General Information:

Id: 3,622
Diseases: Diabetes mellitus, type II - [OMIM]
Hyperthyroidism
Hypothyroidism
Insulin resistance
Mammalia
review
Reference: Brenta G(2011) Why can insulin resistance be a natural consequence of thyroid dysfunction? J Thyroid Res 2011 [PMID: 21941681]

Interaction Information:

Comment Thyroid hormones exert both insulin agonistic and antagonistic actions in different organs. However, this occurs in a fine balance necessary for normal glucose metabolism. Deficit or excess of thyroid hormones can break this equilibrium leading to alterations of carbohydrate metabolism.
Formal Description
Interaction-ID: 34250

affects_activity of

Comment An increase in glucose-6-phosphatase mRNA expression with T3 was reported. This enzyme hydrolyzes glucose-6-phosphate and completes the final step in gluconeogenesis and glycogenolysis, therefore playing an important role in the homeostatic regulation of blood glucose levels.
Formal Description
Interaction-ID: 34259

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

G6PC

in liver
Comment An increase in glucose-6-phosphatase mRNA expression with T3 was reported. This enzyme hydrolyzes glucose-6-phosphate and completes the final step in gluconeogenesis and glycogenolysis, therefore playing an important role in the homeostatic regulation of blood glucose levels.
Formal Description
Interaction-ID: 34260

gene/protein

G6PC

increases_activity of

process

gluconeogenesis

Comment An increase in glucose-6-phosphatase mRNA expression with T3 was reported. This enzyme hydrolyzes glucose-6-phosphate and completes the final step in gluconeogenesis and glycogenolysis, therefore playing an important role in the homeostatic regulation of blood glucose levels.
Formal Description
Interaction-ID: 34261

gene/protein

G6PC

increases_activity of

Comment An increase in glucose-6-phosphatase mRNA expression with T3 was reported. This enzyme hydrolyzes glucose-6-phosphate and completes the final step in gluconeogenesis and glycogenolysis, therefore playing an important role in the homeostatic regulation of blood glucose levels.
Formal Description
Interaction-ID: 34263

gene/protein

G6PC

affects_activity of

Comment T3 decreased the mRNA expression of Akt2 (protein kinase B), a serine/threonine kinase that is an essential molecule in the insulin signaling pathway. Akt2 has been shown to promote glycogen synthesis in liver by inactivating glycogen synthase kinase 3. Thus, a decrease in Akt2 activity would decrease glycogen synthesis explaining the antagonistic insulin effect of thyroid hormones at the liver.
Formal Description
Interaction-ID: 34265

drug/chemical compound

Triiodothyronine

decreases_expression of

gene/protein

AKT2

in liver
Drugbank entries Show/Hide entries for AKT2
Comment T3 decreased the mRNA expression of Akt2 (protein kinase B), a serine/threonine kinase that is an essential molecule in the insulin signaling pathway. Akt2 has been shown to promote glycogen synthesis in liver by inactivating glycogen synthase kinase 3. Thus, a decrease in Akt2 activity would decrease glycogen synthesis explaining the antagonistic insulin effect of thyroid hormones at the liver.
Formal Description
Interaction-ID: 34266

gene/protein

AKT2

increases_activity of

via inactivation of glycogen synthase kinase 3
Drugbank entries Show/Hide entries for AKT2
Comment An induction of beta2-adrenergic receptor mRNA and repression of inhibitory G protein (Gi) RNA of the adenylate cyclase cascade by T3 were also reported.
Formal Description
Interaction-ID: 34267

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

ADRB2

in liver
Drugbank entries Show/Hide entries for ADRB2
Comment An induction of beta2-adrenergic receptor mRNA and repression of inhibitory G protein (Gi) RNA of the adenylate cyclase cascade by T3 were also reported.
Formal Description
Interaction-ID: 34270

drug/chemical compound

Triiodothyronine

decreases_expression of

gene/protein

GNAI1

in liver
Drugbank entries Show/Hide entries for GNAI1
Comment Other hepatic gluconeogenic enzymes that have been found to be positively regulated by thyroid hormones include phosphoenolpyruvate carboxykinase (PEPCK), the enzyme that catalyzes the rate-controlling step of gluconeogenesis and pyruvate carboxylase, involved in the synthesis of oxaloacetate from pyruvate. The catalytic activity of pyruvate carboxylase has been found increased approximately 2-fold in hyperthyroid rats compared with untreated or treated euthyroid controls.
Formal Description
Interaction-ID: 34275

