Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900
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ABSTRACT |
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The effects of
insulin-like growth factor I (IGF-I) and insulin on free fatty
acid (FFA) and glucose metabolism were compared in eight control and
eight type 2 diabetic subjects, who received a two-step euglycemic
hyperinsulinemic (0.25 and 0.5 mU · kg1 · min
1) clamp and a
two-step euglycemic IGF-I (26 and 52 pmol · kg
1 · min
1) clamp
with [3-3H]glucose, [1-14C]palmitate, and
indirect calorimetry. The insulin and IGF-I infusion rates were chosen
to augment glucose disposal (Rd) to a similar extent in
control subjects. In type 2 diabetic subjects, stimulation of
Rd (second clamp step) in response to both insulin and
IGF-I was reduced by ~40-50% compared with control subjects. In
control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired,
whereas EGP suppression by IGF-I was similar to that of controls. In
both control and diabetic subjects, IGF-I-mediated suppression of
plasma FFA concentration and inhibition of FFA turnover were markedly
impaired compared with insulin (P < 0.01-0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects (P < 0.05-0.01). Conclusions:
1) IGF-I is less effective than insulin in suppressing EGP
and FFA turnover; 2) insulin-resistant type 2 diabetic
subjects also exhibit IGF-I resistance in skeletal muscle. However,
suppression of EGP by IGF-I is not impaired in diabetic individuals,
indicating normal hepatic sensitivity to IGF-I.
insulin-like growth factor I; insulin resistance; free fatty acid metabolism; type 2 diabetes mellitus
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INTRODUCTION |
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INSULIN-LIKE GROWTH FACTOR I (IGF-I) is a growth-promoting peptide that shares many structural and functional similarities with insulin. In the circulation, IGF-I is highly protein bound, and only free IGF-I is biologically active. In vitro, physiological concentrations of IGF-I stimulate glucose transport and metabolism in muscle, and these effects are mediated via a specific IGF-I receptor (28), although some effects of IGF-I may be mediated by insulin/IGF-I hybrid receptors (44). The IGF-I receptor is highly homologous to the insulin receptor (17, 36). Both ligands, IGF-I and insulin, activate receptor tyrosine kinase activity, leading to a cascade of intracellular events resulting in the stimulation of glucose utilization.
The effects of IGF-I on whole body and muscle glucose metabolism have been studied extensively in animals (21, 35, 37, 50) and in humans (2, 12, 19, 27, 38, 46). IGF-I augments glucose uptake, glucose oxidation, and nonoxidative glucose disposal in a dose-dependent fashion, similar to insulin (2, 12, 27, 38). IGF-I also suppresses endogenous (primarily hepatic) glucose production (EGP) (2, 12, 38), although it appears to be less effective than insulin in both animals (21, 22, 35) and humans (27). In animal models of type 2 diabetes mellitus (4, 23), the ability of IGF-I to augment glucose disposal is impaired. The acute effects of IGF-I on peripheral and hepatic glucose metabolism in type 2 diabetic humans have been less well characterized. Laagerand and Keller (26) demonstrated that the decline in plasma glucose concentration in response to intravenous IGF-I was impaired in type 2 diabetic individuals, but this study did not examine whether the IGF-I resistance was present in skeletal muscle, in liver, or in both. In a previous study (7), we demonstrated that chronic subcutaneous IGF-I administration in type 2 diabetic patients inhibited EGP, reduced the fasting glucose concentration, and produced a small increase in insulin-mediated glucose disposal. In the present study, we have compared the effects of IGF-I and insulin on peripheral (muscle) and hepatic glucose metabolism by using doses of IGF-I and insulin that elicit a similar stimulation of whole body glucose disposal in healthy control subjects.
Much less is known about the effect of IGF-I on free fatty acid (FFA) metabolism. In vitro, an insulinomimetic effect of IGF-I on adipocytes is observed only at high hormone concentrations and is believed to be mediated through a cross-reaction with the insulin receptor (1, 43, 51), because IGF-I receptors are not present on fat cells (1, 31). Consistent with these observations, several investigators (5, 21, 50) have failed to detect any decline in plasma FFA concentration after intravenous IGF-I administration in animals. Studies in humans have provided inconsistent results. Many investigators (12, 19, 32, 33, 38) have failed to demonstrate any effect of IGF-I on plasma FFA levels, whereas others (2, 27, 33, 46) have documented a reduction in circulating FFA concentrations, albeit with high doses of IGF-I. Little information is available about the effect of low, physiological concentrations of IGF-I on FFA metabolism in humans. In the present study, we have employed [1-14C]palmitate with indirect calorimetry and the euglycemic clamp technique to examine and contrast the effects of physiological levels of IGF-I and insulin on FFA metabolism in healthy control and type 2 diabetic individuals.
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METHODS |
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Subjects.
