Evidence for a Role of Glucocorticoids in the Development of Insulin Resistance After Ischaemic Limb Injury in the Rat

Abstract

Bilateral hind-limb ischaemia in the rat is known to cause insulin resistance, as shown by a sustained rise in plasma glucose concentration with a decreased metabolic clearance rate but no fall in plasma insulin. However, when the concomitant rise in the plasma concentration of corticosterone was diminished by an inhibitor of its biosynthesis, trilostane (WIN 24 540), the hyperglycaemia became transient. The mechanism of this effect has now been studied by measuring the rate of disappearance of [5-3H,U-14C]glucose and the concentration of insulin in plasma. Trilostane did not alter the rate of glucose production or the 3H : 14C ratio (an index of recycling through gluconeogenic precursors). It did , however, raise the metabolic clearance rate while lowering the plasma insulin concentration, i.e. peripheral sensitivity and/or responsiveness to insulin was increased. Insulin resistance was restored by giving corticosterone together with trilostane. Thus an increased concentration of corticosterone in the plasma was necessary for the full development of insulin resistance following ischaemic limb injury. It was, however, probably not the only factor since a similar dose of corticosterone did not lead to hyperglycaemia in uninjured rats.

Glucose, insulin and other plasma metabolites shortly after injury.

“…Values (Fig. 4) were higher in women than in men at ISS 4-8 (P<0.05) and [9][10][11][12][13][14] (P < 0.005), as expected,11 and rose with time after injury at ISS [4][5][6][7][8][9][10][11][12][13][14] [adrenaline] had been measured in them. The residuals were, however, very non-normally distributed.…”

“…2), which were measured within the fairly narrow bands of injury severity shown. These, suggested by Copes et al,13 correspond to minor (ISS 1-3), moderate (4)(5)(6)(7)(8), severe (9)(10)(11)(12)(13)(14), very severe (16)(17)(18)(19)(20)(21)(22)(23)(24) and life-threatening (25+) injuries. Success has been measured by the percentage of the variance within each group that can be accounted for by the various factors.…”

“…There is no rise in glucose after 24 h starvation, when glycogen stores are depleted,4 insulin resistance develops rapidly5 and depends upon increased [corticosterone]. 6 The rise in [glucagon] probably contributes to the maintenance of hyperglycaemia,7 although the [glucagon]/[insulin] ratio is not raised. 8 If this theory is correct then it should be able to account for the values of [glucose] that are measured in patients following injury.…”

The effects of stress and injury on the activity of phosphoenolpyruvate carboxykinase in the liver of the rat

“…Glucagon and cyclic AMP, the latter in a HC104 extract of freeze-clamped liver, were measured according to the instructions with the kits referred to above, except that 1251 measurements were made in a y-counter, and glucagon extracts were dried in a stream of N2 instead of in a desiccator. Insulin was measured by a single-antibody technique (Barton & Passingham, 1980), corticosterone as described by Nicholson & Van Loon (1973), plasma lactate as described by Heath & Rose (1985), and plasma glucose according to the instructions with the kit.…”

The therapeutic implications of some recent research on trauma.

“…[It is thought by some (Alberti & Johnston, 1977) that the active involvement of cortisol in the responses to injury can continue for some time after the 'ebb' phase.] Experiments on rats (Barton & Little, 1978;Barton & Passingham, 1980;1982) have shown that increased glucocorticoid secretion is necessary to maintain the hyperglycaemia of injury and that the adrenal plays an important part in the compensation for the fluid loss associated with limb ischaemia but not with haemorrhage. The reason for this difference is not yet known but inhibition of glucocorticoid secretion in the rat by trilostane increases the mortality after limb ischaemia.…”