Am J Physiol Endocrinol Metab 295: E1380E1389, 2008.
First published October 14, 2008; doi:10.1152/ajpendo.90700.2008.
PPAR activation and increased dietary lipid oppose thyroid hormone
signaling and rescue impaired glucose-stimulated insulin secretion
in hyperthyroidism
Mark J. Holness, Gemma K. Greenwood, Nicholas D. Smith, and Mary C. Sugden
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St. Bartholomews and Royal London
School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
Submitted 18 August 2008; accepted in final form 9 October 2008
Holness MJ, Greenwood GK, Smith ND, Sugden MC. PPAR
activation and increased dietary lipid oppose thyroid hormone signaling
and rescue impaired glucose-stimulated insulin secretion in hyperthyroid-
ism. Am J Physiol Endocrinol Metab 295: E1380 E1389, 2008. First
published October 14, 2008; doi:10.1152/ajpendo.90700.2008.The
aim of the study was to investigate the impact of hyperthyroidism on the
characteristics of the islet insulin secretory response to glucose, particu-
larly the consequences of competition between thyroid hormone and
peroxisome proliferator-activated receptor (PPAR) in the regulation of
islet adaptations to starvation and dietary lipid-induced insulin resistance.
Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/
low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyro-
nine (T3) administration (1 mgkg body wt1 day1 sc, 3 days). The
PPAR agonist WY14643 (50 mg/kg body wt ip) was administered 24 h
before sampling. Glucose-stimulated insulin secretion (GSIS) was as-
sessed during hyperglycemic clamps or after acute glucose bolus injec-
tion in vivo and with step-up and step-down islet perifusions. Hyperthy-
roidism decreased the glucose responsiveness of GSIS, precluding suffi-
cient enhancement of insulin secretion for the degree of insulin resistance,
in rats fed either standard diet or high-fat diet. Hyperthyroidism partially
opposed the starvation-induced increase in the glucose threshold for
GSIS and decrease in glucose responsiveness. WY14643 administration
restored glucose tolerance by enhancing GSIS in fed HT rats and relieved
the impact of hyperthyroidism to partially oppose islet starvation adap-
tations. Competition between thyroid hormone receptor (TR) and PPAR
influences the characteristics of GSIS, such that hyperthyroidism impairs
GSIS while PPAR activation (and increased dietary lipid) opposes TR
signaling and restores GSIS in the fed hyperthyroid state. Increased islet
PPAR signaling and decreased TR signaling during starvation facilitates
appropriate modification of islet function.
islet function; thyroid hormone action; peroxisome proliferator-acti-
vated receptor-; fasting; fat feeding
THYROID HORMONE RECEPTORS are members of the nuclear recep-
tor (NR) family. Both functional thyroid hormone receptors
(TRs) TR1 and TR1 are expressed in islets (5, 6, 11, 39, 41);
however, TR1 is predominantly localized in the pancreatic
-cells (41). Signaling via a cytoplasmic form of TR1
mediates the action of triiodothyronine (T3) in pancreatic
-cells (40) to promote pancreatic -cell survival (39). How-
ever, increased thyroid hormone signaling has a long-term
effect to impair islet function, with inhibition of glucose-
stimulated insulin secretion (GSIS) (8, 11, 23, 26). Glucose
utilization and oxidation by islets of mice treated with thyrox-
ine (T4) is increased (25), suggesting that hyperthyroidism
Address for reprint requests and other correspondence: M. J. Holness,
Centre for Diabetes and Metabolic Medicine, Inst. of Cell and Molecular Science,
4 Newark St., Whitechapel, London E1 2AT, UK (e-mail: m.j.holness@qmul.
ac.uk).
E1380 0193-1849/08 $8.00 Copyright 2008 the American Physiological Society
impairs normal coupling between oxidative glucose metabo-
lism and GSIS.
TRs interact with peroxisome proliferator-activated recep-
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tors (PPARs), other members of the NR family, by sharing
binding sites and heterodimeric partners such as the retinoid X
receptors (RXRs) (reviewed in Refs. 7, 22, 33). PPAR acti-
vation increases gene expression of enzymes that augment
tissue fatty acid (FA) uptake and oxidation in a range of
tissues, including islets (reviewed in Ref. 32), and enhances
islet pyruvate dehydrogenase kinase 4 protein expression (30),
impairing islet glucose oxidation. PPAR activation also im-
pacts GSIS when there is augmented GSIS due to islet com-
pensation for insulin resistance, for example, induced by a
high-saturated-fat diet (16). PPAR activation also mediates,
in part, the suppression of GSIS that is part of the islet
adaptation to starvation (15). Thus PPAR-null mice develop
hyperinsulinemic hypoglycemia on fasting (13, 31), and islets
from fasted PPAR-null mice show increased GSIS (13).
Conversely, PPAR activation increases the glucose threshold
for GSIS, diminishing insulin secretion at low glucose concen-
trations, while PPAR overexpression in -cell lines inhibits
GSIS (13, 15, 37). Increased PPAR signaling in fasting is, in
euthyroid subjects, associated with decreased T3 concentra-
tions, the latter as part of an energy-sparing process (3).
