THs constitute important mediators of body metabolism and affect various metabolic aspects involving glucose and insulin metabolism, through a variety of mechanisms. In SM, triiodothyronine (T₃) regulates muscle fiber type and mitochondrial content through a genomic action, consisting in a direct modulation of gene transcription by ligand-dependent activation of TH receptors (TRs) and specific TH response elements (TREs). Other TH effects, such as modulation of ion channel activity, intracellular Ca²⁺ mobilization, phospholipase, and kinase activation, have been attributed to nongenomic actions of TH. This mode of action explained the TH-induced activation of a signaling cascade involving phospholipase C activation, inositol triphosphate (IP3) accumulation, intracellular Ca²⁺ mobilization and phosphorylation of protein kinase C (PKC) resulting ultimately in activation of plasma membrane Na⁺/H⁺ exchangers and increased intracellular pH in rat SM cells⁹. Furthermore, with the same mode of action, T₃ induces a rapid phosphorylation of both p38 and AMPK (AMP-dependent kinase) in SM fibers and stimulates mitochondrial biogenesis¹⁰. Thus lower the TH levels in plasma lower the sensitivity of tissues to insulin. It is known that T₃ and insulin have a synergistic role in glucose homeostasis, since these hormones possess similar action sites in the regulation of glucose metabolism, at both cellular and molecular levels¹¹. It could therefore be hypothesized that a reduced or increased intracellular content of T₃ could lead to an impaired insulin stimulated glucose disposal. Thus, even subtle decreases or increases in the levels of THs within the physiological range have been shown to correlate inversely with the marker of IR¹².

INSULIN RESISTANCE:

IR is a common pathological state in which target tissues fail to respond properly to normal levels of circulating insulin. Pancreatic β-cells first compensate for peripheral insulin resistance by increasing insulin secretion to maintain euglycaemia. Thereafter, impaired glucose tolerance can develop, leading to overt clinical type 2 diabetes. IR is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and it’s binding to phosphoinositide 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin stimulated glucose transport. Various studies have implicated lipids as a cause of IR in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumor necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1⁷⁸.

INTERLINKING BETWEEN THYROID DISORDER AND INSULIN RESITANCE:

HYPERTHYROIDISM AND INSULIN RESISTANCE:

Hyperthyroidism (HR) is associated with metabolic abnormalities, including disorders of the glucose and insulin metabolism and affect glucose homeostasis¹³. [Figure 1.]

Figure 1: Thyrotoxicosis and glucose homeostasis

Free fatty acid (FFA) induced IR:

Thyrotoxic patients show an elevated FFA concentrations which further favours development of IR by various mechanism like impaired insulin-mediated glucose uptake^14,15. Acute elevations of plasma FFA levels for 5 h induce skeletal muscle IR in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of Protein Kinase-C (PKC)¹⁶. On the other hand chronic elevation in plasma FFA levels is commonly associated with impaired insulin-mediated glucose uptake^17,18. According to the lipid supply hypothesis, the increased FFA availability provides the predominant substrate for intermediate metabolism, resulting in increased NADH/NAD⁺ and acetyl-CoA/CoA ratios. Elevated FFA concentrations promote beta-oxidation, which diminishes glucose uptake and oxidation. In parallel, FFA clearance is decreased and their storage as triglyceride droplets in SM in the form of intramyocellular triglycerides (IMTG) is significantly enhanced^19,20. IR in HR by IMTG accumulation can be explained by two mechanisms forward and backward.

