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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1252-1257
Copyright © 2003 by The Endocrine Society

Normal Insulin-Stimulated Endothelial Function and Impaired Insulin-Stimulated Muscle Glucose Uptake in Young Adults with Low Birth Weight

T. S. Hermann, C. Rask-Madsen, N. Ihlemann, H. Domínguez, C. B. Jensen, H. Storgaard, A. A. Vaag, L. Kober and C. Torp-Pedersen

Department of Cardiology Y (T.S.H., C.R.-M., N.I., H.D., C.T.-P.), Bispebjerg University Hospital, Copenhagen 2400; Department of Endocrinology (C.B.J., H.S.), Hvidovre University Hospital, 2650 Hvidovre; Steno Diabetes Center (A.A.V.), 2820 Gentofte; and Rigshospitalet Heart Center (L.K.), 2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Dr. Thomas S. Hermann, Department of Cardiology Y, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. E-mail: th{at}heart.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Low birth weight has been linked to insulin resistance and cardiovascular disease. We hypothesized that insulin sensitivity of both muscle and vascular tissues were impaired in young men with low birth weight. Blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine and sodium nitroprusside in the forearm of fourteen 21-yr-old men with low birth weight and 16 controls of normal birth weight. Glucose uptake was measured during intraarterial insulin infusion. Dose-response studies were repeated during insulin infusion. The maximal blood flow during acetylcholine infusion was 14.1 ± 2.7 and 14.4 ± 2.1 [ml x (100 ml forearm)-1 x min-1] in low and normal birth weight subjects, respectively. Insulin coinfusion increased acetylcholine-stimulated flow in both groups: 18.0 ± 3.1 vs. 17.9 ± 3.1 [ml x (100 ml forearm)-1 x min-1], NS. Insulin infusion increased glucose uptake significantly in the normal birth weight group, compared with the low birth weight group: 0.40 ± 0.09 to 1.00 ± 0.16 vs. 0.44 ± 0.09 to 0.59 ± 0.1 [µmol glucose x (100 ml forearm)-1 x min-1], P = 0.04. Young men with low birth weight have normal insulin-stimulated endothelial function and impaired insulin-stimulated forearm glucose uptake. Thus, endothelial dysfunction does not necessarily coexist with metabolic alterations in subjects with low birth weight.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN 1991 HALES et al. (1) demonstrated that low birth weight was associated with impaired glucose tolerance and higher blood pressure at mean age 64 yr. The link appears to be insulin resistance, and this abnormality has been demonstrated in young adults (2, 3, 4, 5) and children (6, 7, 8, 9) with low birth weight. A recent study from our group (10) found that 19-yr-old lean men with low birth weight had normal whole-body insulin sensitivity assessed by hyperinsulinemic euglycemic clamp but had impaired insulin-stimulated glycolysis. Impaired endothelial function is generally accepted as the first abnormality in atherosclerosis, and the relationship between endothelial function and birth weight has been the focus of several studies. Some (11, 12, 13) but not all (14, 15) studies of children and young adults with low birth weight have reported endothelial dysfunction using various methods. One investigation reported increased prevalence of carotid stenosis in 70-yr-old subjects with low birth weight (16). In healthy subjects, insulin stimulates endothelium-dependent vasodilation. The effect of insulin on the endothelium is blunted in type 2 diabetic patients (17, 18), but insulin-stimulated endothelial function had never been studied in subjects with low birth weight. One of the most important tissues affected by reduced insulin sensitivity in type 2 diabetes is muscle. Determination of a reduction in muscle specific insulin-stimulated glucose uptake indicates a profound defect in insulin action. Most studies of insulin resistance in low birth weight subjects have focused on whole-body insulin sensitivity. The forearm consists primarily of muscle tissue, and determination of insulin-stimulated glucose uptake in this compartment contributes to a metabolic characterization of the study population.

