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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0478
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4930-4937
Copyright © 2006 by The Endocrine Society

Insulin Action in Adipose Tissue and Muscle in Hypothyroidism

George Dimitriadis, Panayota Mitrou, Vaia Lambadiari, Eleni Boutati, Eirini Maratou, Demosthenes B. Panagiotakos, Efi Koukkou, Marinela Tzanela, Nikos Thalassinos and Sotirios A. Raptis

2nd Department of Internal Medicine (G.D., P.M., V.L., E.B., S.A.R.), Research Institute and Diabetes Center, Athens University Medical School, "Attikon" University Hospital, GR-12462 Haidari, Greece; Hellenic National Diabetes Center (E.M., S.A.R.), GR-10675 Athens, Greece; Department of Statistics (D.B.P.), Harokopio University, GR-17671 Athens, Greece; Department of Endocrinology, "Elena Venizelou" Hospital (E.K.), GR-11521 Athens, Greece; and "Evangelismos" Hospital (M.T., N.T.), GR-10676 Athens, Greece

Address all correspondence and requests for reprints to: George Dimitriadis, M.D., D.Phil., 2nd 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 and gdimitr{at}med.uoa.gr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited.

Methods: To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 ± 3 yr) and 10 euthyroid subjects (EU; aged 42 ± 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase.

Results: The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0–360 min): 1) BF (1290 ± 79 vs. 1579 ± 106 ml per 100 ml tissue in forearm and 706 ± 105 vs. 1340 ± 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 ± 74 vs. 850 ± 155 µmol per 100 ml tissue in forearm and 208 ± 42 vs. 406 ± 47 µmol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 ± 6 vs. 33 ± 6% per minute in forearm and 17 ± 4 vs. 14 ± 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 ± 91 vs. 264 ± 36 nmol/liter·min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 ± 11 vs. 80 ± 21 µmol per 100 ml tissue) and triglyceride clearance (45 ± 10 vs. 109 ± 21 ml per 100 ml tissue) were decreased in HO (P < 0.05).

Conclusions: In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS WELL established that thyroid hormones affect insulin action (1). Although thyroid hormone excess has been consistently found to induce insulin resistance (1, 2), there are only a few studies examining insulin action in thyroid hormone deprivation in humans, with conflicting results.

Glucose regulation by insulin depends on the suppression of endogenous glucose production and the stimulation of peripheral glucose disposal. Hepatic glucose production is decreased (3, 4) or unchanged (5) in hypothyroidism, but there is little information on the effects of insulin in peripheral tissues and, in particular, in vivo.

Whole-body sensitivity of glucose disposal to insulin in hypothyroid patients has been examined by euglycemic-hyperinsulinemic clamps (6, 7) and iv or oral administration of glucose (8, 9, 10) and found to be normal (6, 8), increased (10), or decreased (7, 9). In the forearm muscles of hypothyroid patients, the sensitivity of glucose disposal to insulin was found to be normal (6), whereas in adipocytes isolated from hypothyroid patients and examined in vitro, the sensitivity of glucose oxidation to insulin was normal (11) and that of glucose transport was decreased (12). In rats made hypothyroid, the responsiveness of glucose disposal to insulin was decreased in muscle (13, 14, 15) but increased in adipocytes (16).

Finally, there are no studies in hypothyroidism to examine the effects of insulin on lipid metabolism in vivo. Lipoprotein-lipase (LPL) activity in hypothyroid patients has been estimated in plasma after iv injections of triglyceride emulsion and heparin and found to be decreased (17, 18, 19, 20, 21, 22), whereas the activity of this enzyme in adipose tissue biopsies from hypothyroid patients was either normal (19) or decreased (21).

This study was undertaken in patients with hypothyroidism to investigate insulin action on glucose disposal and lipolysis. This was performed after the consumption of a mixed meal to create a metabolic environment, permitting the interaction of insulin and substrates to be investigated under conditions as close to physiological as possible.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Eleven female patients with primary hypothyroidism [HO; aged 45 ± 3 yr, body mass index (BMI) 24 ± 1 kg/m2, T3 43 ± 10 ng/dl (0.66 ± 0.1 nmol/liter), T4 1.6 ± 0.4 µU/dl, TSH 72 ± 10 µU/ml (range 16–100 µU/ml); three were in the postmenopausal state] were studied before initiation of treatment, and compared with 10 female euthyroid subjects [EU; aged 42 ± 4 yr, BMI 24 ± 1 kg/m2, T3 114 ± 9 ng/dl (1.8 ± 0.1 nmol/liter), T4 9 ± 1 µU/dl, TSH 1 ± 0.08 µU/ml; two were in the postmenopausal state). Body composition was not assessed in our study (23); the percentage of fat was found to be significantly higher in hypothyroid subjects when compared with healthy controls matched for sex, age, height, and weight (24). However, this does not underestimate the value of our findings because in lean females, the depot of visceral adipose tissue is expected to be small (25, 26). The subjects were not taking any medications before or during the study. The study was approved by the hospital ethics committee, and subjects gave informed consent.