As shown in figure 2. by the forward mechanism, IMTG is at a hyper dynamic state characterized by accelerated synthesis²¹ and turnover²² in the earlier stages of metabolic complications such as obesity. This increases the flux and availability of intramyocellular fatty acids (FA/LCFA), DAG, LCACoA and ceramides and thus signaling via PKC system, and promotes mitochondrial β-oxidation. As a result the activity of PI 3-kinase, a key regulator of GLUT4 translocation in muscle leading to increased glucose transport, was found to be reduced in the increased FFA level state²³. Such a reduction in PI 3-kinase activity may occur as a consequence of reduced IRS-1 tyrosine phosphorylation. This in turn would lead to reduced coassociation of PI 3-kinase and IRS-1 and therefore reduced activation of IRS-1 associated PI 3-kinase activity which atlast impairs insulin signalling and impairment of GLUT4 translocation all of which results in reduced insulin-mediated glucose uptake (MIR)¹⁶. Over time, the overloading of mitochondria by β-oxidation gradually causes mitochondrial damages and dysfunctions (MD) via mechanisms such as oxidative stress and DNA damage. When this occurs, mitochondrial β-oxidation reduces. At this stage (e.g. T2D or advanced aging), the backward mechanism prevails. The decline in fatty acid oxidation causes IMTG to accumulate. Also ceramide (which is one of the breakdown product of IMTG) accumulation in skeletal muscle was inversely related to insulin sensitivity. The level of ceramide is markedly elevated in the hyperthyroid liver via the activation of acidic spingomilinase and lipid synthesis and also directly preventing ceramide degradation. This may directly lead IR as it was found that total as well as saturated and unsaturated ceramide content was approximately twofold higher in IR skeletal muscle in animal model as well as human subjects^24,25.

TNF- α and IL-6 and its role in development of IR:

Adipose tissue (AT) is an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a number of bioactive mediators (adipokines) such as interleukin 6 (IL6) and tumor necrosis factor (TNF- α)²⁶.

High circulating TNF-α and IL-6 concentrations are associated with obesity and IR. Increased TNF-α serum concentration have been observed in type 2 diabetes mellitus²⁷. High circulating IL-6 concentrations have also been connected with components of the metabolic syndrome, especially with IR²⁸. In HR both TNF- α and IL-6 levels in serum were found to be elevated²⁹. As regards to the mechanisms, TNF-α directly increases the serine phosphorylation of IRS-1 which inhibits insulin-stimulated tyrosine phosphorylation which modulates the interaction between IRS-1 and PI 3-kinase and/or its activation and impairs insulin signalling^30,31,36. TNF-α-mediated FFA release impairs insulin-signaling in insulin responsive peripheral tissues such as SM^19,37. Interfere with insulin signaling^30,31 and IL-6 has been shown to increase blood glucose through elevated hepatic glucose output^32,33. Increased IL-6 levels have been linked to inhibition of hepatic glycogen synthase, activation of glycogen phosphorylase and lipolysis, and increased triglyceride production^33,34. IL-6 can cause cellular insulin resistance in both the HepG2 cell line and primary hepatocytes. IL-6 is shown to exert an inhibitory effect on both early insulin receptor (IR) signal transduction and downstream insulin action, specifically glycogen synthesis all causing IL-6–induced insulin resistance at the cellular level.³⁵

Increased sympathetic activity and IR:

HR has been associated with an increased activity and density of β-adrenergic receptor in SM^38,39. This increased in sympathetic activity can cause IR by lowering the phosphatidylinositol (PI) 3-kinase activity in 3T3-L1 adipocytes to reduce insulin-stimulated GLUT4 translocation to the plasma membrane and finally the glucose uptake^40-42.

Glucose disposal:

Glucose disposal at the level of muscle appears increased, not decreased, compared with what is observed in euthyroid counterparts⁴³. This apparent contradiction may be explained by specific changes in SM glucose metabolism that occur in thyrotoxicosis, including increased rates of nonoxidative and oxidative glucose disposal and increased non–insulin-dependent glucose transport. [Figure 3].

Figure 3: Effects of excess thyroid hormone at the level of the skeletal muscle. During thyrotoxicosis, skeletal muscle glucose use is increased, owing to increases in oxidative and nonoxidative metabolic pathways. However, overall glucose disposal is decreased because of decreased glycogen synthesis and increased hepatic glucose synthesis from increased Cori cycle metabolism. GLUT indicates glucose transporter.

Overall measured nonoxidative glucose disposal is increased in HR. Nonoxidative glucose disposal is determined by 2 distinct processes: (a) glucose conversion to pyruvate, forming lactate via anaerobic metabolism instead of entering the Krebs cycle and (b) glycogen formation. Under hyperthyroid conditions, insulin in muscle tissue cannot properly stimulate glycogen synthesis, leading to an overall depletion of glycogen stores. Loss of glycogen synthesis results in greater amounts of pyruvate formation which then overwhelms the Krebs cycle. The resulting production of lactate feeds into the Cori cycle to promote hepatic gluconeogenesis. Taken together, oxidative and nonoxidative glucose disposal are increased, yet these increases are independent of insulin signaling. Moreover, since the major nonoxidative glucose disposal pathway becomes the Cori cycle, glucose is not “disposed of” in the muscle, but rather cycled back to liver for gluconeogenesis. Thus, the net effect of altered glucose disposal in the skeletal muscle is hyperglycemia independent of elevated insulin levels, contributing to the elevated homeostasis modeling assessments of IR seen in HR patients⁴⁴.

