The role of peripheral versus central circadian rhythms and Clock in the maintenance of metabolic homeostasis and with ageing was examined using Clock ¹⁹+MEL mice. These have preserved suprachiasmatic nucleus and pineal gland rhythmicity, but arrhythmic clock gene expression in the liver and skeletal muscle. Clock ¹⁹+MEL mice showed fasting hypoglycaemia in young adult males and fasting hyperglycaemia in older females, and substantially impaired glucose tolerance overall. Clock ¹⁹+MEL mice had substantially reduced plasma insulin and plasma insulin/glucose nocturnally in males and during a glucose tolerance test in females, suggesting impaired insulin secretion. Clock ¹⁹+MEL mice had reduced hepatic expression and loss of rhythmicity of gck, pfkfb3 and pepck mRNA, which is likely to impair glycolysis and gluconeogenesis. Clock ¹⁹+MEL mice also had reduced glut4 mRNA in skeletal muscle and this may contribute to poor glucose tolerance. Whole body insulin tolerance was enhanced in Clock ¹⁹+MEL mice, however, suggesting enhanced insulin sensitivity. These responses occurred although the Clock ¹⁹ mutation did not cause obesity and reduced plasma free fatty acids, while increasing plasma adiponectin. These studies on clock gene disruption in peripheral tissues and metabolic homeostasis provide compelling evidence of a relationship between circadian rhythms and the glucose/insulin and adipoinsular axes. It is, however, premature to declare that clock gene disruption causes the full metabolic syndrome.