Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity.

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max (ml·kg-1·min-1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

Investigation of the long-term sustainability of changes in appetite after weight loss.

BACKGROUND/OBJECTIVE: Diet-induced weight loss (WL) leads to a compensatory increase in appetite and changes in the plasma concentration of appetite-regulating hormones are likely to play a role. Whether these changes are transient or sustained remains unclear. This study aimed to assess if changes in subjective and objective appetite markers observed with WL are sustained after 1 year (1Y). SUBJECTS/METHODS: In total 100 (45 males) individuals with obesity (BMI: 37 ± 4 kg/m2, age: 43 ± 10 years) underwent 8 weeks (wks) of a very-low energy diet (VLED), followed by 4 wks refeeding, and a 1Y maintenance program. Fasting/postprandial subjective ratings of hunger, fullness, desire to eat, and prospective food consumption (PFC) were assessed, and plasma concentration of active ghrelin (AG), total peptide YY (PYY), active glucagon-like peptide 1, cholecystokinin (CCK), and insulin measured, at baseline, week 13 (Wk13) and 1Y. RESULTS: At Wk13, 16% WL (-18 ± 1 kg, P < 0.001) was associated with a significant increase in fasting and postprandial hunger ratings (P < 0.01 and P < 0.05, respectively), and postprandial fullness (P < 0.01) combined with a reduction in PFC (P < 0.001). These were accompanied by a significant rise in basal and postprandial AG concentrations (P < 0.001, for both), a reduction in postprandial CCK (P < 0.01) and in basal and postprandial insulin (P < 0.001). At 1Y follow-up, with sustained WL (15%; -16 ± 1 kg, P < 0.001), fasting hunger and postprandial fullness ratings remained increased (P < 0.05 for both), and postprandial PFC reduced (P < 0.001). Basal and postprandial AG remained elevated and insulin reduced (P < 0.001, for all), while postprandial CCK was increased (P < 0.01) and PYY decreased (P < 0.001). CONCLUSION: With a 15% sustained WL at 1Y, the drive to eat in the fasting state is increased, but this may be balanced out by raised postprandial feelings of fullness. To assist with WL maintenance, new strategies are required to manage increased hunger and drive to eat.

Timeline of changes in appetite during weight loss with a ketogenic diet.

BACKGROUND/OBJECTIVE: Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED). SUBJECTS/METHODS: Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m-2) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite-related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13. Data are shown as mean±s.d. RESULTS: A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both). CONCLUSIONS: WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.

Effects of RYGB on energy expenditure, appetite and glycaemic control: a randomized controlled clinical trial.

OBJECTIVES: Increased energy expenditure (EE) has been proposed as an important mechanism for weight loss following Roux-en-Y gastric bypass (RYGB). However, this has never been investigated in a controlled setting independent of changes in energy balance. Similarly, only few studies have investigated the effect of RYGB on glycaemic control per se. Here, we investigated the effect of RYGB on EE, appetite, glycaemic control and specific signalling molecules compared with a control group in comparable negative energy balance. SUBJECTS/METHODS: Obese normal glucose-tolerant participants were randomized to receive RYGB after 8 (n=14) or 12 weeks (n=14). The protocol included a visit at week 0 and three visits (weeks 7, 11 and 78) where 24-h EE, appetite and blood parameters were assessed. Participants followed a low-calorie diet from weeks 0-11, with those operated at week 12 serving as a control group for those operated at week 8. RESULTS: Compared with controls, RYGB-operated participants had lower body composition-adjusted 24-h EE and basal EE 3 weeks postoperatively (both P<0.05) but EE parameters at week 78 were not different from preoperative values (week 7). Surgery changed the postprandial response of glucagon-like peptide-1 (GLP-1), peptide YY3-36 (PYY), ghrelin, cholecystokinin, fibroblast growth factor-19 and bile acids (all P<0.05). Particularly, increases in GLP-1, PYY and decreases in ghrelin were associated with decreased appetite. None of HOMA-IR (homeostasis model assessment-estimated insulin resistance), Matsuda index, the insulinogenic index, the disposition index and fasting hepatic insulin clearance were different between the groups, but RYGB operated had lower fasting glucose (P<0.05) and the postprandial glucose profile was shifted to the left (P<0.01). CONCLUSIONS: Our data do not support that EE is increased after RYGB. More likely, RYGB promotes weight loss by reducing appetite, partly mediated by changes in gastrointestinal hormone secretion. Furthermore, we found that the early changes in glycaemic control after RYGB is to a large extent mediated by caloric restriction.

Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY3-36. SUBJECTS/METHODS: Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY3-36 and (4) Ex-9/sitagliptin combined. RESULTS: In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY3-36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone. CONCLUSIONS: Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY3-36, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.

Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.

AIM: To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake. METHODS: On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled. RESULTS: In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups. CONCLUSIONS: CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.

Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study.

AIMS/HYPOTHESIS: Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes. METHODS: Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements. RESULTS: Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole. CONCLUSIONS/INTERPRETATION: Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass.

OBJECTIVE: To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). DESIGN: Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. MATERIALS AND METHODS: Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. RESULTS: Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition. CONCLUSION: Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

Effects of intraduodenal infusion of lauric acid and L-tryptophan, alone and combined, on glucoregulatory hormones, gastric emptying and glycaemia in healthy men.

BACKGROUND AND AIM: In healthy men, intraduodenal administration of the fatty acid, lauric acid ('C12') and the amino acid, L-tryptophan ('TRP'), at loads that individually do not affect energy intake, reduce energy intake substantially when combined. C12 and TRP may also stimulate cholecystokinin and glucagon-like peptide-1 (GLP-1), which both slow gastric emptying, a key determinant of postprandial blood glucose. Accordingly, combination of C12 and TRP has the potential to reduce post-meal glycaemia more than either nutrient alone. METHODS: Twelve healthy, lean men (age (mean ± SD): 28 ± 7 years) received, on 4 separate occasions, 45-min intraduodenal infusions of C12 (0.3 kcal/min), TRP (0.1 kcal/min), C12 + TRP (0.4 kcal/min), or 0.9% saline (control), in a randomised, double-blind fashion. 30 min after commencement of the infusion a mixed-nutrient drink was consumed and gastric emptying measured (13C breath-test) for 3 h. Blood samples were obtained at baseline, in response to treatments alone, and for 2 h post-drink for measurements of plasma glucose, cholecystokinin, GLP-1, C-peptide, insulin and glucagon. 'Early' (first 30 min) and 'overall' glycaemic and hormone responses were evaluated. RESULTS: C12 + TRP and C12 delayed the rise in, but did not affect the overall glycaemic response to the drink, compared with control and TRP (all P < 0.05). C12 + TRP slowed gastric emptying compared with control and TRP (both P < 0.005), and C12 non-significantly slowed gastric emptying compared with control (P = 0.090). C12 + TRP and C12 delayed the rise in C-peptide and insulin, and also stimulated CCK and glucagon, compared with control and TRP (all P < 0.05). Only C12 + TRP stimulated early and overall GLP-1 compared with control (P < 0.05). CONCLUSIONS: In healthy men, C12 + TRP and C12, in the loads administered, had comparable effects to delay the rise in glucose following a nutrient drink, probably primarily by slowing of gastric emptying, as a result of CCK and GLP-1 stimulation, while TRP had no effect.

Evaluation of fecal elastase and serum cholecystokinin in dogs with a false positive fecal elastase test.

BACKGROUND: An assay for the measurement of pancreatic elastase in dog feces has been introduced. HYPOTHESIS/OBJECTIVES: The goal of this study was to evaluate the rate of false-positive fecal-elastase test results in dogs with suspected exocrine pancreatic insufficiency (EPI) and to assess serum cholecystokinin (CCK) concentrations in dogs with a false positive fecal elastase test result. ANIMALS: Twenty-six fecal and serum samples from dogs suspected of EPI, for which samples had been submitted to a commercial laboratory (Vet Med Labor) for analysis. METHODS: Prospective study. Serum trypsin-like immunoreactivity (TLI) was measured in 26 dogs with a decreased fecal elastase concentration of <10 microg/g feces. Serum CCK concentrations were measured in 21 of these dogs. RESULTS: Of 26 dogs with a decreased fecal elastase concentration, 6 (23%) had serum TLI concentrations within or above the reference range. Serum CCK concentrations were significantly higher in dogs with a true positive fecal elastase test result (median: 1.1 pmol/L; range: 0.1-3.3 pmol/L) than in those with a false positive fecal elastase test result (median: 0.1 pmol/L; range: 0.1-0.9 pmol/L; P value = .0163). CONCLUSIONS AND CLINICAL IMPORTANCE: The rate of false positive fecal elastase test results was high in this group of dogs, suggesting that diagnosis of EPI must be confirmed by other means. The decreased CCK concentration in dogs with a false positive fecal elastase test result could suggest that false positive results are because of decreased stimulation of exocrine pancreatic function caused by other conditions.

