TREATMENT WITH A SOMATOSTATIN ANALOG DECREASES PANCREATIC B-CELL AND WHOLE-BODY SENSITIVITY TO GLUCOSE

To determine the specific alteration in B-cell function caused by a somatostatin analog in man and to determine the effect of the induced insulin deficiency on insulin action, we administered octreotide (SMS 201-995; 50 μg twice daily) to nine healthy male subjects, aged 24–35 yr. B-Cell function was assessed by measuring the acute insulin response (AIR) to glucose (AIRgiucose) at fasting glucose and to arginine (AIRarg) at glucose concentrations of fasting, approximately 14 and more than 28 mm after 2 (n = 7) and 8 days (n = 9) of octreotide. The AIRarg at more than 28 mm glucose (AIR500) is an estimate of B-cell secretory capacity, while the glucose level at which 50% of AIR600 occurs is termed PG50 and can provide an estimate of B-cell glucose sensitivity. Insulin sensitivity and the parameters describing glucose disposal were measured using Bergman’s minimal model. Octreotide administration resulted in the development of mild fasting hyperglycemia, marked fasting hypoinsulinemia, as well as a marked reduction in AIRgiucose [mean ± se; pretreatment, 260 ± 48 pm; 1 day, 62 ± 14 pm (P < 0.005 vs. pretreatment); 8 days, 62 ± 7 pm (P < 0.005 vs. pretreatment)]. In addition, there was an associated marked reduction in iv glucose tolerance. While the AIRarg at fasting glucose (pretreatment, 233 ± 27 pm; 2 days, 144 ± 27 pm; 8 days 281 ± 55 pm) and AIR500 (pretreatment 1000 ± 178 pm; 2 days, 651 ± 82 pm; 8 days, 1041 ± 219 pm) remained unchanged, the AIRarg at 14 mM decreased significantly during octreotide [pretreatment 986 ±178 pm; 2 days, 363 ± 62 pm (P < 0.001 vs. pretreatment); 8 days, 623 ± 130 pm (P < 0.005 vs. pretreatment)], resulting in a rightward shift of the dose-response curve such that the estimated PG60 increased from 8.8 ± 0.6 to 12.9 ± 1.3 mm (P < 0.05) after 2 days and was maintained for 8 days (11.2 ± 0.8 mm; P < 0.05 vs. pretreatment). Despite the development of marked insulin deficiency, the insulin sensitivity index (SI) did not change significantly (pretreatment, 11.34 ± 1.59 × 10−5; 1 day, 10.01 ± 2.28 × 10−5; 7 days, 9.65 ± 1.69 × 10−5 min−1/Pm). However, glucose effectiveness at basal insulin (SG) decreased significantly [pretreatment, 2.06 ± 0.26 × 10−2; 1 day, 1.00 ± 0.12 × 10−2 min−1 (P = 0.005 vs. pretreatment); 7 days, 1.12 ± 0.12 × 10−2 min−1 (P < 0.05 vs. pretreatment); This decrease was still evident when the contribution of basal insulin to glucose effectiveness was factored out [pretreatment, 1.6 ± 0.22 × 10−2; 1 day, 0.82 ± 0.12 × 10−2 min−1 (P < 0.05 vs. pretreatment); 7 days, 0.97 ± 0.14 × 10−2 min−1 (P = 0.06 vs. pretreatment)]. We confirm that octreotide produces marked suppression of fasting and glucose-stimulated insulin secretion with mild fasting hyperglycemia. We conclude that 1) the changes in insulin secretion are the result of diminished B-cell sensitivity to glucose and not the result of decreased B-cell secretory capacity; 2) the marked B-cell dysfunction induced by octreotide does not result in the development of insulin resistance, but 3) octreotide administration is associated with glucose resistance, measured as reductions in glucose effectiveness at basal and zero insulin. © 1990 by The Endocrine Society.