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SAGE-Hindawi Access to Research Journal of Thyroid Research Volume 2011, Article ID 152850, 9 pages doi:10.4061/2011/152850

Review Article Why Can Insulin Resistance Be a Natural Consequence of Thyroid Dysfunction?
Gabriela Brenta
Department of Endocrinology, Dr. C´sar Milstein Hospital, La Rioja 951, C1221ACI, Buenos Aires, Argentina e Correspondence should be addressed to Gabriela Brenta,gbrenta@gmail.com Received 21 April 2011; Accepted 5 July 2011 Academic Editor: Masanobu Yamada Copyright © 2011 Gabriela Brenta. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Evidence for a relationship between T4 and T3 andglucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects ofthyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance.

1. Introduction
The effects of T4 and T3 have a large impact on glucose homeostasis. This concept was acknowledged by Nobel Prize winner Dr. BernardoAlberto Houssay in his lecture in 1947 “The blood sugar and the production and consumption of glucose are kept within normal bounds, therefore there is an equilibrium between the glands of internal secretions which reduce the blood sugar (pancreas) and those which raise it (anterohypophysis, adrenals, thyroid, etc.)”. Thyroid hormones exert both insulin agonistic and antagonistic actions indifferent 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. Overt hyperthyroidism has been related to glucose intolerance and even ketoacidosis. With regards to hypothyroidism, cases of hypoglycemia have been reported in the literature despite the factthat peripheral insulin resistance may be present. In the century that has elapsed, since the first observations of uncontrolled glucose metabolism in thyrotoxic diabetic patients [1], new pathways involved in the regulation of glucose homeostasis by thyroid hormones have been unveiled. Novel findings include the stimulation of hepatic glucose production by thyroid hormones acting via a sympatheticpathway from the hypothalamus [2] and

the discovery of transcriptional regulators of metabolic and mitochondrial genes that, influenced by intracellular T3 levels, may contribute to the development of insulin resistance [3]. The calorigenic-thermogenic activity of T3 long ascribed solely to uncoupling of mitochondrial oxidative phosphorylation has recently been related to T3-induced gating ofmitochondrial permeability transition pore (PTP) of the inner mitochondrial membrane where the whole T3 transduction pathway integrates genomic and nongenomic activities of T3 in regulating mitochondrial energetics [4]. In this paper, we summarize the effects of thyroid hormones in glucose metabolism and its alterations when thyroid dysfunction is present.

2. Effects of Thyroid Hormones on GlucoseMetabolism (Figure 1)
2.1. Direct Effects of Thyroid Hormones at the Liver Level (Table 1). Thyroid receptor-mediated effects on gene transcription and translation are key in the regulation of glucose metabolism. According to the results of studies with complementary DNA (cDNA) microarray analysis in mouse liver, this organ is a major target of thyroid hormones. Several genes involved in...