
and lipid metabolism. Curr HIV/AIDS Rep.
Ethnicity, vs White 2005;2:39-50.
African American –55 .001 –21 .089 Lee GA, Seneviratne T, Noor MA, et al. The
metabolic effects of lopinavir/ritonavir in HIV-
Hispanic –3 .74 +6 .78 negative men. AIDS. 2004;18:641-649.
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