The present study aimed to elucidate the impact of hyper-
thyroidism on the characteristics of the islet insulin secretory
response to glucose, including adaptations of insulin secretion
to starvation, where PPAR activation subserves an important
role in suppressing GSIS (13, 31), and insulin resistance
induced by high-fat feeding, where PPAR activation opposes
augmented GSIS due to islet compensation for insulin resis-
tance (16). The possibility exists that, in the presence of high
levels of nuclear receptors/transcription factors, including TR
and PPAR, sequestration of heterodimeric partners (e.g.,
RXR) from other nuclear receptors could influence the regu-
lation of insulin secretion. In the present study, we therefore
also aimed to determine whether adaptations of the islet insulin
secretory response to glucose observed in response to starva-
tion and insulin resistance might be influenced by competition
between the PPARs and TR.
MATERIALS AND METHODS
Materials. Laboratory reagents were from Roche Diagnostics
(Lewes, UK) or Sigma (Poole, UK). Kits for determination of insulin
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.
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 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
(ELISA, rat insulin as standard) and glucose (glucose oxidase) were
from Mercodia (Uppsala, Sweden) and Roche Diagnostics. Cross-
reactivity with proinsulin was 7% for the insulin assay kit.
WY14643 was from Sigma. Standard rodent diet and dietary compo-
nents were from Special Diet Services (Witham, UK), except for lard
(purchased locally). Female albino Wistar rats were from Charles
River (Margate, UK).
Animal treatment. All procedures performed in this study were
approved by the Local Ethics Review Committee of St Bar-
tholomews and Royal London School of Medicine and Dentistry and
were carried out under the authority of the appropriate Home Office
(UK) personal and project licenses in accordance with the Home
Office Animals (Scientific Procedures) Act 1986. Female rats were
maintained at 22 2C (12:12-h light-dark cycle), with free access to
water and either standard diet [52% carbohydrate, 15% protein, 3%
lipid, 30% nondigestible residue (by weight); 2.61 kcal metabolizable
energy/g] or high-saturated-fat diet (see Ref. 18 for details) or were
E1381
had ceased, pancreases were excised and rats were euthanized. Islets
isolated by collagenase digestion were collected under a dissecting
microscope into HEPES-buffered Hanks balanced salt solution con-
taining 5% BSA. Insulin release from 50 freshly isolated islets (of
approximately equal size) was measured in a perifusion system (see
Refs. 16, 17). In this system, 50 islets were housed in small chambers
on Millicell culture inserts. Islets were perifused in basal medium
(Krebs-Ringer containing 20 mM HEPES, pH 7.4, 5 mg/ml BSA, and
2 mM glucose) for 60 min at a flow rate of 1 ml/min at 37C before
collection of fractions. Perifusate glucose concentrations were modi-
fied to generate rises from 2 mM (basal) to the midphysiological range
(8 mM) and then to the high physiological range (16 mM), before
switching back to 2 mM glucose. Fractions (2 ml) were collected at

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starved for 48 h. High-fat diet (HF) was provided for 4 wk (18). Rats
were rendered hyperthyroid (HT) by injection of T3 (1 mg kg body
wt1 day1 sc, 3 days); euthyroid control (EU) rats were injected
with hormone solvent (10 mM NaOH-0.03% BSA) (10). The dose and
period of T3 treatment were selected on the basis of previous studies
that demonstrated T3-induced changes in metabolic function and gene
expression (results not shown) and, although not measured in these
studies, typically generate serum T3 concentrations of 1520 nM (10,
34, 35). WY14643 was administered as a single injection (50 mg/kg
body wt ip) to EU or HT rats at 24 h before sampling (1517, 31) with
rats in either the fed state (EU-WY, HT-WY) or starved for 48 h with
WY14643 administered after 24-h fasting (EU-ST-WY, HT-ST-WY).
This period of exposure elicits enhanced protein expression of the
PPAR-linked gene pyruvate dehydrogenase kinase 4 in islets (30).
For studies in vivo, animals were fitted with chronic indwelling
jugular cannulas (for infusion and sampling), with 6 8 days of
recovery.
Hyperglycemic clamps. Hyperglycemic clamps were conducted in
conscious, unrestrained immediately postabsorptive rats. After 30-min
equilibration, a 25% glucose solution was infused to maintain glyce-
mia at 11 mM. Blood samples, obtained at 5-min intervals thereafter
for 50 min, were assayed for glucose and insulin. Insulin responses
were used for calculation of the incremental values integrated over the
period of glucose infusion (I0 60). The steady-state glucose infusion
rate (GIR) was calculated as the mean glucose infusion rate during the
last 30 min of glucose infusion.
Intravenous glucose challenge. Glucose was administered as a
bolus (0.5 g glucose/kg body wt, 150 l/100 g body wt) via the
indwelling cannula to conscious, unrestrained immediately postab-
sorptive or 48-h-starved rats (18). The cannula was flushed with saline
after glucose injection to remove residual glucose. Blood samples
(100 l) were withdrawn via the cannula before and at 2, 5, 10, 15,
and 30 min after glucose administration. Samples of whole blood (50
l) were deproteinized with ZnSO4-Ba(OH)2 and centrifuged (10,000
g) at 4C, and the supernatant was assayed for glucose. Blood was
also centrifuged (10,000 g, 4C) and plasma stored at 20C until
being assayed for insulin. The acute insulin response (AIR) was
calculated as the mean of suprabasal 2- and 5-min plasma insulin Fig. 1. Hyperthyroidism elicits insulin resistance and augments insulin secre-
values. Areas under the insulin (I0 30) and glucose (G0 30) curves tion during hyperglycemic clamp in vivo. Rats were rendered hyperthyroid
were calculated as incremental values above values at 0 min inte- (HT) by subcutaneous injection of triiodothyronine (T3; 1 mg kg body
grated over the 30-min period after glucose injection. The insulino- wt1 day1; 3 days); euthyroid (EU) control rats were injected with hormone
genic index, an index of -cell function (38), was calculated as solvent (10 mM NaOH-0.03% BSA). A and B: blood samples were withdrawn
I0 30/G0 30. The rate of glucose disappearance (k) was calculated from EU or HT rats at intervals during sustained intravenous glucose infusion
from the slope of the regression line obtained with log-transformed for measurement of blood glucose (A) and plasma insulin (B) concentrations.
