Download IGF-I increases forearm blood flow without increasing forearm

IGF-I increases forearm blood flow without increasing
forearm glucose uptake
MERRI PENDERGRASS, ELISA FAZIONI, DARLENE COLLINS, AND RALPH A. DEFRONZO
Diabetes Division, Department of Medicine, University of Texas
Health Science Center, San Antonio, Texas 78284
insulin-like growth factor I; insulin resistance
DECREASED INSULIN-MEDIATED glucose uptake by skeletal
muscle is a characteristic feature of type 2 diabetes
mellitus and other insulin-resistant states (14). Theoretically, reduced glucose uptake could result from
defects in either one or both of its components, glucose
extraction and/or glucose delivery (48). Impaired glucose extraction consistently has been demonstrated in
type 2 diabetes mellitus and obesity (8, 14, 17). At the
cellular level, multiple defects in insulin-mediated glucose metabolism have been described, including impaired insulin receptor signal transduction and decreased glucose transport, glucose phosphorylation,
glycogen synthesis, glycolysis, and glucose oxidation
(14). More recently, it has been suggested that an
impairment in the ability of insulin to augment limb
blood flow, resulting in diminished glucose delivery,
may contribute to the insulin resistance of type 2
diabetes mellitus (33), obesity (5, 32, 44), type 1 diabetes (4), and hypertension (3). However, this position has
been challenged for a number of reasons. First, many
studies have failed to demonstrate a vasodilatory effect
of insulin on limb (6, 7, 11, 29, 31, 47), splanchnic (16),
or renal (15, 43) blood flow. Moreover, when a vasodilatory effect of insulin has been demonstrated, it usually
has been observed after prolonged insulin infusion
(3–4 h) or with pharmacological doses of insulin (.100
µU/ml) (reviewed in Refs. 38 and 42). These results
suggest that blood flow is not a primary regulator of
insulin-stimulated muscle glucose uptake under physiological conditions. Second, impaired insulin-stimulated glucose uptake without corresponding impairments in blood flow has been demonstrated (7, 46).
Third, some studies have demonstrated a normal increase in limb blood flow in insulin-resistant obese
subjects even though insulin-mediated glucose uptake
remained severely impaired (39, 19). Fourth, severe
defects in insulin-stimulated glucose disposal persist
when muscle tissues from obese and diabetic subjects
are studied in vitro (23). Last, it is very difficult to
conceptualize how vasodilatation (without recruitment
of new capillary beds) could augment glucose uptake in
the absence of any change in the energy needs of the
cell.
One way to examine whether an increase in blood
flow, per se, contributes to the insulin-mediated stimulation of glucose uptake is to increase blood flow to the
muscle without enhancing its intrinsic ability to extract glucose. If an insulin-mediated increase in glucose
delivery (accomplished solely by augmenting blood
flow) contributes to muscle glucose utilization, other
manipulations that increase glucose delivery (by augmenting blood flow) also should stimulate glucose
uptake. In this study, we used human insulin-like
growth factor (IGF) I in conjunction with the forearm
balance technique to examine the separate effect of
increased glucose delivery, independent of any change
in the intrinsic ability of the muscle to extract glucose,
on glucose uptake in healthy nondiabetic subjects.
IGF-I is a polypeptide hormone that has close structural and functional homology to insulin and has been
shown to stimulate glucose uptake (9), although it is
10–15 times less potent than insulin in promoting
glucose transport (22, 34, 40). IGF-I is also a potent
stimulator of muscle blood flow (13, 26), having a much
more pronounced effect than insulin on this parameter.
Because of the differential dose-related action of IGF-I
to enhance glucose uptake and to stimulate blood flow,
we were able to augment blood flow by 60%, an increase
comparable to that reported with insulin in some
studies (2), without significantly affecting muscle glucose extraction, i.e., intrinsic activity. This study design
allowed us directly to assess the effect of increased
0193-1849/98 $5.00 Copyright r 1998 the American Physiological Society
E345
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Pendergrass, Merri, Elisa Fazioni, Darlene Collins,
and Ralph A. DeFronzo. IGF-I increases forearm blood flow
without increasing forearm glucose uptake. Am. J. Physiol.