Cloned cell lines from a transplantable islet cell tumor are heterogeneous and express cholecystokinin in addition to islet hormones.

A liver metastasis (MSL) with a remarkable in vitro proliferation potential has been identified in an NEDH rat carrying a transplantable x-ray-induced islet cell tumor. Two insulin-secreting cell lines, MSL-G and MSL-H, with doubling times of 3-5 d were established by repeated limiting dilution cloning. In vivo inoculation of MSL-G cells induced severe hypoglycemia caused by a small but highly heterogeneous tumor as revealed by immunocytochemistry. Whereas most cells stained for the islet hormones, insulin, glucagon, and somatostatin, clustered cells were discovered to contain cholecystokinin (CCK). Additional in vitro-limiting dilution cloning, followed by immunocytochemical characterization, clearly demonstrated the capacity of single cell clones to simultaneously express the same four hormones. Radioimmunoassays with a panel of site-specific antisera of culture supernatants and purified cell extracts showed the MSL-G2 cells to produce, store, and secrete readily detectable amounts of processed and unprocessed CCK. Gastrin was not detected while coexpression of glucagon and CCK were demonstrated. Mutant clones selected for resistance to 6-thioguanine (frequency, 2 X 10(-7] and checked for HAT (hypoxanthine, aminopterin, thymidine) sensitivity retained the capacity for multi-hormone expression. We propose that the MSL tumor contains pluripotent endocrine stem cells. The MSL tumor and the MSL-G2 cells in particular will allow studies of not only CCK biosynthesis and processing but also of mechanisms involved in tumor and islet cell differentiation.

Pituitary gastrins occur in corticotrophs and melanotrophs.

The gut hormone gastrin was identified in pituitary cells containing adrenocorticotropic hormone and alpha-melanocyte--stimulating hormone by region-specific immunocytochemistry and radioimmunoassay. Smaller amounts of gastrin were found in nerve fibers of the neural lobe and pituitary stalk. Since adrenocorticotropic hormone--like peptides occur in antropyloric gastrin cells, these data indicate a considerable similarity in peptide composition of pituitary and gastrointestinal endocrine cells and reinforces questions of multiple hormone production.

Somatostatin cell processes as pathways for paracrine secretion.

Somatostatin is produced by gastrointestinal endocrine cells that have long, nonluminal, cytoplasmic processes. Such processes terminate on other cell types, including gastrin-producing and hydrochloric acid-producing cells, whose functions are profoundly affected by somatostatin. The findings suggest that somatostatin cells control the functions of other cells through local release of the peptide by way of cytoplasmic processes. Also, certain other types of gastrointestinal endocrine cells have similar cytoplasmic prolongations, which may have analogous local (paracrine) regulatory functions.

An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.

OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METHOD: The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

Disturbed islet-cell function related to endogenous gastrin release. Studies on insulin secretion and glucose tolerance in pernicious anemia.

The insulin and gastrin response to oral glucose, intravenous glucose, or a protein-rich meal were measured in 44 nondiabetic patients with pernicious anemia (PA) and in 44 control subjects. 36 of the PA-patients had hypergastrinemia, while serum gastrin concentrations in the remaining eight patients were below normal. Three hypergastrinemic PA-patients were in addition studied during an oral glucose loading with synchronous intravenous infusion of gastrin-17. During both oral and intravenous glucose tests blood glucose concentrations were similar in patients and in controls. After ingestion of protein blood glucose concentrations in PA-patients with hypergastrinemia were above those of the controls (P less than 0.05). Parenteral infusion of gastrin-17 during oral glucose loading also increased blood glucose concentrations above the levels observed after glucose alone. In PA-patients with hypergastrinemia the insulin response was augmented in all tests. In patients with hypogastrinemia serum insulin concentrations were lower than normal in the fasting state and during stimulation with glucose intravenously (P less than 0.01). In hypergastrinemic patients serum gastrin concentrations decreased after oral as well as intravenous glucose administration. The decrease was larger during the oral test. In hypogastrinemia oral glucose induced, as in controls, a small initial rise followed by a slow fall in serum gastrin concentrations. No variations were seen in these patients during the intravenous glucose infusion. Gel filtration of serum from hypergastrinemic patients disclosed a decrease in the concentrations of all four main components of gastrin during the glucose loadings. Taken together with earlier studies on the effect of exogenous gastrin the results suggest that endogenous hypergastrinemia induces hyperglycemia and potentiates insulin secretion. In contrast hypogastrinemia is associated with hypoinsulinism.