Altered Glucose Transport and Delivery:

A main mechanism leading to decreased effectiveness of insulin signaling in HR may be related to glucose transport proteins. GLUT-4, the primary insulin mediated complex allowing for glucose influx into SM cells, has been demonstrated to be at near maximum concentrations on the cell surface in HR independent of insulin levels thought to be a direct affect of T₃⁴⁴. Although insulin has been demonstrated to slightly increase GLUT-4 expression in HR intracellular pools of GLUT-4 are nearly depleted in the hyperthyroid state^45,46. Insulin cannot recruit enough transporters to the cell surface to increase intracellular glucose transit, which contributes to apparent IR. In the hyperthyroid state, non–insulin-dependent glucose transport takes on a more important role in the energy balance of skeletal muscle. One such pathway involves insulin like growth factor 1 (IGF-1). In monocytes isolated from hyperthyroid patients, exposure to IGF-1 directly increases surface GLUT-3 and GLUT-4, whereas insulin fails to increase GLUT-4 concentration⁴⁷. IGF-1 binding protein 1 is greatly increased in HPR, providing an increased circulation of IGF-1⁴⁸. The elevated levels of circulating IGF-1 may allow for increased influx of glucose into SM tissue, perhaps by altering glucose transporters other than GLUT-4, like GLUT-11.

Blood flow:

In HR there is increase in cardiac output which leads to increased blood flow and delivery of glucose to peripheral tissues causing decreased glucose uptake in hypothyroid tissue as compared to euthyroid tissue⁴⁹. There is lower glucose extraction from serum in proportion to increased blood flow⁵⁰.

β-cell in HR:

Insulin secretory capacity seems to be disrupted in HR, but the existing data are rather heterogeneous, suggesting increased, normal, or decreased insulin secretion. This estimation has been based on the measurement of circulating C-peptide levels. However, when individually derived C-peptide kinetic parameters were measured, the insulin secretory rate was significantly increased, possibly reflecting an increased response of β-cell to glucose, under increased TH levels. The limitation of these studies is the use of C-peptide as a marker of insulin secretion, which is biased, given its rapid clearance from the circulation in HR⁵¹. However, an increase in the β-cell mass in HR has been also reported⁵². In addition an increased insulin secretory response to epinephrine (increased plasma C-peptide) after T₃ administration, indicating an increased insulin secretory rate in HPR (Liggett et al., 1989).

HYPOTHYROIDISM AND INSULIN RESISTANCE:

Hypothyroidism (HO) has also been shown to affect the glucose homeostasis.[Figure 4.]

Free fatty acid induced IR:

