Background of the study: Thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are known to promote weight loss, which could be beneficial for treating obesity, and type 2 diabetes. Thyroid hormone treatment stimulates energy expenditure resulting in increased body heat production, in which brown adipose tissue play an important role. It is hypothesized that thyroid hormones would induce increased energy expenditure via a process called mitochondrial uncoupling, thereby creating an inefficient energy status. Indeed, an in vivo study showed a 70% increased flux through the tricarboxylic acid cycle (TCA) and an unchanged ATP synthesis rate upon T3 treatment in lean, healthy young men. The disproportionate increase in TCA flux compared with ATP synthesis suggests increased mitochondrial uncoupling. It is however unknown whether increased mitochondrial uncoupling would increase fat oxidation and exerts favorable effects on insulin sensitivity. There is compelling evidence that type 2 diabetic patients have high levels of fat accumulation in non-adipose tissues, such as skeletal muscle, heart and liver. Ectopic fat accumulation is related to insulin resistance, however, why this fat accumulates in peripheral organs is not known. Recently, studies reported compromised mitochondrial oxidative capacity in type 2 diabetic patients and first-degree relatives of diabetic patients, suggested to play an important role. Therefore, subjects suffering from overweight and/or type 2 diabetes with overt hypothyroidism form an interesting group for examining the metabolic effects of thyroid hormone treatment, as less is known about the effects of thyroid hormone treatment in these groups. Objective of the study: The purpose of this study is to evaluate whether thyroid hormone replacement therapy in type 2 diabetic patients suffering from overt hypothyroidism, will improve muscular mitochondrial function, lower ectopic fat accumulation in muscle and liver, increase brown adipose tissue activity and enhance insulin sensitivity. Study design: Type 2 diabetic patients diagnosed with hypothyroidism will undergo 3 months of thyroid hormone replacement therapy (THRT) (Euthyrox®, Merck, Germany). Patients will be metabolically characterized (such as insulin sensitivity and fat accumulation in peripheral tissues) before and after this thyroid hormone replacement therapy. Study population: 17 type 2 diabetic patients diagnosed with overt hypothyroidism (9 from the Netherlands, 8 from Germany which will only do the PET-CT) Primary study parameters/outcome of the study: Thyroid hormone-induced change in whole body insulin sensitivity (change in insulin-stimulated glucose disposal) and muscle mitochondrial function. Secondary study parameters/outcome of the study (if applicable): Thyroid hormone-induced change of lipid content in skeletal muscle and liver and brown adipose tissue activity.
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Thyroid hormone-induced change in whole body insulin sensitivity (change in insulin-stimulated glucose disposal) and muscle mitochondrial function
Timeframe: 3 months