BETA-CELL ACTIVITY AND HEPATIC INSULIN EXTRACTION FOLLOWING DEXAMETHASONE ADMINISTRATION IN HEALTHY-SUBJECTS

Glucocorticoids induce an increase of hepatic glucose production and p eripheral resistance to insulin action. It is further assumed that dex amethasone administration in humans causes insulin hypersecretion, alt hough inferences on beta-cell activity have been made in absolute term s and mostly from observations of systemic insulin concentration. In f act, the role of hepatic insulin extraction in humans treated long-ter m with glucocorticoids has not been investigated. The aim of the prese nt study was to factor out quantitatively the main components of the i nsulin pathway that are responsible for the peripheral hypersecretion observed after steroids. Frequently sampled intravenous (FSIGT) and or al (OGTT) glucose tolerance tests were performed in healthy subjects b efore and after 5 days of oral dexamethasone administration (4 mg/d). Insulin sensitivity, beta-cell secretion, and hepatic insulin extracti on were estimated by means of mathematical modeling. After steroids, i nsulin sensitivity decreased from 6.00 +/- 1.29 to 4.23 +/- 1.04 min(- 1)/(mu U/mL) (P < .04). Basal beta-cell secretion increased from 45 +/ - 7 to 104 +/- 26 pmol/L . min(-1) (P < .004) during the FSIGT and fro m 40 +/- 6 to 88 +/- 21 (P < .05) during the OGTT; total insulin relea se increased from 19 +/- 5 to 36 +/- 7 nmol/L in 180 minutes (P < .005 ) and from 33 +/- 5 to 50 +/- 10 (P < .02), respectively. FSIGT data a lso showed that first-phase beta-cell sensitivity increased from 236 /- 39 to 309 +/- 33 pmol/L . min(-1)/(mg/dl) (P < .04), and second-pha se from 631 +/- 154 to 1,103 +/- 996 +/- 10(4) pmol/L . min(-2)/(mg/dL ) (P < .03). Posthepatic insulin delivery increased only insignificant ly during the FSIGT (from 3.4 +/- 0.6 to 4.5 +/- 0.5 nmol/L, P = .073) due to an augmented hepatic insulin extraction from 73.0% +/- 7.2% to 83.0% +/- 3.5% (P < .05). During the OGTT, posthepatic insulin delive ry increased after treatment from 6.6 +/- 1.2 to 11.4 +/- 2.5 nmol/L ( P < .035) due to an increase, although slight, of hepatic insulin extr action from 77.4% +/- 1.9% to 79.3% +/- 3.3% (P = .319). The increased overall beta-cell activity during both tests was observed also by ana lyzing OGTT profiles of islet amyloid polypeptide (IAPP), the secretio n of which was higher after steroids (basal, 0,081 +/- 0.012 v 0.272 /- 0.082 pmol/L/min, P < .02; total, 35 +/- 8 v 116 +/- 48 pmol/L in 3 hours, P < .05). In conclusion, after dexamethasone administration, p eripheral hyperinsulinemia due to marked prehepatic beta-cell insulin hypersecretion is partially ameliorated by a concomitant increase of h epatic insulin clearance, which is more evident during a FSIGT. Model- derived secretion parameters from the OGTT and FSIGT produced comparab le results, indicating that both tests, when properly analyzed, are fe asible tools to evaluate insulin secretion. (C) 1996 by W.B. Saunders Company