Eight healthy nondiabetic and eight type 2 diabetic subjects
participated in the study. Their clinical and biochemical
characteristics are shown in Table 1. The
diabetic subjects were slightly more obese than the nondiabetic
subjects, and they were in reasonably good glycemic control, as
demonstrated by a mean hemoglobin A1c value of 6.8%. All
nondiabetic subjects had a normal 75-g oral glucose tolerance test, and
none had a family history of diabetes mellitus. Except for the presence
of diabetes, all subjects were in good general health. Two diabetic
subjects were treated with diet alone, and six diabetic subjects were
receiving a sulfonylurea. The sulfonylurea was stopped 2 days before
each study. Other than sulfonylureas, no subject was taking any
medication known to affect glucose metabolism. None of the diabetic
subjects had ever taken metformin, a thiazolidinedione, or insulin.
Body weight was stable for 3 mo before study in all subjects. No
subject participated in any strenuous exercise on a regular basis. Over
the 3 days before study, subjects were instructed to consume a
weight-maintaining diet containing 200-250 g of carbohydrate per
day. The purpose, nature, and potential risks of the study were
explained to all subjects before their written, voluntary consent to
participate in the study was obtained. The protocol was approved by the
Institutional Review Board of the University of Texas Health Science
Center at San Antonio.
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Study design.
All studies were conducted at the General Clinical Research Center of
the University of Texas Health Science Center at San Antonio. Subjects
refrained from eating or drinking anything except water after
2200 on the evening before study. All studies were carried out
at 0700 in the postabsorptive state. Before study, catheters were
placed into an antecubital vein for the infusion of all test
substances, and retrogradely into a vein on the dorsum of the hand for
blood withdrawal. The hand was then placed in a heated box (60°C) to
provide arterialized venous blood. All subjects received both a
two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg1 · min
1) clamp and
a two-step euglycemic IGF-I clamp (26 and 52 pmol · kg
1 · min
1). The
insulin and IGF-I clamp studies were performed in random sequence
within a 7-day period. The insulin infusion rates were chosen to
achieve steady-state plasma insulin concentrations on the steep part of
the curve for the suppression of EGP and FFA turnover
(18). The infusion rates of IGF-I were chosen on the basis
of previous studies (16), which demonstrated that they increased total body glucose disposal in healthy nondiabetic subjects to a level comparable to that observed with insulin. On a molar basis,
the dose of IGF-I is ~18-fold greater than that of insulin. Three
hours before the insulin and IGF-I clamp studies, a primed (25 µCi × fasting plasma glucose/90)-continuous (0.25 µCi/min) infusion of [3-3H]glucose (New England Nuclear, Boston,
MA) was begun. At the same time, a primed (2.2 µCi)-continuous (0.1 µCi/min) infusion of [1-14C]palmitate and a 4-µCi
bolus of [14C]sodium bicarbonate was given. After a 3-h
isotopic equilibration period, the two-step insulin or IGF-I infusion
was started. Each clamp step lasted 120 min. During the last 30 min of
the equilibration period, arterialized blood samples were obtained
every 5-10 min for determination of plasma glucose, FFA, total
IGF-I and insulin concentrations, and plasma tritiated glucose and
[14C]palmitate radioactivity. During the two-step IGF-I
and insulin clamp studies, plasma FFA and insulin concentrations and
plasma FFA and glucose radioactivities were determined every 10-15
min. After the start of insulin or IGF-I infusion, arterialized blood samples were collected every 5 min for the determination of plasma glucose concentration, and the infusion of a 20% glucose infusion was
appropriately adjusted to maintain euglycemia (8). In the diabetic patients, no exogenous glucose was infused until the plasma
glucose concentration declined to ~100 mg/dl, at which level it was
maintained. No tritiated glucose was added to the cold glucose
infusate, because we previously have shown that, at the rates of whole
body glucose disposal achieved with the steady-state plasma insulin and
IGF-I concentrations, the tracer-derived rate of whole body glucose
disposal closely approximates the rate of whole body glucose uptake
(15).
Analytical determinations. Plasma glucose concentration was determined by the glucose oxidase method (Glucose Oxidase Analyzer, Beckman Instruments, Fullerton, CA). Plasma insulin concentration was determined by radioimmunoassay (Diagnostic Product, Los Angeles, CA) and plasma FFA concentration by an enzymatic method (Wako Pure Chemical Industry, Osaka, Japan). Plasma total IGF-I concentration was determined by radioimmunoassay (ALPCO, Windham, NH). Plasma IGF-binding protein-3 (BP-3) concentration was determined by immunoradiometric assay (DSL, Webster, TX). Plasma-tritiated glucose radioactivity was determined on barium hydroxide and zinc sulfate-precipitated plasma samples, as previously described (18). For determination of [1-14C]palmitate radioactivity, 1.5 ml of plasma was extracted with 10 ml of Dole's solution. FFAs were isolated from the liquid phase by use of 0.02 N NaOH and reextracted with heptane after acidification (18). The heptane extraction was repeated three times, and >90% of the radioactivity was consistently recovered in the heptane phase. The extracts were combined and dissolved in scintillation liquid and counted in a beta scintillation counter (Beckman Instruments). 14CO2 radioactivity was determined by bubbling expired air through a CO2-trapping solution (1 M hyamine hydrochloride-absolute ethanol-0.1% phenolphthalein; 3:5:1) that was tritiated with 1 N HCl to trap 1 mmol of CO2 per 3 ml of solution. 14CO2 radioactivity was measured in a beta scintillation counter (LS 6000IC, Beckman Instruments).
Calculations. Basal EGP was calculated by dividing the tritiated glucose infusion rate (dpm/min) by the steady-state plasma tritiated glucose specific activity (dpm/mg) during the last 30 min of the basal equilibration period. During steady-state postabsorptive conditions, the rate of EGP equals the rate of whole body glucose disposal. During the insulin/IGF-I clamp, the glucose system is driven out of steady state, and the rates of glucose appearance and disappearance were calculated by Steele's non-steady-state equation (45) by use of a volume of distribution of 250 ml/kg and a pool factor of 0.65 (6). Rates of whole body glucose disposal are expressed per kilogram of fat-free mass (FFM), because muscle is responsible for the disposal of the majority (80-90%) of glucose disposal under euglycemic conditions.
The plasma FFA turnover rate (expressed as µmol · kgStatistics. Differences between the basal and insulin/IGF-I-mediated rates of glucose and FFA metabolism within a group were determined by the paired t-test. Differences in glucose and FFA turnover rates between the insulin and IGF-I clamp studies and between type 2 diabetic and control subjects were compared by ANOVA. When statistically significant differences were obtained, they were confirmed by the Bonferroni test. Differences were considered to be statistically significant if the P value was <0.05. All data are presented as means ± SE.
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RESULTS |
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Plasma glucose, insulin, IGF-I, and IGFBP-3 concentrations.
The fasting plasma glucose and insulin concentrations were
significantly greater in the diabetic vs. control subjects
(P < 0.01) (Table 1 and Fig.
1). During the first and second steps of
the insulin clamp, the steady-state plasma insulin concentrations were
similarly increased in the control and diabetic groups. During the
first and second steps of the IGF-I clamp, the plasma insulin concentrations declined slightly and similarly in the diabetic and
control groups. In the basal state, the plasma IGF-I concentration was
slightly lower (P = 0.07) in the diabetic than in the
control group (Table 1). The increment in IGF-I was similar in the
control and diabetic groups during the first and second steps of the
IGF-I clamp (Table 2). In the control
group, the plasma glucose concentrations during the fist and second
steps of the insulin (96 ± 2 mg/dl) and IGF-I (95 ± 2 mg/dl) clamps were maintained close to the fasting value, with a
coefficient of variation of <5%. The basal plasma IGFBP-3
concentration in the diabetic subjects was slightly less than in
control subjects (Table 2). During the second IGF-I clamp study, there
was a tendency for the IGFBP-3 levels to increase in both diabetic and
control groups (Table 2). There was no significant change in the
IGFBP-3 levels in either group during the insulin clamp study
(Table 2). There was a strong correlation between the plasma IGF-I and
plasma IGFBP-3 levels during the basal state in both the diabetic and
control groups (r = 0.80, P < 0.001). In the diabetic group, the fasting plasma glucose concentration (142 ± 12 mg/dl) was reduced to 114 ± 8 and 101 ± 1 mg/dl, respectively, during the first and second insulin clamp steps
and to 107 ± 9 and 101 ± 1 mg/dl, respectively, during the
first and second IGF-I clamp steps.
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Whole body glucose uptake, glucose oxidation, and nonoxidative
glucose uptake.
During the first clamp step in control subjects, insulin (from
2.59 ± 0.15 to 3.21 ± 0.20 mg · kg
FFM1 · min
1) and IGF-I (from
2.68 ± 0.13 to 3.01 ± 0.25 mg · kg
FFM
1 · min
1) increased the rate of
total body glucose disposal to similar values [P = nonsignificant (NS), insulin vs. IGF-I]. Likewise, during the second
clamp step in control subjects, insulin (from 3.21 ± 0.20 to
6.43 ± 0.45) and IGF-I (from 3.01 ± 0.25 to 5.86 ± 0.75 mg · kg FFM
1 · min
1)
increased total body glucose to similar values (P = NS,
insulin vs. IGF-I). During the second clamp step (Fig. 2), the increase in total body glucose disposal with both insulin and IGF-I was accounted for approximately equally by increases in both glucose oxidation (P < 0.01) and nonoxidative glucose disposal
(P < 0.01) (Fig. 2).
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EGP.
In the control group during the first clamp step, insulin was five
times more potent than IGF-I in suppressing EGP (0.29 ± 0.14 vs.
1.50 ± 0.19 mg · kg
FFM1 · min
1, P < 0.01; Fig. 3). During the second clamp
step in control subjects, both insulin and IGF-I suppressed EGP by
>90% (0.05 ± 0.04 vs. 0.24 ± 0.10 mg · kg
FFM
1 · min
1, P = 0.15). In the diabetic group, insulin and IGF-I suppressed EGP
similarly during both the first (1.40 ± 0.14 vs. 1.26 ± 0.16 mg · kg FFM
1 · min
1,
P = NS) and second (0.56 ± 0.13 vs. 0.52 ± 0.18 mg · kg FFM
1 · min
1,
P = NS) clamp steps. The ability of insulin to inhibit
EGP in type 2 diabetic vs. control subjects was significantly impaired during both clamp steps (1st step: 1.40 ± 0.14 vs. 0.29 ± 0.14, P < 0.01; 2nd step: 0.56 ± 0.13 vs.