Several studies have shown that plasma free fatty acid (FFA) concentration in HO is within normal range, while some studies suggest that hypothyroid patients have higher plasma FFA concentrations than the normal range⁵³. Increase in FFA concentration develops IR. A raised plasma FFA concentration has for sometimes been implicated in dietary-induced IR. This was thought to occur in the liver and muscle via the glucose fatty-acid cycle. Glycolysis, and hence glucose uptake, is inhibited by increases in acetyl-CoA and NADH derived from lipid and ketone substrate^54,55. More recently, however, it has been shown that when FFA levels are acutely elevated following lipid/heparin infusion, skeletal muscle glucose-6-phosphate levels fall below control levels, indicating inhibition of glucose transport/phosphorylation^54,56,57. Thus, raised plasma FFA availability may induce IR via inhibition of glucose transport, rather than inhibition of glycolysis via operation of the glucose fatty-acid cycle. The mechanism by which raised plasma FFA concentrations may inhibit insulin-stimulated glucose uptake in muscle is not yet fully understood and is likely to be polygenic^54,58. However, recent improvements in the ability to measure intramyocellular triglycerdies (IMTG) content in vivo have implicated these fatty acids stored within the muscle fibre as a in the IR–FFA relationship. increase in FFA was associated with acute increases in intramyocellular lipid-triglyceride (IMCL-TG) with a significant increase in IR. Lowering of plasma FFAs was associated with a tendency for IMCL-TG to decrease^59-61. IMCL-TG has been shown to be a metabolically active pool of fat^62-64 consisting of small oil droplets that are located in close proximity to mitochondria, thereby providing fuel for oxidation⁶⁵. Support for this is found via the observation that, in healthy subjects, inducing an increase in IMTG content via 4–5 h lipid/heparin infusion reduces whole-body sensitivity to insulin^66,67. This makes it unlikely that the decrease in fat oxidation was directly responsible for the IR⁵⁵. In addition, it has shown that IR produced by high-fat feeding in rats was unrelated to changes in fat oxidation⁶⁸. A more likely cause for IR may have been an increase in cytosolic long-chain acyl-CoA (LC-CoA) concentration associated with the synthesis or the lipolysis of (IMCL-TG). LC-CoA is known to increase diacylglycerol (DAG) and PKC. The latter can inhibit insulin action via serine-threonine phosphorylation of IRS-1⁶⁹. An acute increases of plasma FFAs cause IR with a 3- to 4-h delay^66,67. Thus various study claim that an increase in IMCL-TG content comprises a step in the FFA-induced development of IR. In vivo data, emerging from studies in propylthiouracil-induced hypothyroid animals during euglycemic-hyperinsulinemic clamps, showed an association of HP with an adipokine-mediated IR¹⁴.

TNF- α and IL-6 and its role in development of IR:

Also the important role of adipokines in IR, showing a meal-induced IL-6 increase, primarily involved in the observed IR, and a concomitant increase of TNF-α⁷⁰. Which may be further involved in one step developing IR as increase in level of TNF- α and IL-6 increases the level of FFA and develops IR detailed mechanism of which have already been explained in above part of this review.

Glucose disposal:

Studies in patients or rats with overt HO have shown the presence of IR due to impaired glucose disposal in peripheral tissues in response to insulin^14,44,71,72.

Altered Glucose Transport and Delivery:

IR was found to be comparable in both subclinical hypothyroidism (SHO) and overt hypothyroidism (HO). Insulin-stimulated glucose transport in monocytes from patients with HO and SHO was found to be decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane⁷⁰.

Blood flow:

It was noted that a meal-induced increase in plasma insulin levels in subjects with HP and an unchanged rate of glucose uptake in the forearm muscles and adipose tissue (AT) indicating that IR is possibly the result of diminished blood flow in AT and SM (Dimitriadis et al., 2006). Also there is decreased forearm and AT blood flow and glucose disposal rates in patients with HP, during euglycemic-hyperinsulinemic clamps⁷².

β-cell in HO:

HO is associated with a decreased glucose-induced insulin secretion by the β-cells due to changes in the physicochemical properties of the islet membranes and decreased amount of islets ^[73].An effect of TH on insulin receptors has been suggested, but the existing data are rather conflicting, supporting either no relationship between thyroid status and the affinity of insulin receptors or diminished high affinity insulin receptors (HAIRs) in HP⁷⁴. But subclinical HO (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL which are considered as major components of the dyslipidemia of IR^75,76. It has been demonstrated that the amount of insulin specifically bound and the number of insulin receptors per cell were inversely correlated with LDL level. The number of insulin receptors and the amount of insulin bound in the tested subjects with increased LDL were correspondingly low which may develop IR in HO⁷⁷.

Lower the thyroid hormone levels in plasma, the lower the sensitivity of tissues to insulin. It is known that T₃ and insulin have a synergistic role in glucose homeostasis, since these hormones possess similar action sites in the regulation of glucose metabolism, at both cellular and molecular levels¹¹. It could therefore be hypothesized that a reduced intracellular content of T₃ could lead to an impaired insulin stimulated glucose disposal. Interestingly, even subtle decreases in the levels of THs within the physiological range have been shown to correlate inversely with the Homeostatic model assessment (HOMA) index¹².

