JOURNAL ARTICLE

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

J E Henriksen, F Alford, G M Ward, H Beck-Nielsen
Diabetologia 1997, 40 (12): 1439-48
9447952
We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and 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 vs 25.1 +/- 0.9 kg/m2). 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/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives 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 caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These "hyperglycaemic" relatives had diminished first phase insulin secretion (O1) both before and during dex compared with the "normal" relatives and the control subjects (pre-dex O1: 12.6 +/- 3.6 vs 26.4 +/- 4.2 and 24.6 +/- 3.6 (p < 0.05), post-dex O1: 22.2 +/- 6.6 vs 48.0 +/- 7.2 and 46.2 +/- 6.6 respectively (p < 0.05) pmol x l(-1) x min(-1) per mg/dl). However, Si was similar in "hyperglycaemic" and "normal" relatives before dex (0.65 +/- 0.10 vs 0.54 +/- 0.10 10(-4) x min(-1) per pmol/l) and suppressed similarly during dex (0.30 +/- 0.07 vs 0.30 +/- 0.06 10(-4) x min(-1) per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce 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 resistant state.

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