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The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter. Finally, we discuss uncertainties and open questions in differential diagnosis and therapy of euthyroid and toxic MNG.

Recently, it has been shown that the fat-derived factor adiponectin is downregulated in insulin resistance and obesity and that replenishment of this adipocytokine reverses insulin resistance in mice. Growing evidence, on the other hand, suggests that raised levels of catecholamines due to increased activity of the sympathetic nervous system are an integral part in the development of insulin resistance. To clarify whether catecholamines might exert their insulin resistance-inducing effects at least partly via downregulation of adiponectin gene expression, 3T3-L1 adipocytes were treated with isoproterenol, and adiponectin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. In fact, isoproterenol treatment reduced the level of adiponectin mRNA by about 75% in a dose-dependent fashion with significant inhibition detectable at concentrations as low as 10 nM isoproterenol. Furthermore, the inhibitory effect of isoproterenol was almost completely reversed by pretreatment of 3T3-L1 cells with the L L-adrenergic antagonist propranolol and the protein kinase A (PKA) inhibitor H-89. Moreover, the effects of isoproterenol could be mimicked by stimulation of stimulatory guanine nucleotide-binding (G S )-proteins with cholera toxin and adenylyl cyclase with forskolin. Thus, our results suggest that adiponectin gene expression is severely suppressed by L L-adrenergic agents via activation of a G S -protein^PKA-dependent pathway. The data support a possible role of adiponectin in catecholamine-induced insulin resistance. ß

GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have recently been identified as free fatty acids (FFAs). The receptor, now named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose-stimulated insulin release. Guided by molecular modeling, we investigated the molecular determinants contributing to binding of linoleic acid, a C18 polyunsaturated FFA, and GW9508, a synthetic small molecule agonist. Twelve residues within the putative GPR40-binding pocket including hydrophilic/positively charged, aromatic, and hydrophobic residues were identified and were subjected to site-directed mutagenesis. GPR40 was discovered a decade ago, along with its closely related family members GPR41 and 43, in a screen for GPCR 2 homologous sequences that cluster in chromosomal locus 19q13.1 (1). This family of receptors shares an overall sequence homology of 30 -50% (2, 3) and a higher homology within their putative transmembrane domains (3, 4). Nevertheless, their ligands were not known until recently when this family of orphans was found to be activated by free fatty acids of different chain lengths with varying degrees of specificity. GPR40 prefers fatty acids of medium to long chain length (5, 6) and has also been called FFA receptor 1. GPR41 and 43 prefer chain lengths between two to five (7) and are now called FFA receptors 3 and 2, respectively. GPR40 couples to G q (8, 9), which results in activation of phospholipase C (10, 11) and subsequent increases in cytoplasmic free calcium (5, 6). GPR40 has also been reported to inhibit the activity of potassium channels via a cAMP-dependent pathway (12).GPR40 mRNA is expressed primarily in the pancreas, brain, and monocytes (5), and its biology has generated excitement in the field of pancreas and diabetes research. It was generally understood that fatty acids enhance glucose-stimulated insulin secretion through the malonyl-CoA pathway upon intracellular metabolism (reviewed in Refs. 13 and 14), but a number of in vitro and in vivo studies have now demonstrated that fatty acids could potentiate glucose-stimulated insulin secretion by acting on GPR40 (6,9,10,12,15,16). It remains controversial whether GPR40 offers a protective role in glucose metabolism under certain circumstances; however, in one study, GPR40Ϫ/Ϫ knock-out mice were protected from high fat diet-induced hepatic steatosis and impaired glucose homeostasis (16). Together these studies point to a dual role for GPR40 in the regulation of glucose homeostasis in diet-related type II diabetes.Despite their important physiological implications, little is known about the mechanism underlying the interaction of fatty acids with their receptors. Moreover, functional studies of GPR40 have been limited by lack of ligands of high specificity and potency. The potencies of medium to long chain fatty acid range from 2 to 17 M (5). Screening of compound libraries followed by chemical modifications has ...