SUMMARY AND CONCLUSION:

In short to summarize thyroid disorder, including both hypo- and HR have been associated with IR due to various mechanism like altered insulin secretion, change in the insulin receptor affinity, altered blood flow altered peripheral glucose disposal, increased in TNF- increase in FFA and subsequent IMTG accumulation, impaired GLUT4 translocation, decrease glycogen synthesis obvious that, although HP and HPR constitute an insulin resistant state, more studies need to be done in order to clarify the underlying pathogenetic mechanisms. So it can be concluded that even subtle increase or decrease in the thyroid levels can lead to IR which is next step in the development of diabetes and other disorders.

REFERENCES:

1. Rohdenburg GL. Thyroid diabetes. Endocrinol. 4; 1920: 63.

2. Melpomeni P et al. Skeletal muscle insulin resistance in endocrine disease J Biomed Biotechnol. 2010.

3. Kumar HK et al., Association between thyroid hormones, insulin resistance and metabolic syndrome. Endocrine Abs. 19; 2009: 339.

4. Amati F et al., Improvements in insulin sensitivity are blunted by subclinical hypothyroidism. Med Sci Sports Exerc. 41 (2); 2009: 265-269.

5. Raboudi N et al. Fasting and postabsorptive hepatic glucose and insulin metabolism in hyperthyroidism. Am J Physiol.; 256 (1); 1989: E159-E166.

6. Weinstein SP et al., Regulation of GLUT2 glucose transporter expression in liver by thyroid hormone: evidence for hormonal regulation of the hepatic glucose transport system. Endocrinol. 135; 1994: 649-654.

7. Viguerie N et al., Regulation of human adipocyte gene expression by thyroid hormone. J Clin Endocrinol Metab. 87; 2002: 630-634.

8. Clement K et al., In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res. 12; 2002: 281-291.

9. D'Arezzo S et al., Rapid nongenomic effects of 3,5,3'-triiodo-L-thyronine on the intracellular pH of L-6 myoblasts are mediated by intracellular calcium mobilization and kinase pathways. Endocrinol. 145 (12); 2004: 5694-5703.

10. Irrcher I eta l., Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo. J Applied Physiol.104 (1); 2008: 178-185.

11. Kim SR et al., A hypothesis of synergism: the interrelationship of T3 and insulin to disturbances in metabolic homeostasis. Med Hypotheses. 59 (6); 2002: 660-66.

12. Roos A et al., Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 92 (2); 2007: 491-496.

13. Resmini E et al. Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. Acta Diabetol. 46 (2); 2009: 85-95.

14. Dimitriadis G et al., Glucose and lipid fluxes in the adipose tissue after meal ingestion in hyperthyroidism. J Clin Endocrinol Metab. 91 (3); 2006: 1112-1118.

15. Vinik AI, Pinstone BL, and Hoffenberg R. Studies on raised free fatty acids in hyperthyroidism. Metabolism. 19 (2); 1970: 93-101.

16. Griffin ME et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 48 (6); 1999: 1270-1274.

17. Frayn KN. Insulin resistance and lipid metabolism. Curr Opin Lipidol. (4); 1993:197–204.

18. Steiner G, Morita S, and Vranic M. Resistance to insulin but not to glucagon in lean human hypertriglyceridemics. Diabetes. 29; 1980: 899–905.

19. Peppa M et al., Skeletal muscle insulin resistance in endocrine disease. J Biomed Biotechnol. 2010.

20. DeFronzo RA et al.,Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 76 (1); 1985: 149–155.

21. Guo ZK, Jensen MD. Accelerated intramyocellular triglyceride synthesis in skeletal muscle of high-fat-induced obese rats. Intl J Obesity. 27; 2003: 1014-1019.

22. Zhou L, Guo ZK. Muscle type-dependent responses to insulin in intramyocellular triglyceride turnover in obese rats. Obes Res. 13; 2005: 2081-2087.

23. Okada T et al., Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes: studies with a selective inhibitor wortmannin. J Biol Chem. 269; 1994: 3568–3573.

24. Coen PM et al., Insulin Resistance Is Associated With Higher Intramyocellular Triglycerides in Type I but Not Type II Myocytes Concomitant With Higher Ceramide Content. Diabetes. 59 (1); 2010: 80-88.

25. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 45; 2006: 42–72.

