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Insulin-Stimulated Rates of Glucose Uptake in Muscle in Hyperthyroidism: The Importance of Blood Flow

Second Department of Internal Medicine (G.D., P.M., V.L., E.B., N.T., T.E., S.A.R.), Research Institute and Diabetes Center, Athens University Medical School, "Attikon" University Hospital, GR-12462 Haidari, Greece; Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and Its Complications (E.M., S.A.R.), GR-10675 Athens, Greece; Department of Endocrinology (E.K.), Elena Venizelou Hospital, GR-11521 Athens, Greece; and Department of Nutrition Science-Dietetics (D.P.), Harokopio University, GR-17671 Athens, Greece

Address all correspondence and requests for reprints to: George Dimitriadis, M.D., D.Phil., Second Department of Internal Medicine, Research Institute and Diabetes Center, Athens University, Attikon University Hospital, 1 Rimini Street, GR-12462 Haidari, Greece. E-mail: gdimi{at}ath.forthnet.gr; or gdimitr{at}med.uoa.gr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background: In hyperthyroidism, although hepatic insulin resistance is well established, information on the effects of insulin on glucose uptake in skeletal muscle is variable.

Methods: To investigate this, a meal was given to nine hyperthyroid (HR) and seven euthyroid (EU) subjects. Blood was withdrawn for 360 min from a forearm deep vein and the radial artery for measurements of insulin and glucose. Forearm blood flow (BF) was measured with strain-gauge plethysmography. Glucose flux was calculated as arteriovenous difference multiplied by BF and fractional glucose extraction as arteriovenous difference divided by arterial glucose concentrations.

Results: Both groups displayed comparable postprandial glucose levels, with the HR having higher insulin levels than the EU. In the forearm of HR vs. EU: 1) glucose flux was similar [area under the curve (AUC)_0–360 673 ± 143 vs. 826 ± 157 µmol per 100 ml tissue]; 2) BF was increased (AUC_0–360 3076 ± 338 vs. 1745 ± 145 ml per 100 ml tissue, P = 0.005); and 3) fractional glucose extraction was decreased (AUC_0–360 14.5 ± 3 vs. 32 ± 5%min, P = 0.03).

Conclusions: These results suggest that, in hyperthyroidism, insulin-stimulated glucose uptake in muscle is impaired; this defect is corrected, at least in part, by the increases in BF.

	Introduction

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Insulin-resistance is a common finding in hyperthyroidism (1, 2). However, although hepatic insulin resistance is well established (1), information on the effects of insulin in peripheral tissues is variable.

Skeletal muscle is considered as an important tissue for glucose disposal in response to insulin, especially in the postprandial state. In this tissue, although insulin-stimulated glycogen synthesis is markedly decreased in hyperthyroidism (3, 4, 5), insulin-stimulated glucose uptake, examined in vivo by euglycemic-hyperinsulinemic clamps (3, 6, 7, 8, 9), iv administration of glucose (10), or forearm catheterization (11) and in vitro in whole-muscle preparations (12, 13, 14), has been found either normal (3, 7, 8, 9, 10, 14) or increased (6, 11, 12, 13, 14). These studies imply that insulin resistance in hyperthyroidism may be selective in the liver and does not involve peripheral tissues.

Although increased blood flow in hyperthyroidism is well known (11), its impact on glucose uptake in skeletal muscle has not been investigated.

This study was undertaken in patients with hyperthyroidism to examine the hypothesis that increased blood flow rates in muscle mask the defect in insulin-stimulated glucose uptake. This was investigated in the forearm muscles with the arteriovenous difference technique after the consumption of a mixed meal (15, 16).

	Subjects and Methods

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Subjects

Nine hyperthyroid (HR) subjects (six females, three males) were studied before initiation of treatment [aged 38 ± 4 yr, body mass index 23 ± 1 kg/m², T₃ 368 ± 47 ng/dl (5.65 ± 0.7 nmol/liter), T₄ 17.5 ± 1.5 µU/dl, TSH 0.03 ± 0.002 µU/ml] and compared with seven (five females, two males) euthyroid (EU) subjects [aged 40 ± 4 yr, body mass index 22.6 ± 0.9 kg/m², T₃ 119 ± 9 ng/dl (1.8 ± 0.1 nmol/lt), T₄ 9.1 ± 1.3 µU/dl, TSH 1 ± 0.09 µU/ml]. Body composition was not assessed in our study. It is known that after long-lasting hyperthyroidism, there is loss of muscle mass. However, this does not underestimate the value of our findings because our hyperthyroid patients were all newly diagnosed, and our results (blood flow and glucose uptake) were expressed per 100 ml tissue.

The study was approved by the hospital ethics committee, and subjects gave informed consent.

Experimental protocol

The subjects were admitted to the hospital at 0700 h after an overnight fast and had the radial artery (A) and a forearm deep vein (V) catheterized.

A meal (730 kcal, 50% carbohydrate of which 38% was starch, 40% fat, and 10% protein) was given at least 1 h after catheter insertion and consumed within 20 min. The choice to use a mixed meal was based on the reports that the relative importance of different tissues in carbohydrate metabolism may vary with the dose of oral glucose or the levels of glycemia and insulinemia during a clamp (17). Furthermore, the meal creates a metabolic environment that permits the interaction of insulin and substrates to be investigated under conditions as close to physiological as possible (18).