The purpose of the present study was, therefore, to examine endothelial function, insulin-stimulated endothelial function, and insulin-stimulated forearm glucose uptake in a group of young adult men with low birth weight, compared with a group of matched controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Invitations were sent to twenty 21-yr-old men with birth weight below the 10th percentile, compared with gestational age (39–41 wk; mean birth weight, 2.71 ± 0.21 kg; range, 2.35–2.92 kg) and 20 matched controls with normal weight for gestational age (39–41 wk; mean birth weight, 3.79 ± 0.1 kg; range, 3.65–4.00 kg). All subjects were born in 1980 and traced by the Danish Medical Birth Registry. Ethical approval was obtained from the local ethical committee and the Danish Medicines Agency. All participants gave informed consent. The study population represents a subgroup (75%) of the original study population who participated in a study of cellular glucose metabolism and insulin secretion in low birth weight (10).

A total of 32 persons, 15 persons (75%) in the low birth weight group and 17 persons (85%) in the normal birth weight group, accepted to participate. One individual in each group had to be excluded because of technical problems; thus, data from 14 individuals in the low birth weight group and 16 individuals in the normal birth weight groups were analyzed. None of the study subjects received medication. Four low birth subjects and five normal birth weight subjects were smokers and three in each group were heavy smokers (>=20 cigarettes/d). Systolic blood pressure was 127 ± 10 mm Hg in the normal birth weight group vs. 122 ± 9 mm Hg in the low birth weight group (NS). Diastolic blood pressure was 65 ± 7 mm Hg in the normal birth weight group and 63 ± 7 in the low birth weight group (NS). To assess total body fat mass and lean body mass in our study population, we used dual-energy x-ray absorptiometry scan data collected 2 yr earlier by Jensen et al. (10).

All studies were started at 0800 h after an 8-h overnight fast during which they refrained from smoking. During the experiments the subjects lay supine in a quiet room with a constant room temperature of 20–22 C. An arterial cannula with an external diameter of 1 mm was inserted into the brachial artery for drug infusions and blood pressure measurements. A venous cannula was inserted in both arms, retrogradely in the infused arm for aspiration of deep venous blood. The arterial infusion rate was kept constant at 1 ml/min. Forearm blood flow (FBF) was measured in both arms by strain gauge venous occlusion plethysmography (D.E. Hokanson, Bellevue, WA) before and after intraarterial infusion of vasoactive drugs. During measurements, both hands were excluded from the circulation by inflating a wrist cuff to 200 mm Hg. Results are expressed as flow per volume of forearm (ml x (100 ml)-1 x min-1).

Endothelium-dependent vasodilation was studied during incremental doses of acetylcholine (ACh) (CLINALFA, Läufelfingen, Switzerland). Doses were 3.75, 7.5, 15, and 30 µg/min. Each dose was infused for 5 min to obtain a steady state (19). Endothelium-independent vasodilation was studied during infusion of the nitric oxide-donor sodium nitroprusside (SNP) (Roche, Basel, Switzerland) in doses of 1, 2, 4, and 8 µg/min.

The effect of insulin on endothelium-dependent and endothelium-independent vasodilation was assessed by intraarterial infusion of insulin (Actrapid; Novo Nordisk, Scandinavia, Malmö, Sweden) at a rate of 0.05 (mU x (kg body weight)-1 x min-1) for 20 min followed by coinfusion of insulin and either ACh or SNP. Thus, all individuals received six sequential infusions: ACh in a dose-response fashion after a 30-min washout of ACh; insulin alone for 20 min; continuation of the insulin infusion together with the first ACh dose-response study; subsequently after a 30-min washout, SNP in a dose-response manner; after a 30-min washout, insulin for 20 min followed by coinfusion of insulin; and the SNP dose-response study (Fig. 1Go).



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  		Figure 1. Infusion protocol. Each subject received six sequential infusions of ACh, SNP, and insulin on the same day.

 
After every measurement of blood flow, blood pressure was determined via a transducer connected to the arterial cannula.

The plasma concentration of glucose was determined by the glucose oxidase method (Vitros GLU slice, Johnson & Johnson, Ortho-Clinical Diagnostics, Rochester, NY), and serum insulin was determined by a microparticle enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Blood samples were drawn from both arms immediately before blood flow measurements to determine local and systemic effects on plasma glucose and insulin before and during insulin infusion. Insulin-stimulated glucose uptake in the forearm was calculated as the product of arterial-venous glucose difference and FBF (µmol glucose x (100 ml forearm)-1 x min-1).