275 (Endocrinol. Metab. 38): E345–E350, 1998.—Decreased
insulin-mediated muscle glucose uptake is a characteristic
feature of non-insulin-dependent diabetes mellitus and other
insulin-resistant states. It has been suggested that an impairment in the ability of insulin to augment limb blood flow,
resulting in diminished glucose delivery to muscle, may
contribute to this abnormality. In this study, we used human
insulin-like growth factor (IGF) I in conjunction with the
forearm balance technique to determine whether forearm
glucose uptake could be stimulated by increasing blood flow
without directly stimulating the intrinsic ability of the muscle
to extract glucose. IGF-I was infused intra-arterially in
healthy controls at a rate of either 0.4 µg · kg21 · min21 (high
IGF) or 0.04 µg · kg21 · min21 (low IGF) for 140 min. With high
IGF, forearm blood flow increased approximately twofold
(34 6 3 vs. 64 6 8 ml · min21 · l forearm volume21, P , 0.01),
and arteriovenous glucose concentration difference (a-v difference) increased modestly (0.19 6 0.05 vs. 0.31 6 0.08 mM,
P 5 0.32), resulting in an increased forearm glucose uptake
(6.4 6 1.7 vs. 21.7 6 7.4 µmol · min21 · l forearm volume21, P 5
0.09 vs. basal). With low IGF, forearm blood flow increased by
59% (29 6 4 vs. 46 6 9 ml · min21 · l forearm volume21, P ,
0.05) and was associated with a proportional decrease in the
a-v difference (0.29 6 0.04 vs. 0.18 6 0.05 mM, P , 0.05).
Forearm glucose uptake therefore was not significantly different from basal values (7.6 6 0.6 vs. 6.9 6 1.8 µmol ·
min21 · kg21 ). These data demonstrate that increasing blood
flow without increasing the intrinsic ability of the muscle to
extract glucose does not increase forearm muscle glucose
uptake.
E346
INCREASING BLOOD FLOW DOES NOT INCREASE GLUCOSE UPTAKE
blood flow on forearm muscle glucose uptake. Although
IGF-I increased blood flow up to twofold, forearm
glucose uptake did not increase, indicating that enhanced blood flow, per se, is not an independent regulator of muscle glucose uptake.
SUBJECTS AND METHODS
Table 1. Clinical characteristics of subjects
Clinical Characteristics
Number
Gender, F/M
Age, yr
Body weight, kg
BMI, kg/m2
Fasting plasma glucose, mM
Fasting plasma insulin, pM/ml
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
14
10/4
30 6 2
60 6 5
22 6 1
5.0 6 0.1
32 6 4
119 6 3
70 6 2
Values are means 6 SE except for no. of subjects and ratio of female
to male subjects (F/M). BMI, body mass index.
WBGU 5 glucose infusion rate 1 pool correction
where the pool correction takes into account the change in the
whole body glucose pool, as estimated from the change in
plasma glucose concentration (18). Forearm glucose uptake
(FGU) was quantitated according to the Fick principle
FGU 5 (arterial 2 venous glucose concn) 3 (blood flow)
where blood glucose concentration was estimated from plasma
glucose concentration and the hematocrit (Hct) according to
the following formula
Blood concn 5 (plasma concn) 3 (1 2 0.3 Hct)
Forearm blood flow was measured by indocyanine green dye
dilution in the deep vein according to the following formula (1)
Blood flow rate
5 dye infusion rate/(deep vein dye concn)/(1 2 Hct)
(1)
Forearm blood flow is expressed per liter forearm volume.
Statistical analysis. All data are presented as means 6 SE.
All basal values are reported as means of the samples taken
at the time points 270, 230, and 215 min. Test-period values
for insulin and IGF-I levels are reported as the means of all
samples taken during the IGF-I infusions. Test-period values
for FFA levels are reported as the means of samples taken
during the last hour of each study (time points 80, 100, and
140 min). Differences between the basal and test-period
values were tested by the paired Student’s t-test.
RESULTS
Plasma IGF-I, insulin, and FFA concentrations. The
effects of IGF-I infusion on plasma IGF-I, insulin, and
FFA concentrations are shown in Table 2. The deep
venous total IGF-I concentration increased from 117 6
17 to 451 6 68 ng/ml (P , 0.01) during high IGF and
from 93 6 9 to 136 6 11 ng/ml (P , 0.001) during low
IGF. Free IGF-I levels increased from undetectable in
the basal state to 143 6 42 ng/ml during high IGF and
8 6 3 ng/ml during low IGF. Plasma insulin levels were
unchanged in response to both high IGF and low IGF
infusions. During high IGF, plasma arterial FFA concentration fell significantly (P , 0.01) but remained unchanged during the low IGF infusion.
