RISK AND MECHANISM OF DEXAMETHASONE-INDUCED DETERIORATION OF GLUCOSE-TOLERANCE IN NONDIABETIC FIRST-DEGREE RELATIVES OF NIDDM PATIENTS

We tested the hypothesis that glucose intolerance develops in genetica lly prone subjects when exogenous insulin resistance is induced by dex amethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or in sulin resistance. Oral glucose tolerance (OGTT) and intravenous glucos e tolerance tests with minimal model analysis were performed before an d following 5 days of dex treatment (4 mg/day) in 20 relatives of non- insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 +/- 1.7 vs 29.6 +/- 1.6 years, BMI: 25.1 +/- 1.0 v s 25.1 +/- 0.9 kg/m(2)). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 +/- 0.2 [range : 3.2-7.0] vs 5.5 +/- 0.2 [3.7-7.4] mmol/ 1). Although insulin sensiti vity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the rel atives and control subjects (0.30 +/- 0.04 vs 0.34 +/- 0.04 10(-4) min (-1) per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 +/- 0.7 [3.9-17.0] vs 7.5 +/- 0.3 [5.7- 9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was ca used by seven relatives with a higher PG than the maximal value seen i n the control subjects (9.8 mmol/l). These ''hyperglycaemic'' relative s had diminished first phase insulin secretion (empty setl) both befor e and during dex compared with the ''normal'' relatives and the contro l subjects (pre-dex empty set1: 12.6 +/- 3.6 vs 26.4 +/- 4.2 and 24.6 +/- 3.6 (p < 0.05), post-dex empty set1: 22.2 +/- 6.6vs 48.0 +/- 7.2 a nd 46.2 +/- 6.6 respectively (p < 0.05) pmol.l(-1).min(-1) per mg/dl). However, Si was similar in ''hyperglycaemic'' and ''normal'' relative s before dex (0.65 +/- 0.10 vs 0.54 +/- 0.10 10(-4).min(-1) per pmol/l ) and suppressed similarly during dex (0.30 +/- 0.07 vs 0.30 +/- 0.06 10(-4) min(-1) per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent dev elopment of high 2-h post-dex OGTT plasma glucose levels (R-2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induc e impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin re sistant state.