Metabolic studies in thyroid disease
McCulloch, Alan Jackson
The effects of thyroid hormones on intermediary metabolism have been investigated in hyperthyroid and hypothyroid man and in experimentally induced thyroid disease in the rat. Glucose metabolism was investigated by measurement of blood glucose, fasting and in 3 14 response to meals and by using both H-3-glucose and C-l-glucose as tracers in kinetic studies. Analysis of glycerol clearance from blood following bulk infusions of glycerol permitted evaluation of gluconeogenesis. Circulating NEFA and glycerol levels and glycerol kinetic data permitted assessment of lipolysis. Ketogenesis was investigated in vivo by measurement of circulating ketone body concentrations and by ketone body kinetic studies using both 14 14 C-3-acetoacetate and C-3-hydroxybutyrate. Influences of hyperthyroidism on ketone body production in vitro were examined in isolated rat hepatocytes. Sensitivity of glucose metabolism, lipolysis and ketogenesis in vivo in man were evaluated by the euglycaemic clamp technique. Thyroid hormone excess in man caused fasting hyperglycaemia and a 50% increase in total glucose turnover. Much of this increase could be accounted for by increased cycling between glucose and glucose-derived 3-carbon intermediates with only a modest increase in irreversible glucose disposal. Although fasting blood lactate, pyruvate and alanine concentrations were normal, increased recycling and accelerated glycerol clearance suggested enhanced gluconeogenesis. Carbohydrate intolerance to meals was also evident. In hypothyroidism fasting blood glucose concentrations were normal despite a decrease in glucose production and delayed glycerol clearance. Carbohydrate intolerance to meals was less marked than in thyrotoxic subjects. Lipolysis was increased in hyperthyroid man as evidenced by increased blood glycerol and plasma NEFA concentrations and an increase in endogenous glycerol production. Glycerol production I was decreased in hypothyroidism although plasma NEFA concentrations were normal. Ketone body concentrations were increased in hyperthyroidism and ketone body production was increased 4-fold. Ketone body production estimates were normal in hypothyroidism. Experimental hyperthyroidism in rats increased ketone body production by isolated hepatocytes suggesting an increase in hepatic ketogenic potential. In the rat hyperthyroidism was associated with hypoinsulinaemia. Hyperglycaemia, lipolysis and ketogenesis in hyperthyroid man occurred despite apparantly normal peripheral insulin concentrations suggesting either relative hyposecretion of insulin and/or insensitivity to endogenous insulin. Euglycaemic clamp studies suggested normal sensitivity to exogenous insulin in terms of glucose metabolism but a decrease in sensitivity of lipolysis whilst insulin clearance was similar to controls. Thyroid hormones exert stimulating effects on glucose, fatty acid and ketone body metabolism which are not associated with a compensatory increase in insulin secretion.