Experimental protocol

All subjects were admitted to the hospital at 0700 h after an overnight fast and had the radial artery (A) and two veins (Vs), a superficial abdominal and a forearm deep vein, catheterized (27). All experiments were undertaken in a temperature-controlled room at 23 C.

A meal was given (730 kcal, 50% carbohydrate, 40% fat, 10% protein) at least 1 h after catheter insertion and consumed within 20 min (28).

Blood samples were withdrawn from the three sites before the meal (at –30 and 0 min) and at 30- to 60-min intervals for 360 min thereafter for measurements of insulin and glucagon (RIA; Linco Research, St. Charles, MO), leptin, and TNF-{alpha} (ELISA; R&D Systems, Oxon, UK), adiponectin (RIA; DRG Diagnostics, Marburg, Germany), visfatin (ELISA; Phoenix Pharmaceuticals, Belmont, CA), glucose (Yellow Springs Instruments, Yellow Springs, OH), glycerol, triglycerides (corrected for free glycerol), and nonesterified fatty acids (NEFAs; Roche Diagnostics, Mannheim, Germany). The NEFA assay was validated by measuring dilutions of palmitate and found to be accurate for concentrations of 50 µmol/liter. No inhibitor of lipolysis was added in the tubes used for measurement of NEFAs. After collection of blood, the tubes were put into ice; spinning, separation of plasma, and freezing at –20 C was always less than 30 min from collection. With this procedure, the amount of lipolysis in the blood specimens has been shown to be insignificant (29).

Tissue blood flow was measured immediately before each blood sample (27, 28). In the adipose tissue, 133Xe dissolved in sterile saline (4 MBq; DuPont, MDS Nordion, Fleurus, Belgium) was injected into the sc adipose tissue of the anterior abdominal wall within the drainage area of the cannulated abdominal vein (but on the opposite side), about 8 cm from the midline and 5 cm below the level of the umbilicus. The duration of the injection and the withdrawal of the needle were 2 min and 30 sec, respectively. The injection was given at least 45 min before the first measurement and the washout analyzed with a scintillation detector (Oakfield Instruments, Oxford, UK). During measurements, the subjects remained still. These manipulations were necessary to increase the accuracy and precision of adipose tissue blood flow measurements (27). In recent studies, 133Xe washout was found to be higher in the upper areas of the abdominal anterior wall, compared with lower areas (30, 31); moreover, these rates showed significant variation among different subjects and within the same subject on different occasions (32).

Although the AV-difference technique has allowed unique insights into the metabolic fluxes across adipose tissue (33), the limitations should be borne in mind when considering the results. For instance, it is not possible to separate skin drainage from that of adipose tissue. However, the contribution of skin metabolism is minor (34) and human skin takes little part in lipid metabolism (35). Moreover, the concentrations of glucose, glycerol, and lactate reported in the adipose tissue venous effluent are very similar to those in sc adipose tissue interstitial fluid measured by microdialysis (27, 36). These findings suggest that the composition of the blood in the sc abdominal veins is dominated by the metabolic activity of the adipose tissue surrounding them and that skin metabolism had no major influence on our results.

The forearm blood flow was measured immediately after sampling by mercury strain-gauge plethysmography (Hokanson, Bellevue, WA). Two minutes before taking an antecubital sample, a cuff was inflated to a pressure of 220 mm Hg around the wrist for 2 min to exclude the hand circulation from the forearm preparation and prevent the wrist perforators from draining blood from the superficial venous system (skin and sc adipose tissue) into the deep venous system (27, 37). In addition, a cool fan was used over the forearm for 10 min before measurements to minimize contamination with skin blood (27). 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 (38, 39).

Calculations (27, 40)

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

In the fasting state, insulin sensitivity was estimated by the homeostasis model assessment index (41). In the postprandial state, insulin sensitivity was estimated by the Belfiore index (42) and the Matsuda index (43).