glucose values from 2 to 15 min after intravenous glucose adminis- Mean steady-state blood glucose concentrations over the period from 20 to 50
min after initiation of glucose infusion were EU 10.4 0.6 mmol/l (5) and HT
tration. Homeostasis model assessment of insulin sensitivity (HOMA) 10.5 0.3 mmol/l (5). Corresponding steady-state plasma insulin concentra-
scores were calculated as [fasting insulin (U/ml) fasting glucose tions were EU 96 14 U/ml (5) and HT 137 23 U/ml (5). C: steady-state
(mol/ml)]/22.5 (19, 36). rates of glucose infusion (GIR) for EU and HT rats. Data are means SE for
Islet perifusions. Rats were anesthetized (pentobarbital sodium; 60 5 EU rats or 5 HT rats. Statistically significant effects of hyperthyroidism:
mg/ml in 0.9% NaCl, 1 ml/kg body wt ip). Once locomotor activity *P 0.05.

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E1382 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
2-min intervals and stored at 20C before assay for insulin. Insulin
responses during the perifusion were used for calculation of the
incremental insulin values integrated over the 80-min period of the
perifusion (I60 140). To allow quantification and direct comparison
of GSIS, areas under the insulin curves were calculated for discrete
16-min periods over which the perifusate glucose concentrations were
rising and falling: 1, during which the perifusate glucose concentra-
tion increased from 2 to 8 mM; 2, during which the perifusate
glucose concentration increased from 8 to 16 mM; and 3 and 4,
when perifusate glucose was restored to basal level.
Data analysis. Data are means SE, with the numbers of rats or
islet preparations in parentheses. Statistical analysis was performed by
ANOVA followed by Fishers post hoc tests for individual compari-
sons or Students t-test as appropriate (Statview; Abacus Concepts,
Berkeley, CA).
RESULTS
Hyperthyroidism elicits insulin resistance in vivo. Compared
with EU rats, HT rats exhibited a 1.8-fold (P 0.01) increase
in postabsorptive insulin levels (EU 16.0 2.2 U/ml, HT
28.7 3.2 U/ml) and a 32% (P 0.01) increase in postab-
sorptive glycemia (EU 4.09 0.26 mM, HT 5.39 0.28 mM).
As a consequence, insulin-to-glucose ratios were unaffected by
hyperthyroidism (EU 4.38 0.82 U/mol, HT 5.48 0.86
U/mol). HOMA scores revealed that hyperthyroidism de-
creased insulin sensitivity, a 2.4-fold increase (P 0.001)
compared with the euthyroid group (EU 2.78 0.30 U/
mol, HT 6.74 0.52 U/mol).
In hyperglycemic clamps, in which glucose was infused to
maintain steady-state blood glucose concentrations of 10.4
Fig. 2. Hyperthyroidism impairs glucose tolerance in fed, but
not starved, rats. Blood glucose (A and B) and plasma insulin
(D and E) were measured in samples obtained from fed
(immediately postabsorptive) or 48-h-starved (ST) EU or HT
rats before and during an intravenous glucose tolerance test
(IVGTT). Areas under the insulin and glucose curves during
the IVGTT (I0 30 and G0 30, respectively) were calculated
as incremental values above values at 0 min integrated over
the 30-min period after glucose injection. The insulinogenic
index was calculated as the ratio I0 30/G0 30. I0 30 and
I0 30/G0 30 values are shown in C and F, respectively.
Results are means SE for 8 fed EU rats, 6 fed HT rats, 5
EU-ST rats, and 5 HT-ST rats. Statistically significant effects
of hyperthyroidism: *P 0.05. Statistically significant ef-
fects of 48-h starvation: P 0.05, P 0.01, P
0.001.
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mM for 50 min (Fig. 1A), GIR, a measure of insulin sensitivity,
was significantly lowered by hyperthyroidism by 24% (P
0.01) (Fig. 1C), consistent with the development of insulin
resistance. Despite impaired insulin sensitivity, insulin secre-
tion was not significantly enhanced in response to hyperthy-
roidism. Mean steady-state insulin levels (EU 96 14 U/ml,
HT 137 23 U/ml) (Fig. 1B) and I0 60 values during the
hyperglycemic clamps (EU 0.85 0.05 mU/mlmin, HT
0.82 0.07 mU/mlmin) did not differ significantly between
EU and HT groups.