The effect of gastrin on basal- and glucose-stimulated insulin secretion in man.

The effect of gastrin on basal- and glucose-stimulated insulin secretion was studied in 32 normal, young subjects. The concentration of gastrin and insulin in serum was measured radioimmunochemically. Maximal physiologic limit for the concentration of gastrin in serum was of the order of 160 pmol per liter as observed during a protein-rich meal. Oral ingestion of 50 g glucose produced a small gastrin response from 28+/-3 to 39+/-5 pmol per liter (mean +/-SEM, P < 0.01). Intravenous injection or prolonged infusion of gastrin increased the concentration of insulin in peripheral venous blood to a maximum within 2 min followed by a decline to basal levels after a further 10 min. The minimum dose required to induce a significant insulin response (31.2 ng gastrin per kg) increased the gastrin level in serum above the physiologic range. Maximum effect was obtained with 500 ng gastrin per kg. When 15.6 ng (7.1 pmol) gastrin per kg body weight and 25 g glucose were injected simultaneously, the glucose-induced insulin response was potentiated (from 2.32+/-0.33 to 4.33+/-0.98 nmol per liter per 20 min, P < 0.02), even though gastrin concentrations only increased to 71.2+/-6.6 pmol per liter. No effect, however, was noted on glucose disposal. 15.6 ng gastrin per kg given i.v. 30 min before an i.v. glucose tolerance test was without significant effect on the insulin response. The results indicate that gastrin can stimulate a rapid and short-lived release of insulin. In physiologic concentrations gastrin potentiates the glucose-stimulated insulin secretion and is without effect on basal insulin secretion. A small release of gastrin during oral glucose ingestion may to a limited extent contribute to the nonglycemic insulin secretion. During protein ingestion, gastrin probably stimulates insulin secretion significantly.

Effect of atropine on gastrin and gastric acid response to peptone meal.

The action of intravenous atropine on meal-and pentagastrin-induced gastric acid secretion was studied in six duodenal ulcer patients.A test meal of 10% peptone solution adjusted to pH 5.0 was maintained in the stomach at at distention presure of 15 cm H(2)O, and a modification of the intragastric titration method of Fordtran and Walsh was used to measure gastric acid output by monitoring the rate at which a solution of 0.5 M sodium bicarbonate had to be added to keep the pH of the gastric content constant at the initial (pH 5.0) value. Serum gastrin concentrations were measured simultaneously by radioimmunoassy. The dose of 25 mug/kg-h atropine inhibited meal-induced acid secretion by about 70% and that evoked by pentagastrin by about 30%. The serum gastrin response to the test meal was not significantly altered by atropine. We conclude that atropine is a very strong inhibitor of meal-induced gastric acid secretion and does not significantly change serum gastrin response to feeding in duodenal ulcer patients when postprandial gastric acidity (pH 5.0) and intragastric pressure (15 cm H(2)O) are kept constant.

Expression and localization of gastrin messenger RNA and peptide in spermatogenic cells.

In previous studies we have shown that the gene encoding cholecystokinin (CCK) is expressed in spermatogenic cells of several mammalian species. In the present study we show that a gene homologous to the CCK-related hormone, gastrin, is expressed in the human testis. The mRNA hybridizing to a human gastrin cDNA probe in the human testis was of the same size (0.7 kb) as gastrin mRNA in the human antrum. By in situ hybridization the gastrinlike mRNA was localized to seminiferous tubules. Immunocytochemical staining of human testis revealed gastrinlike peptides in the seminiferous tubules primarily at a position corresponding to spermatids and spermatozoa. In ejaculated spermatozoa gastrinlike immunoreactivity was localized to the acrosome. Acrosomal localization could also be shown in spermatids with electron microscopy. Extracts of the human testis contained significant amounts of progastrin, but no bioactive amidated gastrins. In contrast, ejaculated sperm contained mature carboxyamidated gastrin 34 and gastrin 17. The concentration of gastrin in ejaculated human spermatozoa varied considerably between individuals. We suggest that amidated gastrin (in humans) and CCK (in other mammals) are released during the acrosome reaction and that they may be important for fertilization.

Vagal, cholinergic regulation of pancreatic polypeptide secretion.

THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.

Ghrelin stimulates gastric emptying and hunger in normal-weight humans.

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.