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
 |
ABSTRACT |
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 · kg
1 · min
1
(high IGF) or 0.04 µg · kg
1 · min
1
(low IGF) for 140 min. With high IGF, forearm blood flow increased approximately twofold (34 ± 3 vs. 64 ± 8 ml · min
1 · l
forearm volume
1,
P < 0.01), and arteriovenous glucose
concentration difference (a-v difference) increased modestly (0.19 ± 0.05 vs. 0.31 ± 0.08 mM,
P = 0.32), resulting in an increased
forearm glucose uptake (6.4 ± 1.7 vs. 21.7 ± 7.4 µmol · min
1 · l
forearm volume
1,
P = 0.09 vs. basal). With low IGF,
forearm blood flow increased by 59% (29 ± 4 vs. 46 ± 9 ml · min
1 · l
forearm volume
1,
P < 0.05) and was associated with a
proportional decrease in the a-v difference (0.29 ± 0.04 vs. 0.18 ± 0.05 mM, P < 0.05). Forearm
glucose uptake therefore was not significantly different from basal
values (7.6 ± 0.6 vs. 6.9 ± 1.8 µmol · min
1 · kg
1).
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.
insulin-like growth factor I; insulin resistance
 |
INTRODUCTION |
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
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 |
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 · kg
1 · min
1
(high IGF, n = 7) or 0.04 µg · kg
1 · min
1 (low IGF,
n = 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
70,
30,
15, 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
70,
30,
15, 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
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
where
blood glucose concentration was estimated from plasma glucose
concentration and the hematocrit (Hct) according to the following
formula
Forearm
blood flow was measured by indocyanine green dye dilution in the deep
vein according to the following formula
(1)
|
(1)
|
Forearm
blood flow is expressed per liter forearm volume.
Statistical analysis.
All data are presented as means ± SE. All basal values are reported
as means of the samples taken at the time points
70,
30,
and
15 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 ± 17 to
451 ± 68 ng/ml (P < 0.01) during
high IGF and from 93 ± 9 to 136 ± 11 ng/ml
(P < 0.001) during low IGF. Free
IGF-I levels increased from undetectable in the basal state to 143 ± 42 ng/ml during high IGF and 8 ± 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.
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 · kg
1 · min
1
during high IGF and 1.4 mg · kg
1 · min
1
during low IGF.
Forearm blood flow
(ml · min
1 · l
forearm volume
1),
arteriovenous glucose concentration difference, and forearm glucose
uptake (mmol · min
1 · l
forearm volume
1) 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 ± 3 vs. 64 ± 8 ml · min
1 · l
forearm volume
1,
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 ± 0.05 vs. 0.31 ± 0.08 mM, P = 0.32). Forearm glucose
uptake rose notably from 6.4 ± 1.7 to 21.7 ± 7.4 µmol · min
1 · l
forearm volume
1
(P = 0.09 vs. basal).

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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 · kg 1 · min 1
IGF-I). Data are presented as means ± SE.
|
|

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|
Fig. 2.
Forearm blood flow, a-v difference, and FGU during low IGF (0.04 µg · kg 1 · min 1
IGF-I). Data are presented as means ± SE.
|
|
Forearm blood flow increased by ~59% during the low IGF infusion (29 ± 4 vs. 46 ± 9 ml · min
1 · l
forearm volume
1,
P < 0.05; Fig. 2). This increase in
blood flow was associated with a 38% decrease in arteriovenous glucose
concentration difference (0.29 ± 0.04 vs. 0.18 ± 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 ± 0.6 vs. 6.9 ± 1.8 µmol · min
1 · kg
1).
 |
DISCUSSION |
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 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 = 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 · kg
1 · min
1, 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
~4.5-fold 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 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.
 |
ACKNOWLEDGEMENTS |
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.
 |
FOOTNOTES |
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.
 |
REFERENCES |
1.
Andres, R.,
K. L. Zierler,
and
H. M. Anderson.
Measurement of blood flow and volume in the forearm of man with notes on the theory of indicator-dilution and on the production of turbulence, hemolysis and vaso-dilation by intravascular injection.
J. Clin. Invest.
33:
482-504,
1954.
2.
Baron, A. D.
Hemodynamic actions of insulin.
Am. J. Physiol.
267 (Endocrinol. Metab. 30):
E187-E202,
1994[Abstract/Free Full Text].