Statistical analyses

Comparison of flow and glucose uptake data were performed with mixed linear models using the PROC MIXED procedure in the Statistical Analysis Software, version 8.0 (SAS Institute, Inc., Cary, NC). For studies of blood flow, logarithmic transformation of flow was used to satisfy the model assumption (examination of plots of residuals vs. predicted values). The dose-response studies in question entered the model as fixed effects, as did the interaction between dose-response study and dose of vasodilator (ACh or SNP). Study subject and the interaction between study subject and dose of vasodilator entered the model as random effects. Models of glucose uptake data were analyzed with untransformed data. Study group (low birth weight, normal birth weight) and insulin infusion were entered as fixed effects along with the interaction between insulin administration and group. Study subject and the interaction between study subject and insulin administration were entered as random effects. Model assumptions were validated by examination of plots of residuals vs. predicted values. The level of statistical significance was chosen as P of 0.05 or less (two-sided test). Continuous variables are presented as means ± SEM (including error bars in figures).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Endothelial function was measured in 15 men with low birth weight and 16 men with normal birth weight. Group characteristics are shown in Table 1Go. At the time of examination, there was no difference in weight or body mass index. The dual-energy x-ray absorptiometry scan results revealed no significant differences in total body fat and lean body mass between the two groups (Table 1Go). Fasting total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol triglycerides, and hemoglobin A1c were similar in the two groups. The mean arterial pressure (diastolic blood pressure plus one third of pulse pressure) was similar in the two groups during saline infusion (low birth weight 82.4 ± 1.7 vs. normal birth weight 85.4 ± 2.0 mm Hg, P = 0.25).


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  		Table 1. Baseline characteristics

 
Blood flow

There was no statistically significant difference in basal blood flow between the low and normal birth weight group [2.8 ± 0.3 vs. 2.2 ± 0.2 [ml x (100 ml)-1 x min-1], P = 0.1]. Intraarterial infusion of ACh in the low birth weight subjects increased blood flow from basal to 3.8 ± 0.6, 5.5 ± 0.7, 10.3 ± 1.4, and 14.1 ± 2.7 [ml x (100ml)-1 x min-1]. ACh-stimulated flow in low birth weight subjects was not different from that found in normal birth weight subjects (Fig. 2Go, P = 0.8). No change in blood pressure was observed during infusion of ACh.



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  		Figure 2. FBF response to ACh in 14 young adult men with low birth weight (•) and 16 normal birth weight controls ({blacktriangleup}). The ACh response was not significantly different between the two groups (P = 0.8). Insulin-stimulated ACh response in the low birth weight subjects ({circ}) was not different from the insulin-stimulated response in the normal birth weight ({triangleup}) subjects (P = 0.8), but the effect of insulin on the ACh response was significant in both groups (P = 0.001).

 
Insulin infusion for 20 min alone did not affect blood flow in either group. In the low birth weight subjects, blood flow was 2.9 ± 0.4 [ml x (100 ml)-1 x min-1] during saline infusion and 3.1 ± 0.4 [ml x (100 ml)-1 x min-1] after insulin infusion, NS. In the normal birth weight subjects, blood flow during saline infusion was 2.5 ± 0.2 [ml x (100 ml)-1 x min-1] and 2.9 ± 0.2 [ml x (100 ml)-1 x min-1] after insulin infusion, NS. Coinfusion of insulin and ACh caused an average increase in blood flow of 45%, compared with ACh infusion alone. Blood flow during coinfusion in the low birth weight group was 6.2 ± 0.8, 8.8 ± 1.4, 13.8 ± 2.1, and 18.0 ± 3.1 [ml x (100 ml)-1 x min-1], P = 0.001 (Fig. 2Go). There was no difference in insulin-stimulated ACh response between the groups (Fig. 2Go, P = 0.8).