Blood samples were drawn from both sites before the meal (at –30 and 0 min) and at 30- to 60-min intervals for 360 min thereafter for measurements of insulin (Linco Research, St. Charles, MO) and glucose (Yellow Springs Instruments, Yellow Springs, OH). Forearm blood flow (BF) was measured with strain-gauge plethysmography (Hokanson, Bellevue, WA), as previously described (15, 18). Two minutes before taking an antecubital sample, a cuff was inflated to a pressure of 220 mm Hg around the wrist for 2 min. In addition, a cool fan was used over the forearm for 10 min before measurements to minimize contamination with skin blood. With these manipulations, the contribution of skin and sc adipose tissue blood flow to muscle blood flow in the forearm is small and the variability of forearm blood flow measurements is reduced (15, 18).

Calculations

The values obtained from the two preprandial samples were averaged to give a 0 time value. The plasma levels of metabolites were converted to whole blood by using fractional hematocrit (15).

Glucose uptake in the forearm was calculated as: (A-V)_glucose x (BF), and the fractional glucose extraction as: (A-V)_glucose/A_glucose (this calculation is independent of BF) (15).

Results are presented as mean ± SEM of plasma levels or integrated postprandial responses [areas under curve (AUCs)]. Differences between HR and EU subjects were tested with nonpaired t test. A posterior statistical power analysis showed that the enrolled number of participants is adequate to achieve 40% power at P = 0.05 for testing two-sided hypothesis regarding glucose flux levels between HR and EU subjects.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Arterial levels of glucose and insulin

In HR, postprandial plasma glucose levels (AUC_0–360 2212 ± 43 mMmin) were not significantly different from those in EU (2089 ± 41 mMmin). In contrast, plasma insulin levels in HR (AUC_0–360 16333 ± 2804 mUmin) were higher than those in EU (10087 ± 548 mUmin, P = 0.03).

Blood flow

Fasting muscle blood flow rates were elevated in HR (9.2 ± 1.5 ml/min per 100 ml tissue vs. 3.6 ± 0.3 ml/min per 100 ml tissue in EU, P = 0.007) and remained at this level for the whole postprandial period, resulting in overall higher rates (AUC_0–360 3076 ± 338 ml per 100 ml tissue vs. 1745 ± 145 ml per 100 ml tissue in EU, P = 0.005) (Fig. 1A).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Blood flow (A), glucose uptake (B), and fractional glucose extraction (C) by the forearm muscles in EU and HR subjects after a meal (differences between groups were tested with nonpaired t test, *, P < 0.05).

The net uptake of glucose into the forearm of both HR and EU was similar at all time points after meal ingestion (Fig. 1B).

In contrast, the fractional uptake of glucose was markedly decreased in HR (AUC_0–360 14.5 ± 3%min) than in EU (AUC_0–360 30.4 ± 7%min, P = 0.02) (Fig. 1C).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Despite the increase in plasma insulin levels in HR, plasma glucose levels were similar to those in EU, suggesting the presence of insulin resistance. This confirms previous observations (1, 2, 3, 4). Increased insulin circulating levels could not be due to decreased clearance of insulin; the latter has been previously examined in HR and found to be increased (3, 4). Increased insulin clearance in HR could lead to a further increase in insulin secretion, thus aggravating insulin resistance. Indeed, previous studies have shown that hyperinsulinemia can produce or exacerbate insulin resistance (19).

Glucose uptake by the forearm tissue after the meal was normal in HR. This is supported by observations in vivo using euglycemic-hyperinsulinemic clamps or administration of glucose (oral or intravenous) and in vitro in whole-muscle preparations showing that at physiological concentrations of insulin, rates of glucose uptake have been found normal (3, 7, 8, 9, 10, 14) or even increased (6, 11, 12, 13, 14) in the hyperthyroid state.

Previous studies suggest that the effect of insulin on blood flow is an important component of its stimulation of glucose uptake (20), although other studies did not reproduce this result (21, 22, 23). In our study, BF was increased in the forearm muscles of HR in both the fasting and postprandial states confirming previous observations (11). To examine the possibility that this increase masked a defect in insulin-stimulated glucose uptake at the tissue level, we calculated fractional glucose extraction (which is independent of BF). In HR, this rate was markedly decreased in the forearm muscles in the presence of hyperinsulinemia, suggesting that glucose uptake in this tissue was indeed impaired, and this defect was corrected by the increase in BF rates. These data are supported by studies in skeletal muscle of hyperthyroid subjects (3, 4) or rats (5, 14), showing that insulin stimulation of major intracellular pathways of glucose metabolism, such as glycogen synthesis, is markedly decreased.

In summary, in hyperthyroidism, insulin stimulation of glucose uptake in skeletal muscle is impaired. This defect is corrected, at least in part, by the increase in blood flow.

	Acknowledgments

 
We thank Chr. Zervogiani, A. Triantafylopoulou, and N. Koufou for technical support and V. Frangaki, R.N., for help with experiments.

	Footnotes

 
Disclosure Statement: The authors have nothing to declare.

First Published Online March 18, 2008

¹ G.D. and P.M. contributed equally to the work presented in this paper.

Abbreviations: A, Artery; AUC, area under the curve; BF, blood flow; EU, euthyroid; HR, hyperthyroid; V, vein.

Received December 26, 2007.

Accepted March 12, 2008.

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