Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist.

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay. Basal CCK levels averaged 1.0 +/- 0.1 pM (mean +/- SEM, n = 8) and increased to 7.1 +/- 1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68 +/- 3 min. Plasma glucose levels increased from basal levels of 91 +/- 3.9 mg/dl to peak levels of 162 +/- 11 mg/dl and insulin levels increased from 10.7 +/- 1.8 microU/ml to peak levels of 58 +/- 11 microU/ml. After glucose ingestion, with CCK infused at 24 pmol/kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t1/2 increased to 148 +/- 16 min. In concert with this delay in gastric emptying, peak glucose levels rose to only 129 +/- 17 mg% and peak insulin levels rose to only 24.2 +/- 4.2 microU/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen. To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7 +/- 0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values. To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93+/-5 to 148+/-6 mg/dl and insulin levels rose from 10.6+/-3.5 to 29.5+/-5.2 microU/ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in human.

Ectopic pituitary and hypothalamic hormone syndromes.

The pathophysiology and diagnosis of ectopic hormone syndromes are discussed, and a classification of hypothalamic and pituitary ectopic syndromes is provided. Ectopic hypothalamic syndromes resulting from tumor elaboration of GRH, GnRH, CRF, and SRIF and ectopic pituitary hormone hypersecretion of GH, PRL, and TSH are reviewed comprehensively. A practical approach to the clinical work-up and management of these newly described disorders is provided.

Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans.

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.

Relative effects of pregnancy and corticosterone administration on skeletal muscle metabolism in the rat.

The effects of pregnancy and corticosterone treatment on skeletal muscle metabolism were compared using a noncyclically perfused rat hindlimb preparation. Animal groups studied included 3-week-pregnant animals, rats injected with corticosterone (7.5 mg/100 g BW . day) for 3 days, and age-matched control rats. All were fasted 24 h before perfusion. In baseline perfusions devoid of insulin, no differences were observed among the groups with respect to muscle glucose uptake and the release of lactate, pyruvate, and glycerol. Baseline alanine and phenylalanine release were significantly increased in corticosterone-treated rats compared to values observed in control and pregnant animals. In perfusions with 100 or 500 microU/ml insulin, glucose uptake was increased 5-fold above baseline uptake in the control group. At 100 microU/ml insulin concentrations, glucose uptake in pregnant and corticosterone-treated rats achieved only 50% of the increase seen in control experiments. With 500 microU/ml insulin, glucose uptake was decreased 20% in pregnant animals and 40% in rats receiving corticosterone relative to control values. Alanine release was significantly reduced below baseline after the administration of 500 microU/ml insulin in control rats. In these rats, phenylalanine release, an index of net protein degradation, also was reduced with both 100 and 500 microU/ml insulin. Similar insulin concentrations did not suppress the efflux of either amino acid below baseline in pregnant or corticosterone-treated groups. Corticosterone administration to nonpregnant rats appears to duplicate changes in skeletal muscle metabolism that occur during late rat pregnancy. Insulin resistance in both states is manifested by a decrease in insulin-stimulated glucose uptake and an inability of insulin to suppress net muscle proteolysis. Since plasma free glucocorticoid concentrations are increased in late human as well as rat gestation, these steroids may have an important role in the development of insulin resistance at skeletal muscle sites in this state.