SNP infusion increased blood flow in the low birth weight group from 3.5 ± 0.5 (saline) to 4.0 ± 0.5, 9.6 ± 1.0, 12.4 ± 1.1, and 15.8 ± 1.8 [ml x (100 ml)-1 x min-1] (Fig. 3Go). The same response to SNP was seen in subjects with normal birth weight (P = 0.8 between groups). Insulin also enhanced the SNP response. During insulin and SNP coinfusion, flow in the low birth weight group was increased to 8.0 ± 0.6, 11.3 ± 1.0, 14.2 ± 1.4, and 18.6 ± 2.3 [ml x (100 ml)-1 x min-1] (P < 0.001, compared with SNP), and there was no group difference (P = 0.8). Available risk factors (Table 1Go) were included in the calculations in total or one at a time. The vascular data did not change.



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  		Figure 3. FBF response to SNP in 14 young adult men with low birth weight (•) and 16 normal birth weight controls ({blacktriangleup}). The SNP response was not significantly different between the two groups (P = 0.8). Both in the low birth weight subjects ({circ}) and normal birth weight ({triangleup}) subjects (P = 0.8), insulin and SNP coinfusion increased blood flow significantly, compared with SNP alone (P < 0.001).

 
Glucose uptake

Fasting plasma glucose and fasting serum insulin were similar in the groups (Table 2Go). After 20 min of intraarterial insulin infusion, serum insulin in the infused arm was raised to 72.3 ± 10 mU/liter in low birth weight and 68.7 ± 9.2 mU/liter in normal birth weight, P = 0.8. During insulin infusion, systemic levels of insulin increased by 2.7 mU/liter in the low birth weight group and 2.3 mU/liter in the normal birth weight group. Thirty minutes after discontinuation of insulin infusion, serum levels of insulin in the infused arm had returned to baseline values (data not shown).


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  		Table 2. Glucose uptake and serum insulin levels

 
Forearm glucose uptake was assessed on three occasions: before stimulation of endothelium-dependent vasodilation, before insulin infusion, and immediately after the 20-min insulin infusion (Fig. 4Go). Glucose uptake did not differ at baseline in the two groups. Basal glucose uptake was 0.44 ± 0.09 [µmol glucose x (100 ml forearm)-1 x min-1] in the low birth weight group and 0.40 ± 0.09 [µmol glucose x (100 ml forearm)-1 x min-1] in the normal birth weight group. Glucose uptake was slightly but not significantly increased by insulin infusion in subjects with low birth weight: 0.40 ± 0.09 to 0.59 ± 0.1 [µmol glucose x (100 ml forearm)-1 x min-1], P = 0.3, whereas a significant increase was observed in subjects with normal birth weight: 0.4 ± 0.1 to 1.0 ± 0.2 [µmol glucose x (100 ml forearm)-1 x min-1], P = 0.003. Using mixed linear model analysis, the interaction between study group and insulin infusion was significant (P = 0.04), demonstrating a different effect of insulin on glucose uptake in the two study groups. No risk factor (Table 1Go) had independent influence on glucose uptake.



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  		Figure 4. Forearm glucose uptake at baseline (saline infusion) and after 20 min of insulin infusion. Measurement of glucose uptake was obtained from 13 subjects with low birth weight and 15 subjects with normal birth weight. Glucose uptake is given as micromoles glucose per minute per 100 ml of forearm tissue. In the figure, the mean and SEM are given. The insulin-stimulated glucose uptake is significant different between the two groups (P = 0.04).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows that young adult men with low birth weight have normal endothelium-dependent and endothelium-independent vasodilation, normal insulin-stimulated endothelial function, but impaired insulin-stimulated glucose uptake in the forearm.

Our observation of a markedly decreased forearm glucose uptake in the low birth weight subjects during insulin infusion in this study may appear to contrast with our previous finding in this population of a normal whole-body insulin-stimulated glucose uptake during an euglycemic hyperinsulinemic clamp (10). We believe that this difference may be an important finding. In contrast to all previous studies reporting insulin resistance in young adult low birth weight subjects (3, 4), we assessed insulin-stimulated glucose uptake as the arteriovenous glucose difference over the forearm at physiologically elevated insulin concentrations. The vast majority of glucose metabolism in the forearm takes place in muscle. Thus, in contrast to whole-body euglycemic hyperinsulinemic clamp, insulin-stimulated glucose uptake in the perfused forearm is almost exclusively an examination of muscle insulin sensitivity. Stimulation of muscle blood flow can independently increase glucose uptake during infusion of insulin, and studies have shown that blood flow is rate limiting for insulin-stimulated glucose uptake in healthy subjects (20, 21). In our study, blood flow was equal in both groups after insulin infusion, and, therefore, the observed difference in glucose uptake cannot be attributed to differences in flow. Measurement of whole-body glucose uptake during a euglycemic hyperinsulinemic clamp is the determination of a composite of several different insulin-sensitive tissues (22), but the bulk insulin-stimulated forearm glucose uptake is in muscle.