0.05 ± 0.04 mg · kg
FFM
1 · min
1, P < 0.01). In contrast to insulin, the ability of IGF-I to suppress EGP was
similar in type 2 diabetic and control subjects (1st step 1.50 ± 0.19 vs. 1.26 ± 0.16, P = NS; 2nd step 0.24 ± 0.10 vs. 0.42 ± 0.18 mg · kg
FFM
1 · min
1, P = NS).
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Plasma FFA concentration and turnover. In control subjects, the decline in basal plasma FFA concentration was greater with insulin than with IGF-I during both clamp steps (1st step: 123 ± 25 vs. 562 ± 53, P < 0.001; 2nd step: 77 ± 17 vs. 182 ± 47 µmol/l, P < 0.05). In type 2 diabetic subjects, the suppression of plasma FFA concentration by insulin also was significantly greater than with IGF-I during both insulin clamp steps (1st step: 203 ± 35 vs. 571 ± 94, P < 0.01; 2nd step: 118 ± 15 vs. 347 ± 98 µmol/l, P < 0.05).
In type 2 diabetic patients, insulin was less effective in decreasing the plasma FFA concentration than it was in controls during the first clamp step: 123 ± 25 vs. 203 ± 34, P < 0.05. During the second clamp step, suppression of plasma FFA by insulin in the diabetic subjects was slightly but not significantly impaired. In diabetic patients, suppression of plasma FFA concentration by IGF-I during the first (562 ± 53 vs. 123 ± 25, P < 0.001) and second (182 ± 47 vs. 77 ± 17 µmol/l, P = 0.06) clamp steps was impaired compared with insulin (Fig. 4).
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Total lipid oxidation, plasma FFA oxidation, and nonplasma FFA
oxidation.
In both the control and diabetic groups during basal conditions, total
body lipid oxidation (2.84 ± 0.26 vs. 2.72 ± 0.25 µmol · kg1 · min
1,
respectively, P = NS) was ~75% greater than the
plasma FFA oxidation rate (1.60 ± 0.24 and 1.60 ± 0.16 µmol · kg
1 · min
1,
respectively). In both control and type 2 diabetic subjects, inhibition
of total body lipid oxidation and plasma FFA oxidation (Fig.
6) was significantly greater during both
the first and second insulin clamp steps vs. the first and second IGF-I
clamp steps (P < 0.05-0.001). In type 2 diabetic
patients compared with control subjects, the ability of both insulin
and IGF-I to inhibit plasma FFA and total lipid oxidation was
significantly impaired during both clamp steps (Fig. 6).
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DISCUSSION |
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No previous study has employed the euglycemic clamp technique in
type 2 diabetic patients to compare the effects of IGF-I and insulin on
glucose and FFA metabolism at doses of the two hormones that produce a
similar stimulation of glucose disposal in nondiabetic subjects.
Importantly, the insulin infusion rates (0.25 and 0.50 mU · kg1 · min
1) were
selected because they produced plasma insulin concentrations (20-25 and 35-40 µU/ml) that are on the steep part of the
dose-response curve relating the hormone concentration to the
suppression of EGP and plasma FFA turnover.
Consistent with many previous publications, our results demonstrate that type 2 diabetic patients are resistant to insulin and that the defect in insulin-stimulated total body glucose uptake is accounted for primarily by impaired nonoxidative glucose disposal, which reflects glycogen synthesis (39). Several studies have demonstrated that IGF-I can restore normoglycemia in severely insulin-resistant individuals (34, 49), and it has been suggested that IGF-I can bypass the defect in insulin action in type 2 diabetic patients, thereby eliciting a normal increase in tissue glucose disposal. In the present study, IGF-I augmented whole body glucose disposal in healthy lean nondiabetic control subjects to levels that were similar to those observed with insulin. Under euglycemic hyperinsulinemic clamp conditions, the great majority (~80-90%) of infused glucose is taken up and metabolized in muscle (8). However, in our type 2 diabetic patients, the ability of IGF-I to increase glucose disposal was markedly reduced, indicating that the muscle in diabetic patients is resistant to the effects of both IGF-I and insulin. Like insulin, both the oxidative and nonoxidative pathways of glucose disposal are resistant to IGF-I (Fig. 2). Because the plasma IGF-I concentrations achieved during the two clamp steps were in the physiological range, it is unlikely that the hormone could be acting through the insulin receptor. Thus our results argue for primary resistance of the IGF-I signal transduction system to circulating plasma IGF-I levels. In insulin-resistant animal models of type 2 diabetes mellitus, the ability of IGF-I to phosphorylate its own receptor has been shown to be intact (4), but stimulation of phosphoinositol 3-kinase has been reduced (24), accounting for the observed defects in glucose uptake (23, 29) and glycogen synthesis (11, 30). Consistent with a postreceptor defect in IGF-I action, IGF-I binding and IGF-I receptor tyrosine phosphorylation (30) in cultured skeletal muscle cells from type 2 diabetic patients have been shown to be normal despite a marked reduction in IGF-I-stimulated muscle glucose uptake. These observations are most consistent with a postbinding, postreceptor defect in IGF-I action, possibly involving the IGF-I signal transduction system.
Our results in healthy diabetic subjects demonstrate that IGF-I inhibited EGP by 44 and 92% during the first and second clamp steps, respectively (Fig. 2). This effect of IGF-I was significantly less than doses of insulin that produced a similar stimulation of whole body (primarily muscle) glucose uptake in the same individuals (Fig. 3). Previous investigators have shown that, in nondiabetic subjects, the ability of IGF-I to inhibit EGP is less potent than that of insulin (27), and similar observations have been made in rodents (35, 37). The blunted effect of IGF-I to suppress EGP has been attributed to the lack of IGF-I receptors on hepatocytes (3, 48). However, it is possible that a low IGF-I receptor number could be present in the liver but not have been detected in these earlier studies (3, 48) because of receptor loss during the triton extraction that was employed. Although hybrid IGF-I/insulin receptors have been found in adipocytes (13, 44, 45) and muscle (14), such receptors have not been reported in liver. Nonetheless, this remains a potential explanation for the observed suppressive effect of IGF-I on EGP. Interpretation of the IGF-I-mediated suppression of EGP in control subjects in the present study thus depends on whether the liver possesses IGF-I receptors. If such receptors are present but exist in low concentration, this could explain the diminished ability of IGF-I compared with insulin to suppress hepatic glucose production in healthy nondiabetic subjects. It also is possible that the suppressive effect of IGF-I on hepatic glucose production is, in part, indirect and mediated via changes in circulating substrate levels. Recent studies have demonstrated that approximately one-half of the inhibitory effect of insulin on hepatic glucose production is mediated via a reduction in plasma FFA and glucagon concentrations (42). During the first IGF-I clamp step, EGP declined by 48%, yet there was no change in the plasma FFA concentration (Fig. 4). During the second IGF-I clamp step, the plasma FFA declined by 69%, but we failed to observe a significant correlation between the decrease in plasma FFA concentration and reduction in EGP (r = 0.32, P = 0.24). Therefore, the present results do not support a role for reduced plasma FFA concentrations in the IGF-I-mediated suppression of hepatic glucose production. Plasma glucagon concentrations were not measured in the present study. Finally, IGF-I caused a small decline in circulating plasma insulin concentration (Fig. 1), and a parallel decline in portal insulin concentration would be expected. Although it could be argued that this small decline in portal insulin was in part responsible for the lack of potency of IGF-I on the suppression of EGP, we believe that this is unlikely, because insulin infusion would be expected to cause a similar inhibition of endogenous insulin secretion (9). In summary, we believe that the most likely explanation for IGF-I's ability to suppress EGP in control subjects is related to the presence of small numbers of IGF-I receptors, or possibly to the presence of hybrid IGF-I/insulin receptors on human hepatocytes.
Only one previous study has examined the effect of IGF-I on the suppression of EGP (primarily hepatic) in type 2 diabetic subjects (7). In this study, diabetic subjects received 80 µg/kg of IGF-I subcutaneously, twice daily for 7 days. Chronic IGF-I treatment caused a significant decline in basal hepatic glucose production, which was closely related to the reduction in fasting plasma glucose concentration. No previous study has examined the acute effect of IGF-I on EGP in type 2 diabetic individuals. In the present study, IGF-I caused a reduction in EGP in type 2 diabetic patients that was similar to that observed in healthy control subjects (Fig. 3). Thus, regardless of the mechanism(s) by which IGF-I inhibits EGP, there is no resistance to the suppressive effect of IGF-I on hepatic glucose output in type 2 diabetic patients. This is in contrast to insulin, where marked resistance to the suppressive effect of the hormone on hepatic glucose production was observed in type 2 diabetic patients during both the first and second insulin clamp steps.
Previous studies that have examined the effect of IGF-I on plasma FFA
levels have yielded conflicting results. In studies in which IGF-I was
infused at rates <52
pmol · kg1 · min
1, no
demonstrable effect of IGF-I on the plasma FFA concentration was
observed (12, 32, 38). In studies (2, 20, 27, 46) in which IGF-I was infused at rates greater than or equal to
52 pmol · kg
1 · min
1, a
modest reduction in circulating plasma FFA concentration was observed.
Our results are generally in good agreement with these previous
studies. When IGF-I was infused at 26 pmol · kg
1 · min
1 in
healthy nondiabetic subjects, no change in the plasma FFA concentration
was demonstrable. However, at the higher IGF-I infusion rate (52 pmol · kg
1 · min
1), the
plasma FFA concentration fell by 69% (Fig. 4). The decline in plasma
FFA concentration most likely reflects an inhibition of lipolysis,
because the primary source of plasma FFA is from triglycerides that are
stored in fat cells. In nondiabetic control subjects, the decline in
plasma FFA concentration and FFA turnover was associated with
reductions in both plasma FFA oxidation and nonoxidative FFA disposal,
which primarily reflects reesterification. During the first clamp step,
IGF-I had no effect on plasma FFA turnover or plasma FFA concentration.