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

PCK1

in liver
Drugbank entries Show/Hide entries for PCK1
Comment Other hepatic gluconeogenic enzymes that have been found to be positively regulated by thyroid hormones include phosphoenolpyruvate carboxykinase (PEPCK), the enzyme that catalyzes the rate-controlling step of gluconeogenesis and pyruvate carboxylase, involved in the synthesis of oxaloacetate from pyruvate. The catalytic activity of pyruvate carboxylase has been found increased approximately 2-fold in hyperthyroid rats compared with untreated or treated euthyroid controls.
Formal Description
Interaction-ID: 34279

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

PC

in liver
Drugbank entries Show/Hide entries for PC
Comment Another mechanism, whereby thyroid hormones are known to increase hepatic glucose output, is through increased hepatic expression of the glucose transporter GLUT2 as previously shown in a rat model where GLUT2 protein concentration in crude liver membranes was twice as high in chronically hyperthyroid versus hypothyroid animals.
Formal Description
Interaction-ID: 34282

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

SLC2A2

in liver
Drugbank entries Show/Hide entries for SLC2A2
Comment T3 induces lipogenesis through the transcriptional activation of malic enzyme, involved in fatty acid synthesis.
Formal Description
Interaction-ID: 34284

drug/chemical compound

Triiodothyronine

increases_activity of

in liver; via increased ME activity
Comment T3 induces lipogenesis through the transcriptional activation of malic enzyme, involved in fatty acid synthesis.
Formal Description
Interaction-ID: 34286

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

ME

in liver
Comment T3 induces carbohydrate-response element-binding protein (ChREBP) in liver and fat tissue.
Formal Description
Interaction-ID: 34293

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

MLXIPL

in liver, in adipose tissue
Comment In skeletal muscle, the main site of insulin-mediated glucose disposal, glucose transporter GLUT4, is induced by T3, revealing that it can increase basal and insulin-stimulated glucose transport in this tissue.
Formal Description
Interaction-ID: 34308

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

SLC2A4

in skeletal muscle
Comment In skeletal muscle, the main site of insulin-mediated glucose disposal, glucose transporter GLUT4, is induced by T3, revealing that it can increase basal and insulin-stimulated glucose transport in this tissue.
Formal Description
Interaction-ID: 34310

gene/protein

SLC2A4

increases_activity of

process

glucose import

in skeletal muscle
Comment Another T3 target in skeletal muscle is mitochondrial uncoupling protein 3 (UCP3). Unveiling this association may be important since progressive reduction of UCP3 levels results in insulin resistance accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling. Although discrepancies between the regulation by T3 of UCP3 expression in rats, humans, and mice have been observed, the rat model has shed some light into T3 actions in this tissue. T3 intravenous (i.v.) administration in hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle. These findings point to UCP as a possible molecular determinant of the action of T3 on energy metabolism.
Formal Description
Interaction-ID: 34311

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

UCP3

in skeletal muscle
Comment Another T3 target in skeletal muscle is mitochondrial uncoupling protein 3 (UCP3). Unveiling this association may be important since progressive reduction of UCP3 levels results in insulin resistance accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling. Although discrepancies between the regulation by T3 of UCP3 expression in rats, humans, and mice have been observed, the rat model has shed some light into T3 actions in this tissue. T3 intravenous (i.v.) administration in hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle. These findings point to UCP as a possible molecular determinant of the action of T3 on energy metabolism.
Formal Description
Interaction-ID: 34312

gene/protein

UCP3

affects_activity of

disease

Insulin resistance

in skeletal muscle
Comment Another T3 target in skeletal muscle is mitochondrial uncoupling protein 3 (UCP3). Unveiling this association may be important since progressive reduction of UCP3 levels results in insulin resistance accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling. Although discrepancies between the regulation by T3 of UCP3 expression in rats, humans, and mice have been observed, the rat model has shed some light into T3 actions in this tissue. T3 intravenous (i.v.) administration in hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle. These findings point to UCP as a possible molecular determinant of the action of T3 on energy metabolism.
Formal Description
Interaction-ID: 34313

gene/protein

UCP3

increases_activity of

Comment Another T3 target in skeletal muscle is mitochondrial uncoupling protein 3 (UCP3). Unveiling this association may be important since progressive reduction of UCP3 levels results in insulin resistance accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling. Although discrepancies between the regulation by T3 of UCP3 expression in rats, humans, and mice have been observed, the rat model has shed some light into T3 actions in this tissue. T3 intravenous (i.v.) administration in hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle. These findings point to UCP as a possible molecular determinant of the action of T3 on energy metabolism.
Formal Description
Interaction-ID: 34314