We speculate that a compensatory increased glucose uptake in other tissues including adipose tissue or perhaps the liver during a systemic hyperinsulinemic clamp may explain the apparent discrepancy between the current results and our previous results in this population. This is supported by a recent study of mice with targeted disruption of the insulin receptor gene in muscle (23). These animals had increased glucose uptake in adipose tissue, resulting in normal overall glucose tolerance. The duration of the insulin infusion in this study was chosen with regard to earlier studies on endothelial function, which have shown that a 20-min intraarterial insulin infusion provides a significant increase in FBF during insulin and acetylcholine coinfusion, compared with ACh alone. The short duration of insulin infusion does not assure steady state of insulin-stimulated glucose uptake. Recent observations from our group (Hermann, T. S., N. Ihlemann, H. Domínguez, C. Rask-Madsen, L. Kober, and C. Torp-Pedersen, unpublished results) indicate that forearm glucose uptake reaches a maximum after 40 min of insulin infusion and reaches 66% of maximum after 20-min infusion time. Therefore, we cannot extend our conclusions to the steady-state situation, in which the observed difference in glucose uptake may be diminished. However, a delayed effect of insulin on glucose uptake at physiological insulin concentrations may be an important finding with clinical implications. We suggest that our finding may be an early indicator of a defect in muscle glucose uptake that can lead to impaired glucose tolerance and postprandial hyperglycemia in the low birth weight subjects.

With respect to our study of endothelial function, our results are in discordance with a number of studies (11, 12, 13) and in accordance with other studies (14, 15) that have examined endothelial function in children and young adults with low birth weight. In the study by Leeson et al. (11), flow-mediated vasodilation was decreased in young adults with low birth weight. The association was strongest in subjects with no concomitant cardiovascular risk factors and weak in subjects with increasing levels of risk factors, thus implying a weak overall influence of birth weight. In this study we recorded some (smoking habits, body mass index, total cholesterol) but not all (level of physical activity, dietary habits) cardiovascular risk factors. Only a few subjects in each group were heavy smokers. When adjusted for smoking, body mass index, total cholesterol, and low-density lipoprotein-cholesterol, we did not see any differences in endothelial function between the two groups. However, differences in dietary habits and physical activity in the population may have obscured the effect of low birth weight on endothelial function or potentially enhanced a minor difference in forearm glucose uptake. The few existing studies all show endothelial dysfunction in children with low birth weight. Thus, the effect of low birth weight on endothelial function may be weakened by common risk factors in early adult life.

We found that insulin infusion enhanced ACh-stimulated vasodilation to a similar extent in both our study groups. With regard to the control group, this result confirms previous studies in healthy volunteers (18, 24). Insulin-stimulated endothelial function is decreased in subjects with overt insulin resistance and type 2 diabetic patients (17, 18), but our results suggest that vascular insulin sensitivity is preserved in low birth weight subjects.

In conclusion, forearm insulin-stimulated glucose uptake is impaired and basal as well as insulin-stimulated vascular function is preserved in young men with low birth weight. Thus, impairment of insulin-stimulated glucose uptake cannot be explained by abnormalities in insulin-stimulated perfusion, and metabolic alterations need not coexist with endothelial dysfunction in individuals with low birth weight. Efforts should be made to investigate further the interaction between muscle insulin resistance and the metabolic responses of other related tissues.


   Acknowledgments
 
We thank Dorthe Baunbjerg Nielsen for providing skilled technical assistance.


   Footnotes
 
This work was supported by grants from the Danish Diabetes Association and Danish National Research Foundation.

Abbreviations: ACh, Acetylcholine; FBF, forearm blood flow; SNP, sodium nitroprusside.

Received October 7, 2002.

Accepted December 4, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals