Thyroid hormone is a major determinant of energy expenditure and a key regulator 
of mitochondrial activity. We have previously identified a mitochondrial 
triiodothyronine receptor (p43) that acts as a mitochondrial transcription 
factor of the organelle genome, which leads, in vitro and in vivo, to a 
stimulation of mitochondrial biogenesis. Here we generated mice specifically 
lacking p43 to address its physiological influence. We found that p43 is 
required for normal glucose homeostasis. The p43(-/-) mice had a major defect in 
insulin secretion both in vivo and in isolated pancreatic islets and a loss of 
glucose-stimulated insulin secretion. Moreover, a high-fat/high-sucrose diet 
elicited more severe glucose intolerance than that recorded in normal animals. 
In addition, we observed in p43(-/-) mice both a decrease in pancreatic islet 
density and in the activity of complexes of the respiratory chain in isolated 
pancreatic islets. These dysfunctions were associated with a down-regulation of 
the expression of the glucose transporter Glut2 and of Kir6.2, a key component 
of the K(ATP) channel. Our findings establish that p43 is an important regulator 
of glucose homeostasis and pancreatic β-cell function and provide evidence for 
the first time of a physiological role for a mitochondrial endocrine receptor.