gene/protein

UCP3

increases_activity of

Comment Another T3 target in skeletal muscle is mitochondrial uncoupling protein 3 (UCP3). Unveiling this association may be important since progressive reduction of UCP3 levels results in insulin resistance accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling. Although discrepancies between the regulation by T3 of UCP3 expression in rats, humans, and mice have been observed, the rat model has shed some light into T3 actions in this tissue. T3 intravenous (i.v.) administration in hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle. These findings point to UCP as a possible molecular determinant of the action of T3 on energy metabolism.
Formal Description
Interaction-ID: 34316

gene/protein

UCP3

increases_activity of

process

AMPK signaling pathway

Comment In human adipocytes, T3 increases the mRNA levels of the lipolytic beta2-adrenergic receptor, favouring catecholamine-induced lipolysis and it also downregulates Sterol regulatory element binding protein (SREBP1c), involved in lipogenesis, which may constitute a link between hyperthyroidism and insulin resistance.
Formal Description
Interaction-ID: 34317

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

ADRB2

in adipose tissue
Drugbank entries Show/Hide entries for ADRB2
Comment In human adipocytes, T3 increases the mRNA levels of the lipolytic beta2-adrenergic receptor, favouring catecholamine-induced lipolysis and it also downregulates Sterol regulatory element binding protein (SREBP1c), involved in lipogenesis, which may constitute a link between hyperthyroidism and insulin resistance.
Formal Description
Interaction-ID: 34319

gene/protein

ADRB2

increases_activity of

in adipose tissue
Drugbank entries Show/Hide entries for ADRB2
Comment In human adipocytes, T3 increases the mRNA levels of the lipolytic beta2-adrenergic receptor, favouring catecholamine-induced lipolysis and it also downregulates Sterol regulatory element binding protein (SREBP1c), involved in lipogenesis, which may constitute a link between hyperthyroidism and insulin resistance.
Formal Description
Interaction-ID: 34320

drug/chemical compound

Triiodothyronine

decreases_expression of

mRNA/protein variant

SREBF1c

in adipose tissue
Comment In human adipocytes, T3 increases the mRNA levels of the lipolytic beta2-adrenergic receptor, favouring catecholamine-induced lipolysis and it also downregulates Sterol regulatory element binding protein (SREBP1c), involved in lipogenesis, which may constitute a link between hyperthyroidism and insulin resistance.
Formal Description
Interaction-ID: 34321

mRNA/protein variant

SREBF1c

affects_activity of

in adipose tissue
Comment In cultured human fibroblasts, the mRNA of the transcription factor HIF-1alpha (Hypoxia-inducible factor 1), a key mediator of glycolysis, increased in response to T3. As the glucose transporter GLUT1, several enzymes of glycolysis, and the lactate exporter SLC16A3 were all also found induced by T3 and as they are target genes of the transcription factor HIF-1alpha, the authors postulated that the effect of thyroid hormones on the induction of these genes most probably was indirect and HIF-1alpha mediated.
Formal Description
Interaction-ID: 34322

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

HIF1A

in fibroblasts
Drugbank entries Show/Hide entries for HIF1A
Comment In cultured human fibroblasts, the mRNA of the transcription factor HIF-1alpha (Hypoxia-inducible factor 1), a key mediator of glycolysis, increased in response to T3. As the glucose transporter GLUT1, several enzymes of glycolysis, and the lactate exporter SLC16A3 were all also found induced by T3 and as they are target genes of the transcription factor HIF-1alpha, the authors postulated that the effect of thyroid hormones on the induction of these genes most probably was indirect and HIF-1alpha mediated.
Formal Description
Interaction-ID: 34324

gene/protein

HIF1A

affects_activity of

Drugbank entries Show/Hide entries for HIF1A
Comment In cultured human fibroblasts, the mRNA of the transcription factor HIF-1alpha (Hypoxia-inducible factor 1), a key mediator of glycolysis, increased in response to T3. As the glucose transporter GLUT1, several enzymes of glycolysis, and the lactate exporter SLC16A3 were all also found induced by T3 and as they are target genes of the transcription factor HIF-1alpha, the authors postulated that the effect of thyroid hormones on the induction of these genes most probably was indirect and HIF-1alpha mediated.
Formal Description
Interaction-ID: 34325

gene/protein

HIF1A

increases_expression of

gene/protein

SLC2A1

Drugbank entries Show/Hide entries for HIF1A
Comment In cultured human fibroblasts, the mRNA of the transcription factor HIF-1alpha (Hypoxia-inducible factor 1), a key mediator of glycolysis, increased in response to T3. As the glucose transporter GLUT1, several enzymes of glycolysis, and the lactate exporter SLC16A3 were all also found induced by T3 and as they are target genes of the transcription factor HIF-1alpha, the authors postulated that the effect of thyroid hormones on the induction of these genes most probably was indirect and HIF-1alpha mediated.
Formal Description
Interaction-ID: 34326

