Gary M. Green

Rapid Gastric Emptying of a Solid Pancake Meal in Type II Diabetic Patients

OBJECTIVE To estimate the rate of gastric emptying of a solid pancake carbohydrate meal in recently diagnosed asymptomatic type II diabetic patients compared with nondiabetic control subjects. RESEARCH DESIGN AND METHODS Gastric emptying studies using radiolabeled meals were performed on eight recently diagnosed asymptomatic diabetic patients and on eight sex-, BMI- and age-matched nondiabetic control subjects. Although a liquid protein drink was administered along with the pancake meal, the radioactivity was adherent to only the pancake portion of the meal. Plasma glucose and serum insulin levels were measured in fasting and postprandial blood samples collected at 15-min intervals up to 120 min after ingestion of the mixed nutrient meal. RESULTS The average gastric half-emptying time (time it takes for one-half of the meal to empty) was significantly more rapid for the diabetic patients (45.3 ± 4.8 min) when compared with the nondiabetic control subjects (60.4 ± 5.1 min; P = 0.05). The serum insulin concentrations were not statistically different between the two groups. Plasma glucose values were significantly higher in the diabetic patients compared with the nondiabetic control subjects. CONCLUSIONS Type II diabetic patients with no clinical evidence of neuronal dysfunction have a significantly more rapid rate of gastric emptying of a solid high-carbohydrate meal when compared with nondiabetic control subjects.

Treatment With an Oral Proteinase Inhibitor Slows Gastric Emptying and Acutely Reduces Glucose and Insulin Levels After a Liquid Meal in Type II Diabetic Patients

OBJECTIVE To determine whether an oral trypsin/chymotrypsin inhibitor, POT II, will delay the rate of gastric emptying in recently diagnosed type II diabetic patients and improve their postprandial metabolic parameters. RESEARCH DESIGN AND METHODS Two gastric emptying studies were performedon each of six type II diabetic patients. During one study, the patient ingested a glucose/protein solution, and during the other study, the patientingested the same glucose/protein solution with the addition of 1.5 g ofPOT II, a putative stimulant of cholecystokinin (CCK) release. Each patient served as their own control subject. Each of the two oral solutions were administered to the patients in a counterbalanced order separated by at least 1 week. RESULTS Serum insulin, plasma glucose, plasma gastric inhibitory polypeptide (GIP) values, and the rate of gastric emptying were all significantly (P <0.05) decreased over the 2-h testing period when POT II was added tothe oral glucose/protein meal. The area under the curve above baseline for glucose with POT II was 75% of the glucose value without POT II. The areaunder the curve above baseline for insulin with POT II was 68% of the value without POT II. Plasma CCK was significantly increased by POT II 15 min postprandially. CONCLUSIONS A trypsin/chymotrypsin inhibitor, POT II, can delay therate of gastric emptying, and decrease postprandial plasma glucose levels, GIP levels, and serum insulin levels in type II diabetic patients diagnosed recently. Delay of gastric emptying in diabetic patients may provide a uniqueor adjunctive approach to the treatment of type II diabetes.

The sequential changes in pancreatic exocrine function after abdominal surgery in the rat.

The sequential changes in pancreatic secretion in the conscious rat after pancreatic and intestinal surgery were examined. Rats were prepared with two duodenal cannulae and one cannula each for the pancreas, bile, and jugular vein. Pancreatic responses to Trasylol infused intraduodenally, bilepancreatic juice (BPJ) diversion, and exogenous secretin and cerulein administrations were determined every 24 h after the operation. The body weight significantly decreased during the first 24 h after the operation but remained constant thereafter. The basal protein output was significantly lower on the first and second postoperative days compared with values on the third through seventh days, although the fluid output was almost constant throughout the observation period. Intraduodenal infusion of Trasylol failed to stimulate pancreatic secretion on the first and second postoperative days. Pancreatic feedback responses to BPJ diversion were observed during the entire experimental period, but were attenuated during the first 3 days. Responses to exogenous secretin and cerulein were relatively unaffected by postoperative recovery time. Results suggest that the pancreas itself may recover sufficiently within 24 h after the operation to respond consistently to direct stimulation. However, considering the effects on basal secretion and the responses to intestinally mediated secretion, it appears best to wait at least 3 days after the operation before using these rats in experiments on pancreatic exocrine functions.

Effect of Atropine on Rat Basal Pancreatic Secretion during Return or Diversion of Bile-Pancreatic Juice

Abstract The effect of atropine on basal pancreatic exocrine secretion in conscious rats was determined with and without return of bile–pancreatic juice (BPJ) to the intestine. Rats were prepared with cannulas draining bile and pancreatic juice separately and with duodenal cannulas for return of secretions. Experiments were begun 3 days postoperatively. During continuous return of bile-pancreatic secretions, intravenous atropine (100 μg/kg-hr) caused a sustained 80–90% inhibition of pancreatic protein secretion, with a much smaller suppressive effect on pancreatic juice volume. Diversion of bile-pancreatic juice from the intestine markedly increased pancreatic protein and fluid secretion in control and atropine-infused rats, but the response was significantly inhibited by atropine (volume 31% inhibition, protein output 41% inhibition). The results indicate that basal pancreatic protein secretion during return of BPJ is largely maintained by cholinergic influence, possibly due to an enteropancreatic reflex, and that the inhibition of the pancreatic response to acute diversion of BPJ by atropine is probably secondary to inhibition of gastric secretion.