Hyperthyroidism impairs glucose tolerance in fed, but not
starved, rats. Blood glucose profiles after an intravenous glu-
cose load (0.5 g/kg body wt) for fed and starved rats are shown
in Fig. 2, A and B, respectively. Blood glucose concentrations
were significantly increased in fed HT rats compared with fed
EU rats at all time points after the intravenous glucose load
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(Fig. 2A). Although rates of glucose disappearance (k values)
were similar (EU 2.9 0.3%/min, HT 3.1 0.2%/min),
because of higher 2-min glucose values in the HT group
G0 30 values were also significantly increased in fed HT rats
compared with fed EU rats (EU 8.9 0.5 mmol/lmin, HT
10.9 0.5 mmol/lmin; P 0.05). The acute insulin response
values (calculated as the mean of suprabasal 2- and 5-min
plasma insulin values) (EU 113 8 mU/ml, HT 96 14
mU/ml) and the I0 30 values (Fig. 2C) did not differ signif-
icantly between fed EU and fed HT rats. Nevertheless, plasma
insulin concentrations at 5 min after the glucose bolus were
significantly lower (by 30%; P 0.05) in fed HT rats (Fig.
2D), indicating that insulin levels declined more rapidly as
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 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS E1383
blood glucose concentrations declined. The insulinogenic in-
dex (I0 30/G0 30) (an indication of GSIS in relation to
overall glucose tolerance) was significantly suppressed (37%;
P 0.05) by hyperthyroidism in the fed state (Fig. 2F). The
disposition index (DI), a measure of the ability of the -cells to
compensate for insulin resistance [estimated as the product of
-cell function (AIR after a glucose load) and insulin sensi-
tivity (GIR during a hyperglycemic clamp)], was significantly
decreased by 35% by hyperthyroidism [EU 7.1 0.4 (mgml)/
(U minkg), HT 4.6 0.3 (mgml)/(U min kg); P
0.01]. Together these data indicate that, in the fed state, there
is inadequate islet insulin secretion for the degree of insulin
resistance induced by hyperthyroidism.
Blood glucose concentrations before and after the glucose
bolus did not differ significantly between 48-h-starved EU and
48-h-starved HT rats (Fig. 2B). Starvation (48 h) significantly

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reduced insulin secretion after the glucose bolus in both EU
and HT rats (compare Fig. 2, D and E), resulting in a signifi-
cant decrease in I0 30 values in EU (by 59%; P 0.001) and
HT (by 71%; P 0.01) rats (Fig. 2C). As in the fed state,
insulin levels declined more rapidly as blood glucose con-
centrations declined in the starved HT group, although this
did not result in significant differences in insulin values
between the starved HT and EU groups (Fig. 2E). I0 30/
G0 30 was unaffected by hyperthyroidism in the 48-h-
starved state (Fig. 2F).
Islet perifusions demonstrate that hyperthyroidism de-
creases glucose responsiveness in the fed state while partially
opposing effects of starvation to increase glucose threshold
and lower glucose responsiveness. Perifusion profiles for
islets isolated from fed and starved rats are shown in
Fig. 3, A and B, respectively. In the fed state, hyperthyroidism
did not significantly affect the response of insulin secretion to
a rise in glucose in the low physiological range (1 and 2
values; Fig. 3, C and D) but significantly lowered the peak
response to glucose, reflected by a significant (49%; P 0.05)
decrease in 3 values (Fig. 3E). Perifusate insulin concentra-
tions declined more rapidly in the HT group compared with the
EU group after the perifusate glucose level was restored to
basal (2 mM) (Fig. 3A), although there were no significant
differences in 4 values between islets from EU and HT rats
(Fig. 3F). The influence of starvation to lower insulin secretion
was maintained in perifused islets from EU rats (compare Fig. Fig. 3. Islet perifusions demonstrate that hyperthyroidism decreases glucose
3, A and B), resulting in an 88% decline in 2 (P 0.01), a responsiveness in the fed state while partially opposing effects of starvation to
increase the glucose threshold and lower glucose responsiveness. Islets were
67% decline in 3 (P 0.001), and a 79% decline in 4 (P harvested from fed (postabsorptive) or 48-h starved (ST) EU or HT rats. Islets
0.05), together with a 67% decline in I60 140 (EU 0.92 0.13 were perifused (2 mmol/l glucose for 60 min; flow rate of 1 ml/min) before
mU/ml min, EU-ST 0.17 0.06 mU/ml min; P 0.01). In being subjected to square-wave stimulation by raising the perifusate glucose
contrast, the impact of starvation to lower GSIS was partially concentration to 8 mmol/l (16 min) and subsequently to 16 mmol/l (16 min).
After exposure to 16 mmol/l glucose, perifusate glucose was then lowered by
attenuated by hyperthyroidism (HT-ST group), as reflected by switching back to basal medium. Fractions (2 ml) collected at 2-min intervals
a significant (P 0.05) 4.4-fold increase in 2 values and a were assayed for insulin. Patterns of glucose-stimulated insulin secretion
trend toward increased 3 values (Fig. 3, D and E). Thus the (GSIS) are shown for perifused islets from fed (postabsorptive; A) or ST (B)
decline in 2 and 3 values elicited by starvation in EU rats is EU and HT rats. CF: areas under the insulin curves for the fed and ST EU and
HT groups were calculated for discrete 16-min periods during perifusion in
reversed by 48% and 31%, respectively, by hyperthyroidism in which the perifusate glucose concentration varied between 2 and 8 mmol/l and
starvation. As a consequence both of an effect of hyperthy- between 8 and 16 mmol/l (1, 2, respectively), the immediate poststimula-
roidism to lower insulin secretion in the fed state (a 35% tion transition (3), and the longer-term poststimulation period (4). Data are
decline in I60 140) (EU 0.92 13 mU/mlmin, HT 0.600 means SE for 10 fed EU rats, 6 fed HT rats, 5 EU-ST rats, and 5 HT-ST rats.