Glucose uptake from muscle or adipose tissue was calculated as: (A-V)glucose(blood flow), and the fractional glucose extraction as: (A-V)glucose/Aglucose (this calculation is independent of blood flow).

The net release of NEFAs from the adipose tissue was calculated as (V-A)NEFA and multiplied by blood flow to give absolute values.

Reesterification of NEFAs within the adipose tissue was calculated on the assumption that hydrolysis of each triglyceride molecule releases one molecule of glycerol and three molecules of NEFAs as follows: 3[(V-A)glycerol(blood flow)]-[(V-A)NEFA(blood flow)].

Triglyceride clearance across the adipose tissue was calculated as: [(A-V)triglycerides(blood flow]/(Atriglycerides).

The relative rates of LPL activity and adipose tissue lipolysis were calculated as follows: LPL = (A-V)triglycerides(blood flow), and adipose tissue lipolysis = [(V-A)glycerol(blood flow)] – LPL (expressed in glycerol concentration units).

The rates of LPL activity and adipose tissue lipolysis were calculated on the basis of the following assumptions (40): 1) extraction of triglycerides from blood represents the activity of LPL; 2) there is no significant reuse of glycerol or oxidation of fatty acids within the tissue; and 3) both LPL activity and adipose tissue lipolysis release glycerol mole for mole with hydrolysis of triglycerides. This involves the assumption that there is no release of partial hydrolysis products of triglycerides (mono- and diacylglycerol) from the tissue.

Statistical analysis

Results are presented as mean ± SEM of plasma levels or integrated postprandial responses [areas under curve (AUC), calculated with the trapezoid rule from the start of the meal to 360 min (AUC0–360)]. Differences between groups were tested with the Mann-Whitney test. Differences within groups were tested with paired Student’s t test. A repeated-measures ANOVA for ranked measurements was applied to evaluate differences between groups across time, after adjusting for BMI and age (23). Grouping variable was considered as fixed and group-to-time interaction was evaluated; no random effects factors were used. Post hoc analysis was applied to test for the group effect on the investigated variables at specific time points. The Bonferroni rule was applied to account for the inflation in type I error. All hypotheses tested were two sided and the calculated P values were exact. All statistical calculations were performed in SPSS (version 12; SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Arterial levels of hormones and metabolites

Fasting plasma glucose, insulin, and NEFA levels were not altered by hypothyroidism, whereas fasting triglycerides were increased (P = 0.03). Fasting plasma glucagon levels in HO (94 ± 7 pg/ml) were higher than those in EU (72 ± 3 pg/ml, P = 0.04).

In HO, fasting arterial and abdominal venous levels of adiponectin were lower, whereas those of leptin were higher than those in EU (Table 1Go). Fasting arterial and abdominal venous levels of TNF-{alpha}, resistin, and visfatin were similar in both groups (Table 1Go).


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  		TABLE 1. Postabsorptive arterial and abdominal venous levels of leptin, TNF-{alpha}, adiponectin, resistin, and visfatin in HO and EU subjects

 
After the meal, plasma glucose levels were higher at 120 min (P = 0.02) and insulin levels at 90 and 120 min (P = 0.03) in HO vs. EU. Integrative (AUC0–360) plasma glucose and insulin levels were higher in HO vs. EU (2295 ± 159 vs. 2063 ± 36 mM·min, P = 0.001 for glucose and 15 ± 2 vs. 10 ± 0.7 U/liter·min, P = 0.04 for insulin) (Fig. 1Go, A and B). Integrative (AUC0–360) plasma glucagon levels were similar in HO (31 ± 3ng/ml·min) and EU (26 ± 2 ng/ml·min).


Figure 1
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  		FIG. 1. Arterial plasma glucose (A), insulin (B, multiply by 6 to convert to picomoles per liter), NEFA (C), and triglyceride (D) levels in EU and HD subjects after a meal (poverall between groups: 0.04 for insulin, 0.52 for glucose, 0.74 for NEFAs, and 0.024 for triglycerides). *, P < 0.05 from post hoc analysis using Bonferroni rule.

 
Postprandial changes in plasma NEFAs showed a similar pattern in both HO and EU (Fig. 1CGo).

Postprandial plasma triglycerides increased steadily in both groups and by 240 min reached values 1.5- to 2-fold higher than their fasting levels; in HO, these levels were all significantly higher than those of EU (P = 0.02) (Fig. 1DGo).