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Subjects. Fourteen healthy volunteers each participated in
one of two protocols. Clinical characteristics of the subjects
are shown in Table 1. None of the volunteers had a family
history of diabetes or clinical or laboratory evidence of
systemic disease or were taking any medications. Subjects
were instructed not to exercise on the day before the study
and to eat a diet containing at least 200 g of carbohydrate for
at least 3 days preceding the study. Body weight was stable in
all subjects for at least 3 mo before the study. The purpose,
nature, and potential risks of the study were explained to all
subjects, and informed, written consent was obtained before
their participation. The protocol was reviewed and approved
by the Human Investigation Committee of the University of
Texas Health Science Center in San Antonio, Texas.
Experimental design. All studies took place at the Clinical
Research Center of the Audie L. Murphy Memorial Veterans
Administration Hospital and began at 0800 after a 10- to 12-h
overnight fast. After subjects arrived at the research unit,
catheters were introduced percutaneously into the brachial
artery and retrogradely into an ipsilateral deep forearm vein
draining forearm muscle. All blood samples were obtained
through these two catheters. The tip of the deep forearm vein
catheter was advanced for a distance of 2 in. from the
puncture site and could not be palpated in any of the subjects.
Previous studies have documented that such catheter placement allows sampling of the muscle bed perfused by either
the radial or the ulnar artery (12). Catheter patency was
maintained by a slow infusion of normal saline. To exclude
blood flow from the hand, a pediatric sphygmomanometric
cuff was inflated around the wrist to 100 mmHg above the
systolic pressure for 2 min before and during each venous
sampling period. A third catheter was inserted into a contralateral arm vein for infusion of glucose.
After a 70-min basal period, IGF-I (Genentech, South San
Francisco, CA) was infused locally into the brachial artery at
a rate of 0.4 µg · kg21 · min21 (high IGF, n 5 7) or 0.04 µg · kg21 ·
min21 (low IGF, n 5 7) for 140 min. Arterial plasma glucose
concentration was clamped at the basal level by a variable
infusion of 20% glucose determined by a 5- to 10-min sampling (18). At 270, 230, 215, and 140 min, simultaneous
arterial and venous samples were obtained for determination
of plasma glucose concentration. At these same time points,
forearm blood flow was determined by indocyanine green dye
dilution (1). Forearm volume was measured in all subjects by
water displacement. Forearm specific gravity was assumed to
be 1. Arterial samples for insulin and free fatty acid (FFA)
concentrations and venous samples for IGF-I concentrations
were obtained at 270, 230, 215, 40, 80, 100, and 140 min.
During arterial sampling, the IGF-I infusion was interrupted
for a period of ,10 s.
Analytical determinations. Plasma glucose concentration
was determined in duplicate by the glucose oxidase method
on a Beckman Glucose Analyzer II (Fullerton, CA). Plasma
insulin concentrations were measured by specific radioimmunoassay [Coat-a-count insulin kits; Diagnostic Products, Los
Angeles, CA; intra-assay coefficient of variation (CV) 3–10%;
interassay CV 5–10%]. Plasma IGF-I concentrations were
measured by radioimmunoassay (10) in the laboratories of
Genentech. Plasma FFAs were measured by an enzymatic
method (NEFA kit, Wako Chemicals, Dallas, TX; intra-assay
CV 3%; interassay CV 7–10%).
Calculations. Whole body glucose uptake (WBGU) was
calculated during the final 40 min of the clamp according to
the following formula
INCREASING BLOOD FLOW DOES NOT INCREASE GLUCOSE UPTAKE
E347
Table 2. IGF-I, insulin, and FFA concentrations
High IGF
Basal
Total IGF-I, ng/ml
Free IGF-I, ng/ml
Plasma insulin, pM
Arterial FFA, mM
117 6 17
22 6 6
795 6 96
0.4 µg ·
kg21 · min21
451 6 68*
143 6 42*
19 6 4
505 6 34*
Low IGF
Basal
93 6 9
42 6 7
819 6 63
0.04 µg ·
kg21 · min21
136 6 11*
8 6 3*
42 6 9
790 6 11
Values are means 6 SE. Where no value is given, concentration
was undetectable. IGF-I, insulin-like growth factor I; FFA, free fatty
acid. * P , 0.01 vs. basal.
Fig. 2. Forearm blood flow, a-v difference, and FGU during low IGF
(0.04 µg · kg21 · min21 IGF-I). Data are presented as means 6 SE.