0.11 mU/mlmin; P 0.05) and of an effect of hyperthyroid- Statistically significant effects of hyperthyroidism: **P 0.01. Statistically
significant effects of 48-h starvation: P 0.05, P 0.01, P 0.001.
ism to increase GSIS in the starved state (a 78% increase in
I60 140; EU-ST 0.17 0.06 mU/mlmin, HT-ST 0.54 15
mU/mlmin), the decline in I60 140 observed in response to
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E1384 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
Fig. 4. Peroxisome proliferator-activated receptor (PPAR)
activation in hyperthyroidism restores glucose tolerance and
insulin secretion in the fed state. WY14643 (WY) was ad-
ministered to EU or HT rats as a single intraperitoneal
injection (50 mg/kg body wt) at 24 h before sampling in either
the fed state (EU-WY, HT-WY) or after 48-h starvation with
WY14643 administered after 24-h fasting, sampling after a
further 24 h (EU-ST-WY, HT-ST-WY). Blood glucose
(A and B) and plasma insulin (D and E) were measured in
samples obtained from WY14643-treated fed (postabsorp-
tive) or 48-h-starved (ST) EU or HT rats before and during an
IVGTT. I0 30 and I0 30/G0 30 values are shown in C and
F, respectively. Results are means SE for 8 fed EU rats, 5
fed HT rats, 12 EU-ST rats, and 5 HT-ST rats. Statistically
significant effects of hyperthyroidism: *P 0.05. Statisti-
cally significant effects of 48-h starvation: P 0.05; P
0.01; P 0.001.
starvation in the euthyroid state was reduced by 90% by
hyperthyroidism.
PPAR activation in fed hyperthyroid rats restores glucose
tolerance and appropriate insulin secretion. Like PPAR, TRs
heterodimerize with the RXR. We therefore examined whether
pharmacological PPAR activation following the induction of
hyperthyroidism could reverse hyperthyroidism-induced low-
ering of the glucose responsiveness of GSIS in the fed state.
Pharmacological PPAR activation in vivo in fed EU rats did
not affect GSIS after a glucose bolus (compare Fig. 4A with
Fig. 2A) or in vitro with perifused islets from fed rats (compare
Fig. 5A with Fig. 3A). PPAR activation in vivo in fed HT rats
eliminated effects of hyperthyroidism on blood glucose con-
centrations (Fig. 4A), plasma insulin concentrations (Fig. 4, C
and D), and differences in I0 30/G0 30 values between fed
EU and fed HT rats (Fig. 4F). Similarly, PPAR activation in
the fed state normalized GSIS with perifused islets from HT
rats compared with perifused islets from WY14643-treated EU
rats (Fig. 5A). Thus PPAR activation in the fed state restores
glucose tolerance and ensures appropriate insulin secretion in
HT rats.
PPAR activation in hyperthyroidism restores GSIS adap-
tations to starvation. The suppression of GSIS that is a com-
ponent of the islet adaptation to starvation is mediated, in part,
by PPAR activation (13). The ability of hyperthyroidism to
attenuate the response of GSIS to starvation (demonstrated in
the present study) could therefore indicate that ligand-activated
TR competed with ligand-activated PPAR for the common
heterodimerization partner (RXR), thus blocking or attenuating
PPAR signaling and consequent changes in the characteristics
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of GSIS during starvation. We therefore investigated whether
in vivo exposure to WY14643 during starvation could rescue
or relieve hyperthyroidism-induced impairment of islet starva-
tion adaptations. PPAR activation after 24-h fasting, with
sampling after a further 24 h, resulted in similar blood glucose
(Fig. 4B) and plasma insulin (Fig. 4E) concentrations in EU
and HT rats.
GSIS by perifused islets from either fed or 48-h-starved EU
rats was unaffected by antecedent 24-h PPAR activation
in vivo, as demonstrated by I60 140 values (EU 0.92 0.13
mU/mlmin, EU-WY 0.83 0.12 mU/mlmin, ST 0.17
0.06 mU/mlmin, ST-WY 0.18 0.02 mU/mlmin). Thus the
influence of starvation to lower GSIS was retained in perifused
islets of WY14643-treated EU rats (compare Fig. 5, A and B).
PPAR activation after 24-h fasting, with sampling after a
further 24 h, reversed the impact of hyperthyroidism in star-
vation to increase insulin secretion in perifused islets in vitro,
as reflected by 54% and 65% decreases in 2 and 3, respec-
tively, with an overall 50% decline (P 0.05) in I60 140
values (HT-ST 0.54 0.15 mU/mlmin, HT-ST-WY 0.27
0.03 mU/mlmin). Thus, as observed for GSIS after an intra-
venous glucose bolus in vivo, modification by hyperthyroidism
of GSIS in vitro in perifused islets from fed or 48-h-starved rats
was normalized by antecedent PPAR in vivo (compare Fig. 5,
A and B).
Effects of hyperthyroidism on high-fat feeding-induced al-
terations in characteristics of GSIS and their modification by
PPAR activation. Antecedent PPAR activation opposes the
effects of high-fat feeding to augment GSIS to compensate for
lipid-induced insulin resistance in euthyroid rats (16, 18).