The homeostasis model assessment index was not different in the two groups (1.4 ± 0.3 and 1.1 ± 0.1 in HO and EU, respectively), suggesting a normal sensitivity to insulin in the fasting state. In contrast, the Belfiore index in HO was significantly lower than the comparison value of one (0.87 ± 0.08, P = 0.002), and the Matsuda index was lower in HO vs. EU (5.7 ± 0.8 vs. 8.1 ± 0.66, P = 0.04); both indices suggested the presence of insulin resistance in the postprandial state. In the calculation of the Belfiore index, the mean of values of EU are considered equal to 1; values lower than 1 indicate insulin resistance (41, 42, 43).

Blood flow

In EU, forearm and adipose tissue blood flow increased by about 1.5- to 2-fold at 90 min and then progressively returned to baseline by the end of the experiment.

In HO, fasting blood flow rates in the forearm and adipose tissue were not different from those of EU; however, after the meal, blood flow did not increase in either tissue resulting in significantly lower rates at 60–90 min in the forearm (P = 0.007) and 60–180 min in the adipose tissue (P = 0.0001) (Figs. 2AGo and 3AGo).


Figure 2
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  		FIG. 2. Forearm blood flow (A), glucose uptake (B), and fractional glucose uptake (C) in EU and HD subjects after a meal (poverall between groups: 0.021 for blood flow, 0.023 for glucose uptake, and 0.59 for fractional glucose uptake). *, P < 0.05 from post hoc analysis using Bonferroni rule.

 

Figure 3
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  		FIG. 3. Adipose tissue blood flow (A), glucose uptake (B), and fractional glucose uptake (C) in EU and HD subjects after a meal (poverall between groups: 0.0001 for blood flow, 0.03 for glucose uptake, and 0.69 for fractional glucose uptake). *, P < 0.05 from post hoc analysis using Bonferroni rule.

 
Glucose uptake

In the fasting state, the net glucose uptake into the forearm and adipose tissue was similar in both groups.

In HO, glucose uptake after the meal was significantly lower at 60 and 90 min in the forearm (P = 0.02) (Fig. 2BGo) and at 60 min in the adipose tissue (P = 0.015) (Fig. 3BGo). The integrative postprandial glucose uptake in both tissues was significantly lower in HO vs. EU [AUC0–360 464 ± 74 vs. 850 ± 155 µmol per 100 ml tissue in the forearm (P = 0.03) and 208 ± 42 vs. 406 ± 47 µmol per 100 ml tissue in the adipose tissue (P = 0.03)]. In contrast, the fractional extraction of glucose in the forearm and adipose tissue in HO was similar to that of EU at all time points after the meal (Figs. 2CGo and 3CGo).

Lipid fluxes

Fasting net release of NEFAs from the adipose tissue in HO (551 ± 83 nmol/min per 100 ml tissue) was not different from that in EU (406 ± 74 nmol/min per 100 ml tissue); these rates were suppressed to the same extent in both groups after the meal (AUC0–360 23 ± 8 and 30 ± 9 µmol per 100 ml tissue in HO and EU, respectively). The suppression of adipose tissue lipolysis by insulin after the meal was also similar in both groups (AUC0–360 14 ± 6 and 19 ± 9 µmol per 100 ml tissue in HO and EU, respectively).

There were no differences in adipose tissue NEFA reesterification rates between HO and EU (fasting 82 ± 30 and 92 ± 17 nmol/min per 100 ml tissue, respectively, and AUC0–360 149 ± 37 and 140 ± 52 µmol per 100 ml tissue, respectively).

Differences were observed in triglyceride clearance rates across the adipose tissue (AUC0–360 45 ± 10 ml per 100 ml tissue in HO vs. 109 ± 21 ml per 100 ml tissue in EU, P = 0.01) but not in the forearm (AUC0–360 55 ± 14 ml per 100 ml tissue in HO vs. 79 ± 10 ml per 100 ml tissue in EU, P = 0.21) after adjusting for BMI and age.

In HO, values of LPL activity in the adipose tissue [fasting 27 ± 7 nmol glycerol per minute per 100 ml tissue and postprandial (AUC0–360) 42 ± 11 µmol per 100 ml tissue] were also significantly different from respective values in EU [fasting 40 ± 10 nmol glycerol per minute per 100 ml tissue and postprandial (AUC0–360) 80 ± 21 µmol per 100 ml tissue, P = 0.04] after adjusting for BMI and age of the subjects. In the forearm, values of LPL activity in HO [fasting 14 ± 8 nmol glycerol per minute per 100 ml tissue and postprandial (AUC0–360) 48 ± 10 µmol per 100 ml tissue] were not significantly different from those in EU [fasting 28 ± 7 nmol glycerol per minute per 100 ml tissue and postprandial (AUC0–360) 42 ± 9 µmol per 100 ml tissue, P = 0.99].

