Endogenous somatostatin-28 modulates postprandial insulin secretion. Immunoneutralization studies in baboons.

Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic D cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic B cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14. We attempted to demonstrate a hormonal effect of these peptides by measuring their concentrations before and after infusing a somatostatin-specific monoclonal antibody (mAb) into baboons and comparing glucose, insulin, and glucagon-like peptide-1 levels before and for 4 h after intragastric nutrients during a control study and on 2 d after mAb administration (days 1 and 2). Basal growth hormone (GH) and glucagon levels and parameters of insulin and glucose kinetics were also measured. During immunoneutralization, we found that (a) postprandial insulin levels were elevated on days 1 and 2; (b) GH levels rose immediately and were sustained for 28 h, while glucagon fell; (c) basal insulin levels were unchanged on day 1 but were increased two to threefold on day 2, coincident with decreased insulin sensitivity; and (d) plasma glucose concentrations were similar to control values. We attribute the eventual rise in fasting levels of insulin to its enhanced secretion in compensation for the heightened insulin resistance from increased GH action. Based on the elevated postmeal insulin levels after mAb administration, we conclude that S-28 participates in the enteroinsular axis as a decretin to regulate postprandial insulin secretion.

Effect of somatostatin-28 on dynamics of insulin secretion in perfused rat pancreas.

Somatostatin-28 (S-28), originating in gastrointestinal cells, is secreted into the circulatory system and rises in human plasma after ingestion of a mixed meal. Pancreatic beta-cells contain specific, high-affinity receptors for S-28, and it is plausible that this peptide is a physiological modulator of insulin secretion. To evaluate the effects of physiological concentrations of S-28 on glucose-mediated insulin secretion, we used the perfused in situ rat pancreas under two conditions: 1) "square-wave" glucose infusion from 2.8 to 11.1 mM and 2) ramping of glucose at 0.28 mM/min throughout 45 min. S-28 concentrations of 16, 32, and 80 pM were separately coinfused for 40 min in the first condition and at 16 pM in the second condition. During square-wave glucose infusion, biphasic insulin secretion was elicited with marked attenuation of both phases during coinfusion with the two higher concentrations of S-28. At 16 pM S-28, which approximates postprandial At 16 pM S-28, which approximates postprandial concentrations, only first-phase secretion was suppressed. During ramping of glucose, insulin was released gradually and, in the presence of 16 pM S-28, was shifted to the right, indicating an increase in threshold glucose levels for insulin secretion. We concluded that S-28, at levels achieved postprandially, modulates the release of insulin by altering the threshold of sensitivity to glucose.

Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans.

The level of somatostatin-28, a bioactive peptide derived from pro-somatostatin in gastrointestinal epithelial cells, increases in human plasma after food intake. To determine if an equivalent response occurs with individual components of a mixed meal, somatostatin-28 and prosomatostatin, somatostatin-14, and somatostatin-13, in combination, were measured in healthy men before and after intake of (a) a mixed meal (715 kcal), (b) carbohydrate (100 g equivalent glucose), (c) protein (22 and 45 g), and (d) fat (25 and 50 g). After the mixed meal, somatostatin-28 levels doubled within 120 min and gradually declined by 4 h. With carbohydrate, somatostatin-28 levels were unaltered. After 22 and 45 g of protein, somatostatin-28 increased equivalently within 60 min, representing 30% of the amount with the mixed meal. With 25 g fat, a somatostatin-28 increase similar to that with the meal was seen; this response was doubled with 50 g fat. No changes in prosomatostatin, somatostatin-14, or somatostatin-13 were observed with the mixed meal or with the separate macronutrients. The authors conclude that fat is the major stimulus for somatostatin-28 secretion in humans and hypothesize that somatostatin-28 is an inhibitor of the endocrine and exocrine pancreas during nutrient absorption.

Circulating prosomatostatin-derived peptides. Differential responses to food ingestion.

Prosomatostatin (pro-S) and its bioactive posttranslational products, somatostatin-14 (S-14), somatostatin-13 (S-13), and somatostatin-28 (S-28), were measured in human plasma by the use of immunoglobulins to the NH2-terminus of S-28 conjugated with agarose to separate them and, thereafter, by RIA with an antiserum recognizing the COOH-terminus of pro-S, and by specific RIA for the NH2-terminus of S-14 and pro-S. In healthy men, mean basal levels of pro-S were 4 pg equivalent S-14/ml; S-14/S-13 combined were 9 pg equivalent S-14/ml; and S-28 levels were 16 pg/ml. After a 700-kcal meal, pro-S, S-14, and S-14/S-13 did not change, whereas S-28 levels doubled by 120 min and remained elevated for 240 min. To evaluate the origins of these peptides, their levels were compared in peripheral, portal, gastric, and mesenteric veins of anesthetized patients and in patients with total resection of stomach and pancreas before and after nutrient intake. The stomach and small intestine were sources of both peptides; however, most S-28 originated in the small intestine. These findings suggest that, in contrast to S-14, S-28 is a hormone and may modulate postprandial nutrient absorption and use.