295 DECEMBER 2008 www.ajpendo.org
 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
Fig. 5. PPAR activation in hyperthyroidism restores the characteristics of
GSIS induced by starvation. Islets were harvested from WY14643-treated fed
(postabsorptive) or 48-h starved (ST) EU or HT rats. Patterns of GSIS are
shown for perifused islets from WY14643-treated fed (A) and WY14643-
treated 48-h-starved (B) EU rats and HT rats. CF: 1, 2, 3, and 4 values.
Data are means SE for 5 fed EU-WY rats, 6 fed HT-WY rats, 5 EU-ST-WY
rats, and 5 HT-ST-WY rats. There were no statistically significant effects of
hyperthyroidism. Statistically significant effects of 48-h starvation: P 0.05,
P 0.01.
Using a model of high-fat feeding previously demonstrated to
induce whole body insulin resistance after 4 wk (16, 18), we
therefore examined whether the challenge of hyperthyroidism
within the context of high-fat feeding could alter the effect of
high-fat feeding to augment GSIS. In EU rats, high-fat feeding
for 4 wk (EU-HF) did not affect glucose tolerance (Fig. 6A) but
was associated with a 1.8-fold increase in I0 30 values (Fig.
6C), with significantly increased plasma insulin concentrations
at 2 and 5 min after the glucose bolus (1.5- and 2.1-fold; P
0.05) (Fig. 6D). Antecedent high-fat feeding for 4 wk before
the induction of hyperthyroidism by treatment with T3 for the
AJP-Endocrinol Metab VOL 295 DECEMBER 2008
E1385
last 3 days of the protocol (HT-HF group) resulted in a
significant impairment of glucose tolerance (Fig. 6B) and
insulin sensitivity, assessed from a 1.9-fold increase (P
0.001) in HOMA score (HT 6.7 0.5 mol U/ml, HT-HF
13.1 2.8 molU/ml; P 0.001). Impaired insulin sensi-
tivity in vivo in the HT-HF group was accompanied by a
marked increase in GSIS in vivo, with significantly increased
plasma insulin concentrations at all time points after a glucose
load compared with HT rats fed a standard (low fat) diet (Fig.
6E). I0 30 values were increased by 4-fold (P 0.001)
relative to HT and by 1.7-fold (P 0.05) relative to EU-HF
(Fig. 4C), while the insulinogenic index (I0 30/G0 30) was
3-fold (P 0.001) higher relative to HT and 1.4-fold (P
0.05) higher relative to EU-HF (Fig. 4F). Such increases in
insulin secretion reflect a degree of islet compensation for the
exaggerated insulin resistance seen in the HT-HF group com-
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pared with the HT group. Nevertheless, antecedent high-fat
feeding in HT rats resulted in a deterioration of glucose
tolerance, with a 33% increase (P 0.05) in G0 30 values
(HT 10.9 0.5 mmol/lmin, HT-HF 14.5 0.8 mmol/lmin).
Thus in HT rats insulin secretion in vivo was inadequate to
compensate entirely for the increased insulin resistance intro-
duced by high-fat feeding. Further evidence supporting a stable
impairment of insulin secretion was identified in islet perifu-
sions. In EU-HF rats, the increase in insulin secretion observed
in vivo after an glucose load was retained in vitro in perifused
islets (Fig. 7A), as reflected by 3.1-fold (P 0.001), 1.6-fold
(P 0.01), and 2.2-fold increases in 2, 3, and 4, respec-
tively, with an overall 2-fold increase in I60 140 values (EU
0.92 0.13 mU/mlmin, EU-HF 1.86 0.39 mU/mlmin;
P 0.001). In contrast, there was a dramatic impairment of
GSIS in perifused islets from HT-HF rats, as demonstrated by
a 66% (P 0.05) decline in I60 140 values (HT 0.60 0.11
mU/mlmin, HT-HF 0.21 0.01 mU/mlmin). As a conse-
quence, 2, 3, and 4 values were 89% (P 0.001), 88%
(P 0.001), and 94% (P 0.001) lower, respectively, in islets
from HT-HF rats compared with EU-HF islets.
DISCUSSION
PPARs exert important lipid-lowering effects in vivo,
thereby opposing the development of lipid-induced insulin
resistance by relieving inhibition of insulin-stimulated glucose
disposal by muscle. Long-term lipid sensing by the pancreatic
-cell is, in part, coordinated via the PPARs (32). Hyperthy-
roidism is associated with the development of whole body
insulin resistance and altered lipid handling, and, like PPAR,
the TR heterodimerizes with the RXR (reviewed in Ref. 33).
Augmentation of tissue FA oxidation, as observed in fasting
and after PPAR activation in the euthyroid state, is also a
feature of thyroid hormone excess (reviewed in Ref. 14).
Decreased T4 and T3 during starvation represent an important
energy-sparing process (3). We therefore hypothesized that the
islet insulin secretory response to glucose, including adapta-
tions of insulin secretion to starvation, where PPAR acti-
vation subserves an important role in suppressing GSIS (13,
31), might be influenced by competition between the PPARs
and TR.