Venoarterial differences of circulating triglyceride levels across the adipose tissue were not significantly different between HO (AUC0–360 30 ± 10 mmol/liter·min) and EU (AUC0–360 20 ± 8 mmol/liter·min).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Glucose uptake

Despite the increase in plasma insulin levels in HO, net glucose uptake in the forearm muscles and adipose tissue was not increased after the meal, suggesting the presence of insulin resistance.

These results are in agreement with experiments performed in muscle of hypothyroid rats (13, 14, 15) and adipose tissue segments isolated from patients with hypothyroidism (12), showing that rates of glucose transport did not respond when insulin was increased within the physiological range. They also correspond well with observations in hypothyroid subjects using euglycemic-hyperinsulinemic clamps (7), showing resistance of whole-body glucose disposal to plasma insulin levels, similar to those obtained in our HO after the meal.

Our results are not in agreement with a previous report that measured insulin-stimulated glucose disposal in the forearm of hypothyroid patients during euglycemic-hyperinsulinemic clamps: these rates remained unaltered after treatment with thyroxin, implying that hypothyroidism had no effect on insulin action in muscle (6). The results of this study are, however, difficult to interpret because plasma insulin levels during the clamp were about 20% higher before treatment of hypothyroidism than after treatment [most likely due to differences in clearance rates (2)], and no euthyroid group was included for comparison.

The effect of insulin on blood flow is an important component of its stimulation of glucose uptake (44); impairment of this mechanism in insulin-sensitive tissues may partly account for insulin resistance in obesity and type 2 diabetes (45). In our study, forearm and adipose tissue blood flow and glucose disposal rates in HO were significantly decreased at 60–90 min after the meal when plasma insulin levels reached their peak. To examine the possibility that the decreases in blood flow were responsible for the defect in insulin-stimulated glucose disposal in the forearm and adipose tissue, we calculated fractional glucose extraction: this was not impaired, suggesting that the resistance of glucose disposal to insulin in both tissues in HO could be accounted for by the impairment of the vasodilatory response. The increase of blood flow by insulin in muscle is direct, whereas in adipose tissue this effect is indirect through a stimulation of the sympathetic system (44, 45, 46). Our results may therefore be explained by reports demonstrating that hypothyroidism impairs flow-mediated vasodilatation (a marker of endothelial dysfunction) in muscle (47, 48) and decreases sympathetic responses in the adipose tissue (49, 50).

Lipid metabolism

In the euthyroid state, the buffering of NEFA flux by insulin is regulated mainly by the suppression of lipolysis and NEFA release from the adipose tissue via a decrease in the activity of hormone-sensitive lipase and adipose triglyceride lipase (33, 51, 52).

In our study, rates of NEFA release from the adipose tissue of HO and adipose tissue lipolysis were suppressed after the meal to the same extent as in EU, suggesting that the response of hormone-sensitive lipase and adipose triglyceride lipase to insulin was not impaired (plasma insulin levels were similar in both groups from 0 to 60 min). These results correspond favorably with observations made in adipocytes isolated from patients with hypothyroidism and incubated in vitro: at levels of insulin within the physiological range (5–50 µU/ml), the suppression of glycerol release (used as a measure of lipolysis) was similar with that of euthyroid cells (11).

Changes in plasma triglycerides have never been examined after meal ingestion in hypothyroidism: these levels were elevated in the fasting state and continued to rise after the meal (Fig. 1DGo), suggesting a lower triglyceride turnover (17). The plasma triglyceride concentration is the net result of several metabolic processes including: 1) endogenous synthesis of the very low-density lipoprotein (VLDL; the carrier for triglycerides of endogenous origin) by the liver and secretion into plasma, and 2) clearance from plasma, which depends on the activities of LPL and hepatic triglyceride lipase and tissue blood flow (33, 51). In the fasting state, the activity of hepatic triglyceride lipase is higher than that of LPL; in the postprandial state, the increase in plasma insulin stimulates the activity of LPL, whereas that of hepatic triglyceride lipase remains unaltered (53).