0.31 6 0.08 mM, P 5 0.32). Forearm glucose uptake
rose notably from 6.4 6 1.7 to 21.7 6 7.4 µmol · min21 · l
forearm volume21 (P 5 0.09 vs. basal).
Forearm blood flow increased by ,59% during the
low IGF infusion (29 6 4 vs. 46 6 9 ml · min21 · l forearm
volume21, P , 0.05; Fig. 2). This increase in blood flow
was associated with a 38% decrease in arteriovenous
glucose concentration difference (0.29 6 0.04 vs. 0.18 6
0.05 mM, P , 0.05; Fig. 2). Because the increase in
forearm blood flow was associated with a proportional
decrease in arteriovenous glucose concentration difference, forearm glucose uptake was not significantly
different from basal values (7.6 6 0.6 vs. 6.9 6 1.8
µmol · min21 · kg21 ).
DISCUSSION
Fig. 1. Forearm blood flow, arteriovenous glucose concentration
difference (a-v difference), and forearm glucose uptake (FGU) during
high insulin-like growth factor (IGF) infusion (0.40 µg · kg21 · min21
IGF-I). Data are presented as means 6 SE.
We have shown that IGF-I, infused locally into the
brachial artery at doses that increase blood flow by
59%, does not stimulate forearm muscle glucose uptake
because of a proportional decrease in glucose extraction. Thus the average forearm glucose uptake after
140 min was not significantly increased from basal
values. Thus the low-dose IGF-I infusion allowed us to
completely dissociate the effects of IGF-I on blood flow
and glucose metabolism in forearm tissues. In response
to an isolated increase in forearm blood flow of 59%, a
value similar to that reported for insulin (2), glucose
extraction was not stimulated in any subject. The
arteriovenous glucose concentration difference fell in
five subjects and remained unchanged in two subjects
(P , 0.05). This resulted in no change in forearm
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Whole body glucose uptake and forearm blood flow,
arteriovenous glucose concentration difference, and glucose uptake. The glucose infusion rate required to
maintain euglycemia was 2.5 mg · kg21 · min21 during
high IGF and 1.4 mg · kg21 · min21 during low IGF.
Forearm blood flow (ml · min21 · l forearm volume21 ),
arteriovenous glucose concentration difference, and
forearm glucose uptake (mmol · min21 · l forearm volume21 ) are shown in Figs. 1 (high IGF) and 2 (low IGF).
Forearm blood flow increased approximately twofold
after 140 min of the high IGF infusion (34 6 3 vs. 64 6 8
ml · min21 · l forearm volume21, P , 0.01; Fig. 1). In
response to high IGF, the arteriovenous glucose concentration difference increased slightly in four subjects
and decreased in three subjects. On average, the arteriovenous glucose concentration difference increased
slightly, although not significantly (0.19 6 0.05 vs.
E348
INCREASING BLOOD FLOW DOES NOT INCREASE GLUCOSE UPTAKE
is increased with vasodilators, there is a reciprocal
decrease in glucose extraction. Consequently, muscle
glucose uptake remains unchanged. Thus increasing
blood flow without simultaneously increasing the intrinsic ability of the muscle to extract glucose does not
stimulate muscle glucose uptake.
Some investigators have suggested that the overall
action of insulin to enhance muscle glucose disposal is
related specifically to its vasodilatory effect (2). In
addition to the findings of our study and the evidence
reviewed above (38, 41, 46), several lines of evidence
indicate that, under physiological conditions, blood flow
is not a regulator of muscle glucose uptake. First,
increased glucose uptake in response to insulin infusions that result in physiological levels of hyperinsulinemia has consistently been demonstrated without any
increase in muscle blood flow (6, 7, 11, 29, 31, 47).
Under more physiological conditions, i.e., ingestion of a
mixed meal, leg blood flow in healthy volunteers is not
significantly increased over basal values, even though
muscle glucose uptake is increased four- to fivefold in
response to the accompanying hyperinsulinemia (35). A
normal increase in forearm glucose uptake also has
been demonstrated during the oral glucose tolerance
test without any change in blood flow from baseline (25,
30). Conversely, the blood flow responses to an oral
glucose load in obese subjects have been reported to be
increased relative to controls (25). Further evidence
that blood flow does not regulate glucose uptake under
physiological conditions is provided by studies examining glucose uptake in insulin-resistant individuals.
Impaired insulin-mediated glucose uptake in these
studies repeatedly has been shown to occur without any
impairment in muscle blood flow (6, 7, 16, 19, 39, 46).