gene/protein

HIF1A

increases_expression of

gene/protein

SLC16A3

Drugbank entries Show/Hide entries for HIF1A or SLC16A3
Comment T3 bound to TRbeta, in lieu of initiating gene transcription in the nucleus, activates the phosphatidylinositol 3-kinase (PI3K) signaling pathway in the cytosol in order to activate HIF-1alpha gene expression.
Formal Description
Interaction-ID: 34327

drug/chemical compound

Triiodothyronine

increases_activity of

Comment PPAR gamma coactivator-1 alpha (PGC-1 alpha), a key transcriptional regulator of mitochondrial content and function, fatty acid oxidation, and gluconeogenesis, has been involved in the process whereby thyroid hormones regulate mitochondrial function. It has been shown that PGC-1 alpha gene expression is increased by T3, as much as 13-fold 6 hours after T3 treatment.
Formal Description
Interaction-ID: 34328

drug/chemical compound

Triiodothyronine

increases_expression of

gene/protein

PPARGC1A

Comment A lower expression and activity of type 2 iodothyronine-deiodinase (D2), the enzyme that is key for the conversion of T4 into T3 in muscle and thus, amplifies thyroid hormone signaling in individual cells, has been found linked to insulin resistance. Bile acids are potent stimulators of the enzyme and may play an important role in the relationship between thyroid action and glucose metabolism. On the other hand, the natural occurrence of polymorphisms of deiodinase type 2 such as Thr92Ala, with a lower activity, has also been implicated with increased risk for diabetes type 2.
Formal Description
Interaction-ID: 34329

gene/protein

DIO2

decreases_quantity of

drug/chemical compound

Thyroxine

in muscle
Comment A lower expression and activity of type 2 iodothyronine-deiodinase (D2), the enzyme that is key for the conversion of T4 into T3 in muscle and thus, amplifies thyroid hormone signaling in individual cells, has been found linked to insulin resistance. Bile acids are potent stimulators of the enzyme and may play an important role in the relationship between thyroid action and glucose metabolism. On the other hand, the natural occurrence of polymorphisms of deiodinase type 2 such as Thr92Ala, with a lower activity, has also been implicated with increased risk for diabetes type 2.
Formal Description
Interaction-ID: 34330

gene/protein

DIO2

increases_quantity of

drug/chemical compound

Triiodothyronine

in muscle
Comment A lower expression and activity of type 2 iodothyronine-deiodinase (D2), the enzyme that is key for the conversion of T4 into T3 in muscle and thus, amplifies thyroid hormone signaling in individual cells, has been found linked to insulin resistance. Bile acids are potent stimulators of the enzyme and may play an important role in the relationship between thyroid action and glucose metabolism. On the other hand, the natural occurrence of polymorphisms of deiodinase type 2 such as Thr92Ala, with a lower activity, has also been implicated with increased risk for diabetes type 2.
Formal Description
Interaction-ID: 34331

gene/protein

DIO2

affects_activity of

in muscle
Comment A lower expression and activity of type 2 iodothyronine-deiodinase (D2), the enzyme that is key for the conversion of T4 into T3 in muscle and thus, amplifies thyroid hormone signaling in individual cells, has been found linked to insulin resistance. Bile acids are potent stimulators of the enzyme and may play an important role in the relationship between thyroid action and glucose metabolism. On the other hand, the natural occurrence of polymorphisms of deiodinase type 2 such as Thr92Ala, with a lower activity, has also been implicated with increased risk for diabetes type 2.
Formal Description
Interaction-ID: 34332

gene/protein

DIO2

affects_activity of

disease

Insulin resistance

Comment A lower expression and activity of type 2 iodothyronine-deiodinase (D2), the enzyme that is key for the conversion of T4 into T3 in muscle and thus, amplifies thyroid hormone signaling in individual cells, has been found linked to insulin resistance. Bile acids are potent stimulators of the enzyme and may play an important role in the relationship between thyroid action and glucose metabolism. On the other hand, the natural occurrence of polymorphisms of deiodinase type 2 such as Thr92Ala, with a lower activity, has also been implicated with increased risk for diabetes type 2.
Formal Description
Interaction-ID: 34335