3.
Baron, A. D.,
G. Brechtel-Hook,
A. Johnson,
and
D. Hardin.
Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure.
Hypertension
21:
129-135,
1993[Abstract].
4.
Baron, A. D.,
M. Laakso,
G. Brechtel,
and
S. V. Edelman.
Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow.
J. Clin. Endocrinol. Metab.
73:
637-643,
1991[Abstract].
5.
Baron, A. D.,
M. Laakso,
G. Brechtel,
B. Hoit,
C. Watt,
and
S. V. Edelman.
Reduced postprandial skeletal muscle blood flow contributes to glucose intolerance in human obesity.
J. Clin. Endocrinol. Metab.
70:
1525-1533,
1990[Abstract].
6.
Bonadonna, R. C.,
S. Del Prato,
E. Bonora,
M. P. Saccomani,
G. Gulli,
A. Natali,
S. Frascerra,
N. Pecori,
E. Ferrannini,
D. Bier,
C. Cobelli,
and
R. A. DeFronzo.
Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM.
Diabetes
45:
915-925,
1996[Abstract].
7.
Bonadonna, R. C.,
S. Del Prato,
M. Saccomani,
E. Bonora,
G. Gulli,
E. Ferrannini,
and
R. A. DeFronzo.
Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes.
J. Clin. Invest.
92:
486-494,
1993[Medline].
8.
Bonadonna, R. C.,
L. Groop,
N. Kraemer,
E. Ferrannini,
S. Del Prato,
and
R. A. DeFronzo.
Obesity and insulin resistance in man. A dose response study.
Metabolism
39:
452-459,
1990[Medline].
9.
Boulware, S. D.,
W. V. Tamborlane,
and
R. S. Sherwin.
Effects of IGF-1 on carbohydrate and lipid metabolism.
Diabetes Rev.
3:
196-205,
1995.
10.
Breier, B. H.,
B. W. Gallaher,
and
P. D. Gluckman.
Radioimmunoassay for insulin-like growth factor-I: solutions to some potential problems and pitfalls.
J. Endocrinol.
128:
347-357,
1991[Abstract].
11.
Capaldo, B.,
R. Napoli,
P. Di Bonito,
G. Albano,
and
L. Sacca.
Dual mechanism of insulin action on human skeletal muscle: identification of an indirect component not mediated by FFA.
Am. J. Physiol.
260 (Endocrinol. Metab. 23):
E389-E394,
1991[Abstract/Free Full Text].
12.
Coles, D. R.,
K. E. Cooper,
R. F. Mottram,
and
O. V. Occleshaw.
The source of blood samples withdrawn from deep forearm veins via catheters passed upstream from the medium cubital vein.
J. Physiol. (Lond.)
142:
258-267,
1958.
13.
Copeland, K. C.,
and
K. S. Nair.
Recombinant human insulin-like growth factor-I increases forearm blood flow.
J. Clin. Endocrinol. Metab.
79:
230-232,
1994[Abstract].
14.
DeFronzo, R.,
R. Bonadonna,
and
E. Ferrannini.
Pathogenesis of NIDDM: a balanced overview.
Diabetes Care
15:
318-366,
1992[Abstract].
15.
DeFronzo, R. A.,
C. R. Cook,
R. Andres,
G. R. Faloona,
and
P. J. Davis.
The effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man.
J. Clin. Invest.
55:
845-855,
1975[Medline].
16.
DeFronzo, R. A.,
E. Ferrannini,
R. Hendler,
P. Felig,
and
J. Wahren.
Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia.
Diabetes
32:
35-45,
1983[Medline].
17.
DeFronzo, R. A.,
R. Gunnarson,
O. Bjorkman,
M. Olson,
and
J. Wahren.
Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent (type II) diabetes mellitus.
J. Clin. Invest.
76:
149-155,
1985[Medline].
18.
DeFronzo, R. A.,
J. D. Tobin,
and
R. Andres.
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
Am. J. Physiol.
237 (Endocrinol. Metab. Gastrointest. Physiol. 6):
E214-E223,
1979[Abstract/Free Full Text].
19.
Dela, F.,
J. J. Larsen,
K. J. Milkines,
and
H. Galbo.
Normal effect of insulin to stimulate leg blood flow in NIDDM.
Diabetes
44:
221-226,
1995[Abstract].
20.
Dela, F.,
K. Mikines,
B. Sonne,
and
H. Galbo.
Effect of training on interaction between insulin and exercise in human muscle.
J. Appl. Physiol.
76:
2386-2393,
1994[Abstract/Free Full Text].
21.
Dela, F.,
K. J. Mikines,
M. von Linstow,
N. H. Secher,
and
H. Glabo.
Effect of training on insulin-mediated glucose uptake in human muscle.
Am. J. Physiol.
263 (Endocrinol. Metab. 26):
E1134-E1143,
1992.
22.
Dimitriadis, G.,
M. Parry-Billings,
S. Bevan,
D. Dunger,
T. Piva,
and
U. Krause.
Effects of insulin-like growth factor I on the rates of glucose transport and utilization in rat skeletal muscle in vitro.
Biochem. J.
285:
269-274,
1992[Medline].
23.
Dohm, G. L.,
E. B. Tapscott,
W. J. Pories,
D. J. Dabbs,
E. C. Flickinger,
D. Meelheim,
T. Fushiki,
S. M. Atkinson,
C. W. Elton,
and
J. F. Caro.
An in vitro human muscle preparation suitable for metabolic studies: decreased insulin-stimulation of glucose transport in muscle from morbidly obese and diabetic subjects.
J. Clin. Invest.
82:
486-494,
1988[Medline].
24.
Ebeling, P.,
R. Bourey,
L. Koranyi,
J. A. Tuominen,
L. C. Groop,
J. Henriksson,
M. Mueckler,
A. Sovijärvi,
and
V. A. Koivisto.
Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentrations, and glycogen synthase activity.
J. Clin. Invest.
92:
1623-1631,
1993[Medline].
25.
Egan, B. M.,
and
K. Stepniakowski.
Compensatory hyperinsulinemia and the forearm vasodilator response during an oral glucose-tolerance test in obese hypertensives.
J. Hypertens.
12:
1061-1067,
1994[Medline].
26.
Fryburg, D. A.
Insulin-like growth factor I exerts growth hormone and insulin-like actions on human muscle protein metabolism.
Am. J. Physiol.
267 (Endocrinol. Metab. 30):
E331-E336,
1994[Abstract/Free Full Text].
27.
Hales, C. N.,
and
P. J. Randle.
Immunoassay of insulin with insulin antibody precipitate.
Biochem. J.
88:
137-146,
1946.
28.
Hardin, D.,
B. Azzarelli,
J. Edwards,
J. Wigglesworth,
L. Maianu,
G. Brechtel,
A. Johnson,
A. Baron,
and
W. T. Garvey.
Mechanisms of enhanced insulin sensitivity in endurance-trained athletes: effects on blood flow and differential expression of GLUT 4 in skeletal muscles.
J. Clin. Endocrinol. Metab.
80:
2437-2446,
1995[Abstract].
29.
Jackson, R. A.,
J. B. Hamling,
P. M. Blix,
B. M. Sim,
M. I. Hawa,
J. B. Jaspan,
J. Belin,
and
J. D. N. Navarro.
The influence of graded hyperglycemia with and without physiological hyperinsulinemia on forearm glucose uptake and other metabolic responses in man.
J. Clin. Endocrinol. Metab.
63:
594-604,
1986[Abstract].
30.
Jackson, R. A.,
N. Peter,
U. Advani,
G. Perry,
J. Rogers,
W. H. Brough,
and
T. R. E. Pilkington.
Forearm glucose uptake during the oral glucose tolerance test in normal subjects.
Diabetes
22:
442-458,
1973[Medline].
31.
Kelley, D. E.,
J. P. Reilly,
T. Veneman,
and
L. J. Mandarino.
Effects of insulin on skeletal muscle storage, oxidation, and glycolysis in humans.
Am. J. Physiol.
258 (Endocrinol. Metab. 21):
E923-E929,
1990[Abstract/Free Full Text].
32.
Laakso, M.,
S. V. Edelman,
G. Brechtel,
and
A. D. Baron.
Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel mechanism for insulin resistance.
J. Clin. Invest.
85:
1844-1852,
1990[Medline].
33.
Laakso, M.,
S. V. Edelman,
G. Brechtel,
and
A. D. Baron.
Impaired insulin mediated skeletal muscle blood flow in patients with non-insulin dependent diabetes mellitus.
Diabetes
41:
1076-1083,
1992[Abstract].
34.
Lund, S.,
A. Flyvbjerg,
G. D. Holman,
F. S. Larsen,
O. Pedersen,
and
O. Schmitz.
Comparative effects of IGF-I and insulin on glucose transporter system in rat muscle.
Am. J. Physiol.
267 (Endocrinol. Metab. 30):
E461-E466,
1994[Abstract/Free Full Text].
35.
Mijares, A. H.,
and
M. D. Jensen.
Contributions of blood flow to leg glucose uptake during a mixed meal.
Diabetes
44:
1165-1169,
1995[Abstract].
36.
Natali, A.,
R. Bonadonna,
D. Santoro,
A. Q. Galvan,
S. Baldi,
S. Frascerra,
C. Palumbo,
S. Ghione,
and
E. Ferrannini.
Insulin resistance and vasodilatation in essential hypertension. Studies with adenosine.
J. Clin. Invest.
94:
1570-1576,
1994[Medline].
37.
Natali, A.,
G. Buzzigoli,
S. Taddei,
D. Santoro,
M. Cerri,
R. Pedrinelli,
and
E. Ferrannini.
Effects of insulin on hemodynamics and metabolism in human forearm.
Diabetes
39:
490-500,
1990[Abstract].
38.
Nuutila, P.,
M. Raitakari,
H. Laine,
O. Kirelä,
T. Takala,
T. Utriainen,
S. Mäkimattila,
O.-P. Pitkanen,
U. Ruotsalainen,
H. Lida,
J. Knuuti,
and
H. Yki-Järvinen.
Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]-water and [18F]-fluoro-deoxy-glucose and PET.
J. Clin. Invest.
97:
1741-1747,
1996[Abstract/Free Full Text].
39.
Pendergrass, M.,
J. Koval,
C. Vogt,
H. Yki-Järvinen,
P. Iozzo,
R. Pipek,
H. Ardehali,
R. Printz,
D. Granner,
R. A. DeFronzo,
and
L. Mandarino.
Insulin-induced hexokinase II expression is reduced in obesity and non-insulin-dependent diabetes mellitus.
Diabetes
47:
387-394,
1998[Abstract].
40.
Poggi, C.,
Y. Le Marchand-Brustel,
J. Zapf,
E. R. Froesch,
and
P. Freychet.
Effects and binding of insulin-like growth factor I in the isolated soleus muscle of lean and obese mice: comparison with insulin.
Endocrinology
105:
724-730,
1979.
41.
Pöyry, K., J. A. Tuominen, and P. Ebeling.
Stimulation of blood flow by endothelium independent vasodilator
increases glucose uptake (Abstract).
Diabetes 44, Suppl. 1: 195, 1995.
42.
Utriainen, T.,
R. Malmstrom,
S. Makimattila,
and
H. Yki-Järvinen.
Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects.
Diabetologia
38:
555-564,
1995[Medline].
43.
Vierhapper, H.,
S. Gasic,
M. Roden,
and
W. Waldhausl.
Increase in skeletal muscle blood flow but not in renal blood flow during euglycemic hyperinsulinemia in man.
Horm. Metab. Res.
25:
438-441,
1993[Medline].
44.
Vollenweider, P.,
D. Randin,
L. Tappy,
E. Jéquier,
P. Nicod,
and
U. Scherrer.
Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.
J. Clin. Invest.
93:
2365-2371,
1994[Medline].
45.
Vollenweider, P., D. Randin, L. Tappy, E. Jéquier, P. Nicod, and U. Scherrer. Significance of insulin for glucose
metabolism in skeletal muscle during contractions.
Diabetes 45, Suppl. 1: S99-S104, 1996.
46.
Yki-Järvinen, H.,
K. Sahlin,
J. M. Ren,
and
V. A. Koivisto.
Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients.
Diabetes
39:
157-167,
1990[Abstract].
47.
Yki-Järvinen, H.,
A. A. Young,
C. Lamkin,
and
J. E. Foley.
Kinetics of glucose disposal in whole body and across the forearm in man.
J. Clin. Invest.
79:
1713-1719,
1987[Medline].
48.
Zierler, K. L.
Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and nonsteady states.
J. Clin. Invest.
40:
2111-2125,
1961.
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