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Treatment with a Somatostatin Analog Decreases Pancreatic B-Cell and Whole Body Sensitivity to Glucose^*

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, and Veterans Affairs Medical Center Seattle, Washington 98108
The Department of Physiology and Biophysics, University of Southern California (R.N.B.) Los Angeles, California 90033

Address all correspondence and requests for reprints to: Steven E. Kahn, M.B., Ch.B., Veterans Affairs Medical Center (151), 1660 South Columbian Way, Seattle, Washington 98108.

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 (AIR_giucose) at fasting glucose and to arginine (AIR_arg) at glucose concentrations of fasting, approximately 14 and more than 28 mM after 2 (n = 7) and 8 days (n = 9) of octreotide. The AIR_arg 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 AIR_giucose [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 AIR_arg 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 (S_I) did not change significantly (pretreatment, 11.34 ± 1.59 x 10^–5; 1 day, 10.01 ± 2.28 x 10^–5; 7 days, 9.65 ± 1.69 x 10^–5 min^–1/PM). However, glucose effectiveness at basal insulin (S_G) decreased significantly [pretreatment, 2.06 ± 0.26 x 10^–2; 1 day, 1.00 ± 0.12 x 10^–2 min^–1 (P = 0.005 vs. pretreatment); 7 days, 1.12 ± 0.12 x 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 x 10^–2; 1 day, 0.82 ± 0.12 x 10^–2 min^–1 (P < 0.05 vs. pretreatment); 7 days, 0.97 ± 0.14 x 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.

^* This work was presented in part at the 48th Annual Meeting of the American Diabetes Association, New Orleans, LA, June 1988, and at the 13th International Diabetes Federation, Sydney, Australia, November 1988. This work was supported by NIH Grants RR-37, DK-12829, and DK-17047 and by the Department of Veterans Affairs.

Received April 2, 1990.

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