This is in contrast to the 68% suppression observed with insulin.
During the second clamp step, the suppression of plasma FFA and FFA
turnover with IGF-I was approximately one-half of that observed with
insulin. Because inhibition of lipolysis is very sensitive to insulin
(18), it is possible that the small decline in peripheral
insulin concentration could explain, in part, the weak inhibitory
effect of IGF-I on FFA turnover. However, we believe that it is
unlikely that a 2-3 µU/ml decline in plasma insulin
concentration can account for the threefold greater suppression of FFA
turnover (5.8 vs. 1.8 µmol · kg
1 · min
1) by
insulin (compared with IGF-I) during the first clamp step and the
nearly twofold greater suppression by insulin during the second clamp
step. The difference between the effects of IGF-I and insulin on the
suppression of lipolysis by fat cells most likely is explained by two
factors: 1) the lack of, or at least fewer, IGF-I vs.
insulin receptors on human fat cells (1, 31) and
2) the greater intrinsic potency of insulin vs. IGF-I on
suppression of lipolysis (47). In type 2 diabetic
patients, IGF-I also was less effective than insulin in suppressing
total body FFA turnover, FFA oxidation, nonoxidative FFA disposal, and
the plasma FFA concentration compared with insulin. During the first
clamp step, IGF-I had no effect on the plasma FFA concentration or FFA
turnover in the diabetic (or control) group. During the second IGF-I
clamp step, the ability of IGF-I to inhibit plasma FFA turnover and to
reduce the plasma FFA concentration was impaired in the diabetic
compared with the control group, indicating that the adipocyte is
resistant to both IGF-I and insulin in patients with type 2 diabetes mellitus.
In summary, the present results indicate that the ability of IGF-I (when given in doses that produce a comparable stimulation of total body glucose disposal to insulin in nondiabetic control subjects) to suppress EGP, to reduce plasma FFA levels, and to inhibit total FFA turnover is significantly less than that of insulin. In type 2 diabetic patients, the ability of IGF-I to augment total body glucose disposal and to suppress plasma FFA concentration/total FFA turnover is impaired compared with nondiabetic control subjects, indicating that both muscle and fat tissues are resistant to the action of IGF-I. In contrast, the ability of IGF-I to suppress hepatic glucose production (EGP) is similar in nondiabetic control and type 2 diabetic patients.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. A. DeFronzo, Diabetes Division, Dept. of Medicine, Univ. of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00335.2001
Received 24 July 2001; accepted in final form 24 February 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bolinder, J,
Lindblad A,
Engfeldt P,
and
Arner P.
Studies of acute effects of insulin like growth factor I and II in human fat cells.
J Clin Endocrinol Metab
65:
732-737,
1987[Abstract].
2.
Boulware, SD,
Tamborlane WV,
Rennert NJ,
Gesundheit N,
and
Sherwin RD.
Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin: dose-response relationships in healthy young and middle aged adults.
J Clin Invest
93:
1131-1139,
1994[ISI][Medline].
3.
Caro, JF,
Poulos J,
Itoop O,
Pories WJ,
Flickinger EG,
and
Sinha MK.
Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating and fatal rat liver.
J Clin Invest
81:
976-981,
1988[ISI][Medline].
4.
Cascieri, MA,
Slater EE,
Vicario PP,
Green BG,
Bayne ML,
and
Saperstein R.
Impaired insulin growth factor I-mediated stimulation of glucose incorporation into glycogen in vivo in the ob/ob mouse.
Diabetologia
32:
342-347,
1989[ISI][Medline].
5.
Cottam, YH,
Blair HT,
Gallaher BW,
Purchas RW,
Breier BH,
McCutcheon SN,
and
Gluckman PD.
Body growth, carcass composition, and endocrine changes in lambs chronically treated with recombinantly derived insulin-like growth factor-I.
Endocrinology
130:
2924-2930,
1992[Abstract].
6.
Cowan, JS,
and
Hetenyi C.
Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method.
Metabolism
20:
360-372,
1971[ISI][Medline].
7.
Cusi, K,
and
DeFronzo R.
Recombinant human insulin-like growth factor I treatment for 1 wk improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance.
J Clin Endocrinol Metab
85:
3077-3084,
2000
8.
DeFronzo, RA.
Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.
Diabetes Rev
5:
177-269,
1997[ISI].
9.
DeFronzo, RA,
Binder C,
Wahren J,
Felig P,
Ferrannini E,
and
Faber O.
Sensitivity of insulin secretion to feedback inhibition by hyperinsulinemia.
Acta Endocrinologica
98:
81-86,
1981[Medline].
10.
DeFronzo, RA,
Tobin JD,
and
Andres R.
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
Am J Physiol Endocrinol Metab Gastrointest Physiol
237:
E214-E223,
1979
11.
Dohm, GL,
Elton CW,
Raju MS,
Mooney ND,
DiMarchi R,
Pories WJ,
Flickinger EG,
Atkinson SM,
and
Caro JF.
IGF-I-stimulated glucose transport in human skeletal muscle and IGF-I resistance in obesity and NIDDM.
Diabetes
39:
1028-1032,
1990[Abstract].
12.
Elahi, D,
McAloon-Dyke M,
Fukagawa NK,
Sclater AL,
Wong GA,
Shannon RP,
Minaker KL,
Miles JM,
Rubenstein AH,
Vandepol CJ,
Guler HP,
Good WR,
Seaman JJ,
and
Wolfe RR.
Effects of recombinant human IGF-I on glucose and leucine kinetics in men.
Am J Physiol Endocrinol Metab
265:
E831-E838,
1993
13.
Federici, M,
Porzio O,
Zucaro L,
Giovannone B,
Borboni P,
Marini MA,
Lauro D,
and
Sesti G.
Increased abundance of insulin/IGF-I hybrid receptors in adipose tissue from NIDDM patients.
Mol Cell Endocrinol
135:
41-47,
1997[ISI][Medline].
14.
Federici, M,
Zucaro L,
Porzio O,
Massoud R,
Borboni P,
Lauro D,
and
Sesti G.
Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects.
J Clin Invest
98:
2887-2893,
1996
15.
Ferrannini, E,
Smith JD,
Cobelli C,
Toffolo G,
Pilo A,
and
DeFronzo RA.
The effect of insulin on the distribution and disposition of glucose in man.
J Clin Invest
76:
357-364,
1985[ISI][Medline].
16.
Giordano, M,
Castellino P,
Carroll CA,
and
DeFronzo RA.
Comparison of the effects of human recombinant insulin-like growth factor I and insulin on plasma amino acid concentrations and leucine kinetics in humans.
Diabetologia
38:
732-738,
1995[ISI][Medline].
17.
Giorgetti, S,
Ballotti R,
Kowalski-Chauvel A,
Tartare S,
and
Van Obberghen E.
The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro.
J Biol Chem
268:
7358-7364,
1993
18.
Groop, LC,
Bonadonna RC,
DelPrato S,
Ratheiser K,
Zyck K,
Ferrannini E,
and
DeFronzo RA.
Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance.
J Clin Invest
84:
205-213,
1989[ISI][Medline].
19.
Guler, HP,
Zapf J,
and
Froesch ER.
Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults.
N Engl J Med
317:
137-140,
1987[Abstract].
20.
Hartmann, ML,
Clayton PE,
Johnson ML,
Celniker A,
Perlman AJ,
Alberti KGMM,
and
Thorner MO.
A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting enhanced pulsatile growth hormone secretion in human.
J Clin Invest
91:
2453-2462,
1993[ISI][Medline].
21.
Jacob, R,
Barrett E,
Plewwe G,
Fagin KD,
and
Sherwin RS.
Acute effects off insulin-like growth factor I on glucose metabolism in the awake fasted rat: comparison with insulin.
J Clin Invest
83:
1717-1723,
1989[ISI][Medline].
22.
Jacob, RJ,
Sherwin RS,
Bowen L,
Fryburg D,
Fagin K,
Tamborlane WV,
and
Shuman GI.
Metabolic effects of IGF-I and insulin in spontaneously diabetic BB/w rats.
Am J Physiol Endocrinol Metab
260:
E262-E268,
1991
23.
Jacob, RJ,
Sherwin RS,
Greenawalt K,
and
Shulman GI.
Simultaneous insulin-like growth factor I and insulin resistance in obese Zuker rats.
Diabetes
41:
691-697,
1992[Abstract].
24.
Jullien, D,
Heydrick SJ,
Gautier N,
Van Obberghen E,
and
Le Marchand-Brustel Y.
Effect of IGF-I on phosphatidylinositol 3-kinase in soleus muscle of lean and insulin-resistant obese mice.
Diabetes
45:
869-875,
1996[Abstract].
25.
Kushner, RF.
Bioelectrical impedance analysis: a review of principles and applications.
J Am Coll Nutr
11:
199-209,
1992[Abstract].
26.
Laager, R,
and
Keller U.
Effects of recombinant human insulin-like growth factor I and insulin on counter regulation during acute plasma glucose decrements in normal and type 2 (non-insulin-dependent) diabetic subjects.
Diabetologia
36:
966-971,
1993[ISI][Medline].
27.
Laager, R,
Ninnis R,
and
Keller U.
Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in human.
J Clin Invest
92:
1903-1909,
1993[ISI][Medline].
28.
LeRoth, D,
Wermer H,
Beither-Johnson D,
and
Roberts CT.
Molecular and cellular aspects of the insulin-like growth factor I receptor.
Endocr Rev
16:
143-163,
1995[ISI][Medline].
29.
Liu, S,
Baracos VE,
Quinney HA,
Le Bricon T,
and
Clandinin MT.
Parallel insulin-like growth factor I and insulin resistance in muscles of rats fed a high fat diet.
Endocrinology
136:
3318-3324,
1995[Abstract].
30.
Livingston, N,
Pollare T,
Lithell H,
and
Arner P.
Characterization of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects.
Diabetologia
31:
871-877,
1988[ISI][Medline].
31.
Massague, J,
and
Czech MP.
The subunit structures of two distinct receptors for insulin-like growth factors I and II and their relationship to the insulin receptor.
J Biol Chem
257:
5038-5045,
1982
32.
Mauras, N,
Horber FF,
and
Haymond MW.
Low dose recombinant human insulin-like growth factor-I fails to affect protein anabolism but inhibits islet cell secretion in humans.
J Clin Endocrinol Metab
75:
1192-1197,
1992[Abstract].
33.
Miell, JP,
Taylor AM,
Jones J,
Buchanan CR,
Rennie J,
Sherwood R,
Leicester R,
and
Ross RJM
Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery.
Clin Endocrinol
37:
542-551,
1992[ISI][Medline].
34.
Morrow, LA,
O'Brien MB,
Moller DE,
Flier JS,
and
Moses AC.
Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin action in the type A syndrome of severe insulin resistance.
J Clin Endocrinol Metab
79:
205-210,
1994[Abstract].
35.
Moxley, RT, III,
Arner P,
Moss A,
Skottner A,
Fox M,
James D,
and
Livingston JN.
Acute effects of insulin like growth factor I and insulin on glucose metabolism in vivo.
Am J Physiol Endocrinol Metab
259:
E561-E567,
1990
36.
Myers, MG, Jr,
Sun XJ,
Cheatham B,
Jachna BR,
Glasheen EM,
Backer JM,
and
White MF.
IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase.
Endocrinology
132:
1421-1430,
1993[Abstract].
37.
Rossetti, L,
Frontoni S,
DiMarchi R,
DeFronzo RA,
and
Giaccari A.
Metabolic effects of IGF-I in diabetic rats.
Diabetes
40:
444-448,
1991[Abstract].
38.
Russell-Jones, DL,
Bates AT,
Umpleby AM,
Hennessy TR,
Bowes SB,
Hopkins KD,
Jackson N,
Kelly J,
Shojaee- Moradie F,
and
Jones RH.
A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers.
Eur J Clin Invest
25:
403-411,
1995[ISI][Medline].
39.
Shulman, GI,
Rotherman DL,
Jue T,
Stein P,
DeFronzo RA,
and
Shulman RG.
Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin dependent diabetes mellitus by 13C-nuclear magnetic resonance spectroscopy.
New Engl J Med
322:
223-228,
1990[Abstract].
40.
Sidossis, LS,
Loggan AR,
Gastaldelli A,
and
Wolfe RR.
A new correction factor for use in tracer estimations of plasma fatty acid oxidation.
Am J Physiol Endocrinol Metab
269:
E649-E656,
1995
41.
Simonson, D,
and
DeFronzo RA.
Indirect calorimetry: methodological and interpretative problems.
Am J Physiol Endocrinol Metab
258:
E399-E412,
1990
42.
Sindelar, DK,
Chu CA,
Rohlic M,
Neal DW,
Swift LL,
and
Cherrington AD.
The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog.
Diabetes
46:
187-196,
1997[Abstract].
43.
Sinha, MK,
Buchanan C,
Leggett N,
Martin L,
Khanzanie PG,
Dimarchi R,
Pories WJ,
and
Caro JF.
Mechanism of IGF-I stimulated glucose transport in human adipocytes: demonstration of specific IGF-I receptors not involved in stimulation of glucose transport.
Diabetes
38:
1217-1225,
1989[Abstract].
44.
Soos, MA,
Field CE,
and
Siddle K.
Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity.
Biochem J
290:
419-426,
1993[ISI][Medline].
45.
Steele, R.
Influences of glucose loading and of injected insulin on hepatic glucose output.
Ann NY Acad Sci
82:
420-430,
1959[ISI].
46.
Turkalj, I,
Keller U,
Ninnis R,
Vosmeer S,
and
Stauffacher W.
Effect of increasing doses of recombinant human insulin like growth factor I on glucose, lipid, and leucine metabolism in man.
J Clin Endocrinol Metab
75:
1186-1191,
1992[Abstract].
47.
Urso, B,
Cope DL,
Kalloo-Hosein HE,
Hayward AC,
Whitehead JP,
O'Rahilly S,
and
Siddle K.
Differences in signaling properties of the cytoplasmic domains of the insulin receptor and insulin-like growth factor receptor in 3T3-L1 adipocytes.
J Biol Chem
274:
30864-30873,
1999
48.
Venkatesan, N,
and
Davidson MB.
Insulin-like growth factor I receptors in adult rat liver: characterization and in vivo regulation.
Am J Physiol Endocrinol Metab
258:
E329-E337,
1990
49.
Vestergaard, H,
Rossen M,
Urhammer SA,
Muller J,
and
Pedersen O.
Short- and long-term metabolic effects of recombinant human IGF-I treatment in patients with severe insulin resistance and diabetes mellitus.
Eur J Endocrinol
136:
475-482,
1997[ISI][Medline].
50.
Zapf, J,
Hauri C,
Waldovogel M,
and
Froesch ER.
Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats.
J Clin Invest
77:
1768-1775,
1986[ISI][Medline].
51.
Zapf, J,
Schoeule E,
Waldvogel M,
Sand I,
and
Froesch ER.
Effect of trypsin treatment of rat adipocytes on biological effect and binding of insulin and insulin-like growth factors.
Eur J Biochem
13:
605-609,
1981.