affects_activity of

Comment Thyrotoxic subjects frequently show impaired glucose tolerance. This is a result of increased glucose turnover with increased glucose absorption through the gastrointestinal tract, postabsorptive hyperglycemia, elevated hepatic glucose output, with elevated fasting and/or postprandial insulin and proinsulin levels, elevated free fatty acid concentrations and elevated peripheral glucose transport and utilization.
Formal Description
Interaction-ID: 34343

increases_activity of

Comment Thyrotoxic diabetic patients are more prone to ketosis.
Formal Description
Interaction-ID: 34345

increases_activity of

in diabetic patients
Comment Thyrotoxicosis has been reported to increase endogenous glucose production in the liver in the basal state and to decrease hepatic insulin sensitivity in humans. The different mechanisms to explain this phenomenon include increased rates of gluconeogenesis and glycogenolysis mainly explained by effects on the liver by thyroid hormones. These effects include thyroid receptor-mediated effects on liver gene transcription, increased sympathetic action in the liver mediated by hypothalamus, and increased concentrations of the GLUT2 glucose transporters in the liver plasma membrane that allows for glucose efflux together with increased concentration of free fatty acids in plasma.
Formal Description
Interaction-ID: 34346

increases_activity of

process

hepatic glucose production

Comment Alternative explanations for peripheral insulin resistance in hyperthyroidism include an increased secretion of bioactive mediators (adipokines) such as interleukin 6 (IL6) and tumour necrosis factor a (TNFalpha) from adipose tissue in hyperthyroidism. These adipokines, that exert both proinflammatory and insulin resistant effects, have been found elevated in hyperthyroid women.
Formal Description
Interaction-ID: 34355

increases_expression of

gene/protein

IL6

Drugbank entries Show/Hide entries for IL6
Comment Alternative explanations for peripheral insulin resistance in hyperthyroidism include an increased secretion of bioactive mediators (adipokines) such as interleukin 6 (IL6) and tumour necrosis factor a (TNFalpha) from adipose tissue in hyperthyroidism. These adipokines, that exert both proinflammatory and insulin resistant effects, have been found elevated in hyperthyroid women.
Formal Description
Interaction-ID: 34356

increases_expression of

gene/protein

TNF

Drugbank entries Show/Hide entries for TNF
Comment In hyperthyroidism, decreased, normal, or even increased levels of plasma insulin have been reported. However, a rather consistent finding has been the increased degradation of insulin in hyperthyroid subjects.
Formal Description
Interaction-ID: 34357

increases_activity of

Comment With regards to glucagon, its secretion and metabolic clearance rates have been reported increased, explaining the normal fasting plasma levels described in hyperthyroidism.
Formal Description
Interaction-ID: 34358

increases_activity of

Comment With regards to glucagon, its secretion and metabolic clearance rates have been reported increased, explaining the normal fasting plasma levels described in hyperthyroidism.
Formal Description
Interaction-ID: 34359

increases_activity of

process

glucagon clearance

Comment Subclinical hyperthyroidism has also been associated with insulin resistance in some but not all studies. The heterogenous nature of this condition can partly explain this controversy. Endogenous subclinical hyperthyroidism may have a larger impact on glucose metabolism due to its chronicity and higher T3 levels when compared to exogenous administration of T4.
Formal Description
Interaction-ID: 34361

phenotype

decreased activity of thyroid gland, subclinical

affects_activity of

disease

Insulin resistance

Comment Hypothyroidism can also lead to insulin resistance.
Formal Description
Interaction-ID: 34362

increases_activity of

disease

Insulin resistance

Comment In adipocytes and skeletal muscle of mature rats rendered hypothyroid by a low iodine diet and propylthiouracil, it was observed that glucose conversion to glycogen was partially inhibited while the glycolytic flux stimulation by insulin was totally frustrated.
Formal Description
Interaction-ID: 34363

decreases_activity of

Comment Decreased insulin-stimulated glucose transport and/or phosphorylation, as well as a lower rate of glycolysis was found in the isolated, incubated soleus muscle of the hypothyroid rat.
Formal Description
Interaction-ID: 34364
Comment Decreased insulin-stimulated glucose transport and/or phosphorylation, as well as a lower rate of glycolysis was found in the isolated, incubated soleus muscle of the hypothyroid rat.
Formal Description
Interaction-ID: 34365

decreases_activity of

in muscle
Comment Plasma leptin levels were lower and adipose tissue mRNA expression of resistin higher, in the hypothyroid state.
Formal Description
Interaction-ID: 34366
Comment Plasma leptin levels were lower and adipose tissue mRNA expression of resistin higher, in the hypothyroid state.
Formal Description
Interaction-ID: 34367

increases_expression of

gene/protein

RETN

in adipose tissue