Nevertheless, it is possible that in some specific situations, such as during exercise (20, 45) and in aerobically
trained athletes (21, 24, 28), fuel requirements of the
muscle are provided by increases in both glucose extraction and glucose delivery.
In conclusion, our results demonstrate that when
IGF-I is infused at a dose that is sufficient to increase
forearm blood flow by 59%, an amount comparable to
that reported for insulin in some studies, there is a
reciprocal decrease in glucose extraction. The result is
no net increase in glucose uptake. Glucose uptake is
increased only when IGF-I is infused at a high enough
dose to stimulate glucose extraction as well as delivery.
Thus blood flow, per se, does not appear to be a primary
regulator of muscle glucose uptake.
We gratefully acknowledge the nursing assistance of Joe Noonan;
the technical assistance of Cindy Munoz and Sheila Taylor; and the
administrative assistance of Lorrie Albarado, Sheri Contero, and
Yvonne J. Kreger.
This study was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant DK-24092, a Veterans Affairs
Merit Award (to R. A. DeFronzo), General Clinical Research Center
(GCRC) Grant RR-MO1-RR-O1346, and GCRC Clinical Associate
Physician Award (to M. Pendergrass).
Address for reprint requests and present address of M. Pendergrass: Tulane Univ., School of Medicine, Dept. of Medicine SL53, 1430
Tulane Ave., New Orleans, LA 70112-2699.
Received 22 December 1997; accepted in final form 30 April 1998.
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glucose uptake from basal values. These data demonstrate that increasing blood flow without increasing the
intrinsic ability of the muscle to extract glucose does
not increase forearm muscle glucose uptake. We therefore conclude that increased blood flow, per se, is not a
primary regulator of glucose uptake.
Seven subjects received a brachial artery IGF-I infusion that was 10-fold greater than during the low-dose
IGF-I infusion. This infusion rate was chosen because it
produces plasma free IGF-I levels that are known to
increase the intrinsic activity of the muscle to extract
glucose (26). Even at these high infusion rates, we
failed to observe a significant rise (P 5 0.09) in forearm
glucose uptake because the marked vasodilatation (forearm blood flow increased ,2-fold) offset the intrinsic
ability of muscle to extract glucose and a consistent
increase in arteriovenous glucose concentration difference did not occur. In fact, in three subjects, the
arteriovenous glucose concentration difference actually
decreased. Thus both the high- and the low-dose IGF-I
infusion studies are consistent and demonstrate that
an increase in blood flow alone is not sufficient to
augment forearm muscle glucose uptake.
The results of this study are in agreement with
results reported by Fryburg (26), who primarily was
interested in the effect of IGF-I on amino acid metabolism. This investigator infused IGF-I at 0.03 µg · kg21 ·
min21, a dose similar to the low dose used in our study.
Although blood flow increased by 44% (similar to the
increase in our study) after 3 h of IGF-I infusion and by
76% after 6 h, glucose extraction was unchanged and
there was no change in forearm glucose uptake. Our
study more specifically addresses the issue of whether
increased blood flow contributes to insulin-mediated
glucose uptake. First, measurements were made after
140 min, which is a more physiological period of time
(38, 42) than the study of Fryburg. Second, blood flow
was raised by 59%, an amount comparable to that
reported for insulin in some studies (2).
Several recent studies have also used vasodilators to
examine whether muscle glucose uptake can be increased simply by increasing blood flow (36, 38, 41).
Pöyry et al. (41) stimulated forearm blood flow ,4.5fold with the use of acetylcholine. Increased blood flow
was associated with a decrease in arteriovenous glucose concentration difference of ,73%, and, as a result,
glucose uptake remained unchanged. Pöyry et al. also
noted reciprocal decreases in glucose extraction when
blood flow was increased by sodium nitroprusside.
Neither acetylcholine nor sodium nitroprusside is believed to have any effects on glucose metabolism.
Similar results have been provided by Natali et al. (36),
who used adenosine to increase blood flow by 100% yet
observed no rise in forearm glucose uptake. The study
of Nuutila et al. (38) is of particular interest. Leg blood
flow and leg glucose uptake were measured using
positron emission tomography. They found that when
blood flow was increased 60% with the use of bradykinin, leg glucose uptake remained unchanged. Taken
collectively, these studies are consistent with the findings we report here for IGF-I. When muscle blood flow
INCREASING BLOOD FLOW DOES NOT INCREASE GLUCOSE UPTAKE
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INCREASING BLOOD FLOW DOES NOT INCREASE GLUCOSE UPTAKE