26. Mohamed-Ali V, Pinkney JH and Coppack SW. Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity and Related Metabolic Disorders, 22; 1998: 1145–1158.

27. Katsuki A et al., Serum levels of tumor necrosis factor-alpha are increased in obese patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 83; 1998: 859–862.

28. Fernandez-Real JM et al., Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J. Clin. Endocrinol. Metab. 86; 2001: 1154–1159.

29. Ahmet K et al., Serum IL-6 and TNF-a in Patients With Thyroid Disorders. Tr. J. of Medical Sciences. 29; 1999: 25–29.

30. Hotamisligil GS et al., IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 271; 1996: 665–668.

31. Hotamisligil GS, Shargill NS, and Spiegelman, BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 259; 1993: 87–91.

32. Sundgren-Andersson AK, Ostlund P and Bartfai T. IL-6 is essential in TNF-alpha-induced fever. Am. J. Physiol. 275; 1998: R2028 –R2034,

33. Tsigos C et al., Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J. Clin. Endocrinol. Metab. 82; 1997: 4167 –4170.

34. Kanemaki T et al., Interleukin 1β and interleukin 6, but not tumor necrosis factorα, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. Hepatology. 87; 1998: 1296 –1303.

35. Senn JJ et al., Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 51; 2002: 3391-9.

36. Rui L et al., Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest. 107 (2); 2001: 181–189.

37. Pirola L, Johnston AM, and Van Obberghen E. Modulation of insulin action. Diabetologia. 47 (2); 2004: 170-184.

38. Liggett SB, Shah SD, and Cryer PE. Increased fat and skeletal muscle β-adrenergic receptors but unaltered metabolic and hemodynamic sensitivitiy to epinephrine in vivo in experimental human thyrotoxicosis. J Clin Invest. 83 (3); 1989: 803–809.

39. Martin WH et al., Skeletal muscle beta-adrenoceptor distribution and responses to isoproterenol in hyperthyroidism. Am J Physiol. 262 (4); 1992: E504-510.

40. Chiasson JL, Shikama H, Chu DT, Exton JH. Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle. J Clin Invest. 68; 1981: 706–713.

41. Mulder AH et al., Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation. Am J Physiol Endocrinol Metab. 289 (4); 2005: E627-633.

42. Lee AD et al., Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle. Am J Physiol Cell Physiol. 273; 1997: C1082–1087.

43. Dimitriadis GD, Raptis SA. Thyroid hormone excess and glucose intolerance. Exp Clin Endocrinol Diabetes. 109 (2); 2001: S225-239.

44. Bevan S et al. The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats. Eur J Clin Invest. 27(6); 1997: 475-83.

45. Weinstein SP, O'Boyle E, and Haber RS. Thyroid hormone increases basal and insulin-stimulated glucose transport in skeletal muscle. The role of GLUT4 glucose transporter expression. Diabetes. 43 (10); 1994: 1185-1189.

46. Dimitriadis G et al., Thyroid hormone excess increases basal and insulin-stimulated recruitment of GLUT3 glucose transporters on cell surface. Horm Metab Res. 37 (1); 2005: 15-20.

47. Maratou E et al., Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 160(5); 2009: 785-90.

48. Dimitriadis G et al., IGF-I increases the recruitment of GLUT4 and GLUT3 glucose transporters on cell surface in hyperthyroidism. Eur J Endocrinol. 158 (3); 2008: 361-366.

49. Jenkins RC et al., Association of elevated insulin-like growth factor binding protein-1 with insulin resistance in hyperthyroidism. Clin Endocrinol. 52 (2); 2000: 187-195.

50. Dimitriadis G et al., Insulin-stimulated rates of glucose uptake in muscle in hyperthyroidism: the importance of blood flow. J Clin Endocrinol Metab. 93 (6); 2008: 2413-2415.

51. Harris PE et al., Forearm muscle metabolism in primary hypothyroidism. Eur J Clin Invest. 23 (9); 1993: 585-588.

52. O'Meara NM et al., Alterations in the kinetics of C-peptide and insulin secretion in hyperthyroidism. J Clin Endocrinol Metab. 76 (1); 1993: 79-84.