Gastric emptying in Mexican Americans compared to non-Hispanic whites

Mexican Americans, a group at high risk for type II diabetes mellitus, have higher postprandial insulin and glucose levels when compared to non-Hispanic whites. A rapid rate of gastric emptying contributes to an increased rate of nutrient absorption and subsequent greater elevation of postprandial glucose and insulin levels. A more rapid rate of gastric emptying and hyperinsulinemia have been observed in patients with recently diagnosed type II diabetes mellitus. In this study, we examined whether Mexican Americans have a more rapid rate of gastric emptying than non-Hispanic whites. Gastric emptying studies were performed on 32 nondiabetic Mexican Americans and on 31 nondiabetic non-Hispanic whites. The rate of gastric emptying following a liquid glucose meal was measured. Serum insulin, plasma glucose, and GIP levels were measured in fasting and postprandial blood samples collected at 15-min intervals for 2 hr. Adjusting for age, body mass index, and gender, the gastric half-emptying time of a glucose meal was significantly (P<0.05) more rapid for the Mexican American subjects (56.5±3.4 min) compared to the non-Hispanic white subjects (66.4±3.5 min). Nondiabetic Mexican Americans empty a liquid glucose meal more rapidly from their stomachs than nondiabetic non-Hispanic whites. Rapid gastric emptying is associated with hyperinsulinemia as a normal physiologic response to increased nutrient availability. The rapid gastric emptying observed in nondiabetic Mexican Americans is associated with hyperinsulinemia and could be a contributing factor for the increased risk of obesity and type II diabetes in this population.

Accelerated gastric emptying of glucose in Zucker type 2 diabetic rats: role in postprandial hyperglycaemia

Summary Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia.To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10–13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30 % glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t1/2 = 37.3 ± 1.5 vs 58.8 ± 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t1/2 = 123 ± 23 and 166 ± 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying may improve glucose control in this disease. [Diabetologia (1997) 40: 136–142]

Endogenous cholecystokinin, the major factor responsible for dietary protein-induced pancreatic growth.

This study was undertaken to clarify the role of endogenous cholecystokinin (CCK) in induction of pancreatic growth stimulated by a high protein diet. Rats with i.v. jugular cannulae in place and kept in Bollman cages were adapted to 5% casein diet for 9 days and switched to 70% casein for 2 days. MK-329, a CCK receptor antagonist, and SMS 201–995, a somatostatin agonist, were continuously infused at 0.5 mg/kg/h and 5 pg/kg/h, respectively, starting at the onset of feeding 70% casein. The 5 and 70% casein control groups were infused with saline. Feeding 70% casein significantly stimulated pancreatic hyperplasia and tissue hypertrophy. MK-329 and SMS 201–995 totally prevented 70% casein-induced increases in pancreatic weight and total RNA and DNA contents. The results indicate that endogenous CCK is the major factor responsible for pancreatic growth induced by a high protein diet.

Feedback Inhibition of Cholecystokinin Secretion by Bile Acids and Pancreatic Proteases

Feedback inhibition of CCK release by bile acids and pancreatic proteases is well established in the rat. The question of whether these mechanisms are important in humans has not been completely resolved, but current evidence strongly suggests that feedback regulation of CCK release by bile acids is present in humans and is physiologically significant, whereas the existence and importance of feedback regulation of CCK release by pancreatic proteases in humans are still highly controversial.

Interaction of Dietary Protein and Trypsin Inhibitor on Plasma Cholecystokinin and Pancreatic Growth in Rats

Pancreatic exocrine secretion in the rat is inhibited by trypsin, chymotrypsin and elastase in the proximal small intestine (Green and Lyman, 1972; Schneeman and Lyman, 1973; Green and Levan, 1985). Recent studies have supported the hypothesis that this negative feedback control of pancreatic secretion is mediated by cholecystokinin (CCK). Orogastric administration of trypsin inhibitors to rats caused a transient reduction of intestinal levels of CCK (Brand and Morgan, 1981) and greatly increased plasma levels of CCK (Liddle, Goldfine and Williams, 1984). Diversion of bile-pancreatic juice from the intestine increased plasma CCK levels, which were returned to normal by intraduodenal infusion of trypsin (Louie et al, 1985; Folsh et al, 1984). The mechanism by which pancreatic proteases inhibit CCK release is not known. Miyasaka and Green (1983) hypothesized that trypsin inhibited pancreatic secretion by inactivating an intraluminally-secreted peptide, possibly a CCK-releasing factor.

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.