Our results show that the increase in plasma triglycerides in HO was secondary to a decreased rate of removal by the adipose tissue because both fasting and postprandial LPL activities were significantly decreased in the presence of hyperinsulinemia. Because the venoarterial differences of plasma triglycerides across the adipose tissue were similar in the two groups, low LPL activity in HO may be due, at least in part, to the decrease in the blood flow rates. However, establishment of this suggestion would require experiments with direct measurements of LPL activity in the adipose tissue. Previous studies in patients with hypothyroidism using iv injections of triglyceride emulsions and heparin suggested that the removal of both endogenous and exogenous triglycerides was reduced (17, 18, 19, 20, 21, 22); however, this method measures only an average systemic lipase activity and cannot detect changes in LPL activity that may occur in individual tissues (53). In rat adipose tissue, thyroid hormones have been shown to regulate LPL posttranscriptionally, resulting in changes in both synthetic rate and activity (54). Direct measurements of LPL in adipose tissue biopsies in patients with hypothyroidism have been done in two studies: the total activity of LPL was found to be normal, but the activated form of this enzyme (measured in vitro as the heparin-elutable enzyme) was either normal (19) or decreased (21).

Although not investigated in our study, the possibility that triglyceride increases in HO could be accounted for, at least in part, by a lower rate of triglyceride removal by the liver cannot be excluded. This is supported by studies in humans suggesting that hypothyroidism decelerates the capacity of the liver for removal of remnants of chylomicrons and VLDL due to a decreased activity of hepatic triglyceride lipase (20, 22).

Could increased VLDL-triglyceride production by the liver account for the elevated plasma triglyceride levels? This is suggested by experiments in rats made hypothyroid, showing that the output of VLDL-triglycerides from the isolated perfused liver was increased (55). However, in patients with hypothyroidism, hepatic VLDL-triglyceride synthesis and release were found to be normal (55).

Finally, it is likely that a delay in meal absorption may be responsible, at least in part, for the late increases of plasma triglyceride levels after the meal in HO. Hypothyroidism has been shown to delay gastric emptying and meal absorption rates (56).

Although overnight NEFA kinetics were not investigated in our study (57), it is unlikely that these were different between HO and EU: in HO, fasting plasma NEFA levels and NEFA fluxes in the adipose tissue (output and reesterification) and adipose tissue lipolysis were all similar to those in EU.

To support insulin resistance in HO, we measured parameters related to adipose tissue that could be responsible for the decrease in insulin sensitivity in the postprandial state (see Results and Table 1Go) (58, 59, 60, 61). In HO, plasma levels of leptin (62, 63, 64, 65) were increased, whereas those of adiponectin (62, 64) were decreased. In muscle and adipocytes, adiponectin has been found to stimulate glucose use by activating AMP-activated protein kinase, whereas leptin to reduce insulin stimulated glucose uptake (66, 67). In recent reports, plasma adiponectin levels were found to correlate positively with endothelium-dependent vasodilatation (68), an effect that was independent of that on insulin sensitivity (69), and in insulin-resistant subjects with type 2 diabetes or obesity, low adiponectin levels were closely linked to decreases in tissue blood flow rates (70). These results may explain, at least in part, low blood flow rates and insulin resistance in the forearm and adipose tissue in HO in our study.

Concluding remarks

Our study showed that in hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) the suppression of lipolysis by insulin is not impaired; 3) plasma levels of triglycerides are elevated due to decreased clearance by the adipose tissue; 4) a major finding to explain most of the metabolic defects is the decrease in adipose tissue blood flow rates.

These results, taken together with our recently published data on hyperthyroidism (71), suggest that thyroid hormone excess and deprivation do not make a consistent story: in hypothyroidism the decrease of blood flow in adipose tissue and muscle may be considered as part of the pathogenetic mechanism of insulin resistance explaining most of the metabolic defects in these tissues; in contrast, in hyperthyroidism the increase of blood flow seems to correct the intrinsic metabolic defects in muscle and adipose tissue (71). Moreover, in hypothyroidism the targets of insulin action are not uniformly impaired: glucose uptake and proteolysis (72) are resistant to insulin, but lipolysis is not; the latter may be necessary to relieve tissues from the burden of NEFA surplus after meals. In contrast, in hyperthyroidism all three targets are resistant to insulin (1, 71).


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


   Footnotes
 
The authors have nothing to declare.

First Published Online September 26, 2006

Abbreviations: A, Artery; AUC, area under curve; BMI, body mass index; EU, euthyroid; HO, hypothyroid; LPL, lipoprotein lipase; NEFA, nonesterified fatty acid; V, veins; VLDL, very low-density lipoprotein.

Received March 1, 2006.

Accepted September 19, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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