53. Makino M et al., Effect of eicosapentaenoic acid ethyl ester on hypothyroid function. J Endocrinolo. 171 (2); 2001: 259-265.

54. Stannard SR, Johnson NA. Insulin resistance and elevated triglyceride in muscle: more important for survival than ‘thrifty’ genes?. J Physiol. 554 (3); 2004: 595–607.

55. Randle PJ et al., The glucose fatty-acid cycle: Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1; 1963: 785–789.

56. Roden M et al., Mechanism of free-fatty acid-induced insulin resistance in humans. J Clin Invest. 97; 1996: 2859–2865.

57. Krebs M et al., Free fatty acids inhibit the glucose-stimulated increase of intramuscular glucose-6-phosphate concentration in humans. J Clin Endocrinol Metab. 86; 2001: 2153–2160.

58. Kraegen EW, Cooney GJ. The role of free fatty acids in muscle insulin resistance. Diabetes Ann. 12; 1999: 141–159.

59. Boden J et al., Effects of Acute Changes of Plasma Free Fatty Acids on Intramyocellular Fat Content and Insulin Resistance in Healthy Subjects. Diabetes. 50 (7); 2001: 1612-1627.

60. Kayar SR et al., Acute effects of endurance exercise on mitochondrial distribution and skeletal muscle morphology. Eur J Appl Physiol. 54; 1986: 578–584.

61. Dagenais GR, Tancredi RG and Zierler KL. Free fatty acid oxidation by forearm muscle at rest, and evidence for an intramuscular lipid pool in the human forearm. J Clin Invest. 58; 1976: 421–431.

62. Madden MC et al., ¹H NMR spectroscopy can accurately quantitate the lipolysis and oxidation of cardiac triacylglycerols. Biochim Biophys Acta. 1169; 1993: 176 –182.

63. Vock R et al., Design of the oxygen and substrate pathways. VI. structural basis of intracellular substrate supply to mitochondria in muscle cells. J Exp Biol. 199; 1996: 1689–1697.

64. Taylor CR et al., High fat diet improves aerobic performance by building mitochondria. Physiologist. 37; 1994: A84.

65. Boden G et al., Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest. 88; 1991: 960–966.

66. Han DH et al., Insulin resistance of muscle glucose transport in rats fed a high-fat diet: a re-evaluation. Diabetes. 46; 1997: 1761–1767.

67. Prentki M, Corkey BE. Are the β-cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes. 45; 1996: 273–283.

68. Boden G et al., Mechanisms of fatty-acid induced inhibition of glucose uptake. J Clin Invest. 93; 1994: 2438–2446.

69. Momose M et al., Increased cardiac sympathetic activity in patients with hypothyroidism as determined by iodine-123 metaiodobenzylguanidine scintigraphy. Eur J Nucl Med., 24 (9); 1997: 1132-1137.

70. Mitrou P et al., Insulin resistance in hyperthyroidism: the role of IL6 and TNF alpha. Eur J Endocrinol. 162 (1); 2010: 121-126.

71. Cettour-Rose P et al., Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion. Diabetologia. 48 (4); 2005: 624-633.

72. Rochon C et al., Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism Clin Sci. 104 (1); 2003: 7-15.

73. Diaz GB et al., Changes induced by hypothyroidism in insulin secretion and in the properties of islet plasma membranes. Arch Int Physiol Biochim Biophys. 101 (5); 1993: 263-269.

74. Mackowiak P et al., The influence of hypo- and hyperthyreosis on insulin receptors and metabolism. Arch Physiol Biochem. 107 (4); 1999: 273-279.

75. Duntas LH. Thyroid disease and lipids. Thyroid. 12 (4); 2002: 287-293.

76. Howard BV. Insulin resistance and lipid metabolism. Am J Cardiol. 84 (1A); 1999: 28J-32J.

77. Sanghvi A et al., Differential suppression of lymphocyte cholesterol synthesis by low density lipoprotein and erythrocyte insulin receptors in normolipidemic subjects. Atherosclerosis. 49 (3); 1983: 307-318.

78. Gual P et al., Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem Soc Trans.31(6); 2003: 1152-56.

Received on 06.07.2011

Accepted on 31.08.2011

Research J. Pharmacology and Pharmacodynamics. 3(5): Sept –Oct. 2011, 234-240