Abnormal glucose metabolism with impaired glucose toler-
ance is observed in thyrotoxicosis (1, 3), and hyperthyroidism
can induce a condition termed thyroid diabetes (24). How-
www.ajpendo.org
E1386 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
Fig. 6. Induction of hyperthyroidism during high-fat feed-
ing enhances GSIS but is inadequate to compensate en-
tirely for the increased insulin resistance introduced by
high-fat feeding. High-fat-fed rats were rendered HT by
subcutaneous injection of T3 (1 mg kg body wt1 day1;
3 days) for the last 3 days of the dietary protocol (HT-HF
group). Blood glucose (A and B) and plasma insulin (D and
E) were measured in samples obtained from fed (postab-
sorptive) EU or HT rats fed either a standard (low fat) diet
(C) or a high-fat diet (HF) before and during an IVGTT.
I0 30 and I0 30/G0 30 values are shown in C and F,
respectively. Results are means SE for 8 EU rats, 6 HT
rats, 8 EU-HF rats, and 5 HT-HF rats. Statistically signif-
icant effects of hyperthyroidism: *P 0.05. Statistically
significant effects of high-fat feeding: P 0.05, P
0.001.
ever, in vivo, hyperthyroidism in humans has been variously
reported to enhance GSIS during a hyperglycemic clamp,
suggesting increased glucose responsiveness, or to impair
GSIS (1, 27). In healthy euthyroid Pima Indians, plasma free
T3 concentrations correlated with direct and indirect indexes of
insulin secretion that were independent of insulin sensitivity
and glucose concentrations (28). In the present study, rates of
glucose disappearance (k values) were similar in EU and HT
fed (postabsorptive) rats; however, in HT rats the 2-min glu-
cose values were markedly higher. Similar rates of glucose
clearance, despite hyperglycemia in the HT group that should
enhance glucose clearance by a mass action effect, indicate
impaired glucose clearance in the HT group. Glucose toler-
ance, assessed as G, was impaired. The present study dem-
onstrates that, although insulin secretion is similar during
sustained hyperglycemia or immediately after a glucose bolus
in EU and HT rats in the immediately postabsorptive state,
insulin concentrations after a glucose bolus decline more rap-
idly in HT rats. The impaired insulin secretion pattern in the
HT group may, in part, underlie the observation that the
magnitude of insulin secretion is inadequate to compensate for
the degree of insulin resistance induced by hyperthyroidism
and may be one reason why glucose tolerance deteriorates in
hyperthyroid individuals.
A hyperbolic relationship exists between whole body insulin
sensitivity and insulin secretion such that for any difference in
insulin sensitivity, a reciprocal proportionate change occurs in
insulin secretion mediated by (as yet undefined) in vivo factors
that feed back to the islet (2, 20). Consequently, in vivo studies
do not discriminate between direct effects of hyperthyroidism
AJP-Endocrinol Metab VOL
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on insulin secretion and peripheral effects of hyperthyroidism
to alter insulin sensitivity that are transmitted to the islet to
modify insulin secretion. Further studies therefore investigated
GSIS by isolated pancreatic islets from immediately postab-
sorptive rats. Under these ex vivo conditions, systemic and
neuronal influences on GSIS are eliminated. Perifused islet
studies identified a marked direct effect of hyperthyroidism to
lower insulin secretion (decrease glucose responsiveness), and
to elicit a more rapid decline in insulin secretion once the
perifusate glucose level was restored to basal (2 mM). Because
this effect of hyperthyroidism persists ex vivo, it is implied that
this effect is intrinsic to the -cells and does not reflect in vivo
factors such as increased insulin clearance. Although the
mRNA expression of the glucose sensor glucokinase (GK) in
islets is reduced by T3 (9, 12), neither GK activity (9) nor
GLUT2 mRNA or protein expression (12) is affected by T3. It
has, however, been shown with a -cell line (RIN-5mF cells)
ex vivo (where compensation for insulin resistance cannot be
reproduced) that T3 decreases proinsulin mRNA expression,
which may, in part, account for impaired insulin secretion in
isolated perifused islets (9). Thus our data suggest that 1) the
ability to maintain GSIS during hyperglycemic clamps at levels
comparable to those observed in ET rats in vivo confirms a
degree of islet compensation for insulin resistance by a never-
theless failing islet, but 2) a direct impairment of islet function
induced by hyperthyroidism precludes sufficient enhancement
of insulin secretion to maintain glucose tolerance.
We demonstrated profound suppression of GSIS following
48-h starvation both in vivo after a glucose bolus and in vitro
in isolated perifused islets, supporting previous studies both
295 DECEMBER 2008 www.ajpendo.org
 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
Fig. 7. Induction of hyperthyroidism during high-fat feeding causes a dramatic
impairment of GSIS in perifused islets. Islets were harvested from fed
(postabsorptive) EU or HT rats fed either a standard (low fat) diet (C) or a
high-fat diet (HF). Patterns of GSIS are shown for perifused islets from EU (A)
or HT (B) rats. CF: 1, 2, 3, and 4 values. Data are means SE for 10
EU rats, 6 HT rats, 5 EU-HF rats, and 5 HT-HF rats. Statistically significant
effects of hyperthyroidism: ***P 0.001. Statistically significant effects of
48-h starvation: P 0.05, P 0.01, P 0.001. fat feeding from enhancing islet function to an extent sufficient
in vivo and ex vivo (perifused pancreases) (21, 26). GSIS
in vivo after a glucose bolus was also significantly reduced by
48-h starvation in HT rats. However, studies in vitro using
perifused islets revealed that hyperthyroidism partially op-
posed the effects of starvation to increase the glucose threshold
for GSIS and lower glucose responsiveness. Since TRs and
PPAR both heterodimerize with the RXR, this may reflect
competition between the liganded TR and PPAR for the
RXR, with TR blocking or attenuating PPAR signaling and
consequent changes in the characteristics of GSIS during
starvation. Since starvation reduced GSIS in HT rats in vivo
whereas insulin secretion by isolated islets from HT rats was
AJP-Endocrinol Metab VOL 295 DECEMBER 2008
E1387
largely unaffected by starvation, in vivo factors may feed back
peripheral effects of hyperthyroidism to the islet.
Studies undertaken with the INS-1E -cell line indicate that
endogenous RXR levels may, under certain circumstances, be
limiting for the action of heterodimerization partners (e.g.,
PPAR) and that sequestration of RXR from other nuclear
receptors can occur in the presence of high levels of het-
erodimerization partners (29). To investigate potential conse-
quences of competition between liganded TR and PPAR for
the RXR, the PPAR agonist WY14643 was administered to
EU and HT rats. PPAR activation in fed EU rats does not
affect GSIS during islet perifusions in vitro or after intravenous
glucose challenge in vivo (16). In contrast, studies in vivo and
in perifused islets demonstrated that WY14643 administration,
with sampling after 24 h, restored glucose tolerance and
ensured appropriate insulin secretion in fed HT rats. PPAR
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activation increases the glucose threshold for GSIS, diminish-
ing insulin secretion at low glucose concentrations, while
PPAR overexpression in -cell lines inhibits GSIS (13, 15,
37). Administration of WY14643 after 24-h fasting, with
sampling after 24 h, had no further significant effect on GSIS
in vitro in EU rats beyond that induced by fasting (15). In
contrast, WY14643 treatment in vivo during starvation re-
lieved the impact of hyperthyroidism to partially oppose the
effects of starvation to increase the glucose threshold for GSIS
and lower glucose responsiveness of insulin secretion in peri-
fused islets in vitro. This observation indicates that competition
between the liganded TR and PPAR influences the charac-
teristics of GSIS. In fasted HT rats, in vivo factors transmitting
peripheral effects of hyperthyroidism to the islet that oppose
direct effects of hyperthyroidism on the islet may include (as
yet unidentified) PPAR agonists.
We also examined interactions between hyperthyroidism
and increased dietary lipid. Although hyperthyroidism induced
insulin resistance in rats maintained on standard diet, it pre-
cluded sufficient enhancement of insulin secretion to maintain
glucose tolerance. Antecedent high-fat feeding for 4 wk before
treatment with T3 for the last 3 days of the protocol (HT-HF
group) augmented GSIS in vivo compared with the HT group;
however, glucose tolerance deteriorated. Thus the failure to
augment insulin secretion in vivo in HT rats maintained on
standard diet to an extent sufficient to normalize glucose
tolerance is retained when HT rats are maintained on high-fat
diet, but at a higher level of insulin secretion. These data
suggest that increased dietary lipid facilitates insulin hyperse-
cretion in vivo. Nevertheless, hyperthyroidism precludes high-
to oppose the degree of insulin resistance. In EU rats high-fat
feeding elicited a dramatic increase in GSIS in perifused islets,
indicating that enhanced GSIS in vivo reflected a stable effect
on islet function. In contrast, GSIS was impaired in perifused
islets from HT rats maintained on high-fat diet compared with
HT rats maintained on low-fat diet. This indicates that hyper-
thyroidism elicits an intrinsic malfunction of the pancreatic
islet. Because insulin secretion in vivo was also enhanced in
the hyperthyroid state by antecedent PPAR activation and, in
liver, dietary FAs (new fat) act as endogenous activators of
PPAR (4), our data suggest that dietary FAs may also activate
islet PPAR and that liganded PPAR evokes changes in gene
expression that augment GSIS in the hyperthyroid state, pos-
sibly by competing with liganded TR for RXR and thereby
www.ajpendo.org
E1388 PPAR AND LIPID OPPOSE THYROID SIGNALING TO GSIS
opposing the effects of TR signaling to suppress insulin secre-
tion.
In summary, we demonstrate that hyperthyroidism markedly
modifies islet function in states associated with altered char-
acteristics of insulin secretion. Hyperthyroidism modifies islet
function by decreasing glucose responsiveness of GSIS to the
extent that it preludes sufficient enhancement of insulin secre-
tion for the degree of insulin resistance that is induced in the
hyperthyroid state, both in rats maintained on a low-fat/high-
carbohydrate diet and in rats fed a high-fat/low-carbohydrate
diet. However, the impact of hyperthyroidism on islet function
in the fed state can be overcome by adequate activation of
PPAR. Hyperthyroidism also partially opposes starvation-
induced increases in the glucose threshold for GSIS and de-
creases in glucose responsiveness, effects relieved by in vivo
exposure to an exogenous PPAR agonist during starvation.
These observations suggest that competition may exist between
the liganded TR and PPAR and emphasize the role of in-
creased islet PPAR signaling and suppression of T3 levels
during starvation to facilitate appropriate modification of islet
function.
GRANTS
This study was supported in part by project grants from the Wellcome Trust
(060965) and Diabetes UK (BDA:RD04/0002863 and BDA:RD06/0003424).
G. K. Greenwood was a recipient of a Diabetes UK studentship.
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