Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects.

Recombinant glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5 d by prandial subcutaneous injections (PSI) (76 nmol 30 min before meals, four times daily; a total of 302.4 nmol/24 h) or by continuous subcutaneous infusion (CSI) (12.7 nmol/h; a total of 304.8 nmol/24 h). This was performed in nineteen healthy obese subjects (mean age 44.2 (sem 2.5) years; BMI 39.0 (sem 1.2) kg/m(2)) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15 % reduction in mean food intake per meal (P=0.02) after 5 d treatment. A weight loss of 0.55 (sem 0.2) kg (P<0.05) was registered after 5 d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0.001) and CSI (P<0.05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5 d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes.

OBJECTIVE: To establish the antidiabetogenic effect of glucagon-like peptide-1 (GLP-1) when differently administered relative to meal intake in subjects with type 2 diabetes. DESIGN: The study was a placebo-controlled comparison with random assignment to treatment sequence. A 3-h stepwise infusion of GLP-1 (17 nmol) was started either at the onset of a standard meal (550 kCal) (A) or at 30 min (B) or 60 min (C) after the start of the meal. SETTING: The study was conducted at a university hospital. SUBJECTS: Eight patients with type 2 diabetes (four women and four men), age 62 +/- 3.9 years (range 47-74 years), weight 79.8 +/- 5.4 kg (range 62-104 kg), BMI 26.2 +/- 1.3 kg m(-2) (range 21-31 kg m(-2)), diabetes duration 10.5 +/- 2.0 years (range 3-19 years) and HbA1c levels 6.1 +/- 0.3% (range 4.7-7.7%) participated in the study. All patients were treated with oral sulphonylureas. RESULTS: Glucagon-like peptide-1 significantly lowered postprandial glycaemia by a similar degree in all three situations versus the control meal (P < 0.05). Postprandial insulin levels were not different in the four experimental series, whereas the postprandial glucagon levels were significantly lowered by GLP-1 in (A) and (B) (P < 0.03) but not in (C). Gastric emptying, as determined by the paracetamol test, was retarded by GLP-1 only in (A) (P < 0.01), but not affected in (B) or (C). CONCLUSIONS: GLP-1 reduced postprandial hyperglycaemia in subjects with type 2 diabetes regardless of administration at the onset of meal intake or at 30 or 60 min after start of meal intake, although the mechanism of the antidiabetogenic action of GLP-1 depended on administration versus meal intake. Thus, when administered at the start of a meal, GLP-1 was antidiabetogenic mainly through retarding gastric emptying, whereas when given at 30 or 60 min after meal ingestion, changes in islet hormone secretion seem to be predominant.

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.

BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite. OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects. DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol x kg(-1) min(-1)) or saline. SUBJECTS: Eight obese (body mass index, BMI, 45.5 +/- 2.3 kg/m2) male subjects. MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique. RESULTS: Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7 +/- 0.5 MJ (21 +/- 6%) by GLP-1 infusion (P = 0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6 +/- 0.35 mmol/L; nadir: 5.3 +/- 0.15 mmol/L). No nausea was recorded during GLP-1 infusion. CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.

Glucagon-like peptide-1 retards gastric emptying and small bowel transit in the rat: effect mediated through central or enteric nervous mechanisms.

This study investigated effects of glucagon-like peptide-1(7-36)amide (GLP-1) on gastric emptying, small intestinal transit, and contractility of smooth muscle strips in rats. GLP-1 at doses of 10 and 20 pmol/kg/min administered intravenously dose-dependently retarded transit of the small intestine (P < 0.001), while only the higher dose of 20 pmol/kg/min retarded gastric emptying (P < 0.01). GLP-1 at concentrations up to 10(-4) M did not affect the basal tone or contractility of the gastrointestinal muscle strips that were stimulated with electric field stimulation or acetylcholine. Our results demonstrate that small intestinal transit seems more sensitive than gastric emptying to inhibition by GLP-1 at physiologic levels in plasma. Furthermore, this inhibition appears to be mediated through central mechanisms rather than through peripheral actions. Thus, GLP-1 is suggested to inhibit gastric emptying and small intestinal transit through an indirect effect via central or enteric nervous mechanisms.

Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men.

The gut peptide glucagon-like peptide 1(7-36) amide (GLP-1) is released into the circulation after food intake. GLP-1 has been shown to have an incretin effect and inhibits gastrointestinal motility in humans. In rats, intracerebral administration of GLP-1 results in reduced food intake. Obese humans have been found to have an attenuated plasma GLP-1 response to a mixed meal. To approximate the physiologic state, GLP-1 or saline was administered intravenously and randomly at the beginning of a test meal served on a universal eating monitor to 6 obese subjects to test our hypothesis that GLP-1 influences termination of food intake (and thus food intake during a meal) and feelings of satiety in humans. As a marker for gastric emptying, 1.5 g acetaminophen was given at the start of the meal. Blood samples for analysis of acetaminophen, insulin, glucose, glucagon, and C-peptide were obtained. Hunger, fullness, and food choice were assessed with visual analogue scales and food-choice questionnaires. GLP-1 infusion resulted in a prolonged period of reduced feelings of hunger, desire to eat, and prospective consumption after the meal. The rate of gastric emptying was slower during infusion of GLP-1. Postprandial blood glucose concentrations were reduced during the GLP-1 infusion, but the amount of energy consumed, eating rate, and plasma concentrations of insulin, glucagon, and C-peptide were unchanged. GLP-1 given exogenously at the start of a meal did not seem to affect meal termination or the amount of food eaten. However, postprandial feelings of hunger decreased, suggesting that exogenous GLP-1 may influence feelings of hunger and satiety in humans.

Inhibitory effect of glucagon-like peptide-1 on small bowel motility. Fasting but not fed motility inhibited via nitric oxide independently of insulin and somatostatin.

Effects of glucagon-like peptide-1 (GLP-1)(7-36)amide on fasted and fed motility in the rat small intestine were investigated in relation to its dependence on nitric oxide (NO), insulin, and somatostatin. Small bowel electromyography was performed using bipolar electrodes implanted 15, 25, and 35 cm distal to pylorus, and transit was studied with a radioactive marker. In the fasted state, GLP-1 (5-20 pmol kg-1min-1), reaching physiological plasma levels, prolonged the migrating myoelectric complex (MMC) cycle length along with slowed transit. This effect was antagonized by exendin(9-39)amide. The NO synthase inhibitor Nomega-nitro- L-arginine (L-NNA) also blocked the response to GLP-1, whereas L-arginine restored the response. Insulin (80-200 pmol kg-1min-1) induced irregular spiking, whereas somatostatin (100-500 pmol kg-1min-1) increased the MMC cycle length, independently of NO. In the fed state, GLP-1 (20-40 pmol kg-1min-1) reduced motility, an inhibition unaffected by L-NNA, whereas motility was stimulated by exendin(9-39)amide. Infusion of GLP-1 (20-100 pmol kg-1min-1) did not affect plasma insulin, but somatostatin was increased. In conclusion, GLP-1 seems to inhibit small bowel motility directly via the GLP-1 receptor. Inhibition of fasting motility is dependent of NO and not mediated via insulin or somatostatin, whereas inhibition of fed motility is independent of NO.

The ethanol augmentation of glucose-induced insulin secretion is abolished by calcium antagonism with nifedipine: no evidence for a role of glucagon-like peptide-1 (GLP-1).

We studied the effect of ethanol and calcium antagonism (nifedipine) on insulin- (n = 8) and glucagon-like peptide-1 (GLP-1) (n = 6) secretion in healthy subjects. Four experiments in random order were performed (control, ethanol, nifedipine, and combination). Intravenous glucose tolerance tests were performed with and without pretreatment with oral ethanol and nifedipine. Ethanol pretreatment was followed by increased insulin (ethanol vs. control; p < 0.01) and C-peptide (ethanol vs. control; p < 0.05) areas after intravenous glucose (0-20 min), indicating that ethanol augments insulin secretion. Calcium antagonism with nifedipine abolished the ethanol augmentation of insulin secretion (insulin area 0-20 min, ethanol vs. combination, p < 0.05; and C-peptide area 0-20 min, ethanol vs. combination, p < 0.01). The GLP-1 response (area 0-90 min) was not significantly affected by ethanol.

GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions.

OBJECTIVE: To examine the absorption of glucagon-like peptide (GLP)-1(7-36) amide from the buccal mucosa of type 2 diabetic patients. Previously, the effects of the peptide have been studied following intravenous and subcutaneous injection. Now, a mucoadhesive, biodegradable buccal GLP-1 tablet (9 mm) containing 119 nmol has been developed as a possible alternative to injection. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients received a single tablet under fasting conditions and before a standard meal in this randomized placebo-controlled study. RESULTS: The mean peak GLP-1 concentration was 125.1 pmol/l and occurred 30 min after application. The mean placebo-adjusted area under the curve was 5,334 min pmol/l, consistent with a relative bioavailability of 6% vs. intravenous injection and 42% vs. subcutaneous injection. The half-life of total peptide activity after buccal administration was 17 min. The placebo-adjusted glucose concentrations decreased by 1.4 mmol/l in fasting experiments and by 4.2 mmol/l after a standard mixed meal. In the fasting state at 30 min, plasma insulin increased by 185% and glucagon decreased by 20%, consistent with the increase in plasma GLP-1 concentrations. The peptide exerted a significant insulinotropic effect during meals (calculated as an insulinogenic index, 0-120 min; 84.1 vs. 45.7 in placebo experiments). CONCLUSIONS: Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single buccal tablet in type 2 diabetic patients. The peptide had a marked glucose-lowering effect during the first 2 h. This new GLP-1 tablet may become a feasible alternative treatment for type 2 diabetic patients, although a more prolonged pharmacokinetic profile is required.

No correlation between insulin and islet amyloid polypeptide after stimulation with glucagon-like peptide-1 in type 2 diabetes.

OBJECTIVES: To examine whether glucagon-like peptide-1 (GLP-1), which has been suggested as a new therapeutic agent in type 2 diabetes, affects circulating islet amyloid polypeptide (IAPP), a B-cell peptide of potential importance for diabetes pathophysiology. DESIGN: GLP-1 was administered in a buccal tablet (400 micrograms) to seven healthy subjects and nine subjects with type 2 diabetes. Serum IAPP and insulin levels were measured before and after GLP-1 administration. RESULTS: In the fasting state, serum IAPP was 4.1 +/- 0.3 pmol/l in the controls vs 9.8 +/- 0.9 pmol/l in the subjects with type 2 diabetes (P < 0.001). IAPP correlated with insulin only in controls (r = 0.74, P = 0.002) but not in type 2 diabetes (r = 0.26, NS). At 15 min after GLP-1, circulating IAPP increased to (6.0 +/- 0.5 pmol/l in controls P = 0.009) and to 13.8 +/- 1.2 pmol/l in type 2 diabetes (P = 0.021). In both groups, serum insulin increased and blood glucose decreased compared with placebo. In controls serum IAPP increased in parallel with insulin (r = 0.79, P = 0.032), whereas in type 2 diabetes the increase in IAPP did not correlate with the increase in insulin. CONCLUSION: Type 2 diabetes is associated with elevated circulating IAPP; GLP-1stimulates IAPP secretion both in healthy human subjects and in type 2 diabetes; IAPP secretion correlates with insulin secretion only in healthy subjects and not in type 2 diabetes.

The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.

OBJECTIVE: To investigate the long-term antidiabetogenic effect of glucagon-like peptide 1 (GLP-1) and its influence on diabetic dyslipoproteinemia, patients with NIDDM were treated with GLP-1 subcutaneously for 1 week. RESEARCH DESIGN AND METHODS: Twelve patients participated in the study. The 1st week of the study, all of them were on intensive insulin treatment and from day 8, four were randomized to a control group continuing with insulin, and eight to a treatment group where GLP-1 was given at meals together with regular insulin from day 8 to 12. On days 13 and 14, they were only given GLP-1 at meals. NPH insulin at bedtime was given throughout the study. RESULTS: In the GLP-1-treated patients, the doses of regular insulin, given to keep a satisfactory blood glucose control, were reduced compared with treatment with insulin only. GLP-1 virtually inhibited the early increase in blood glucose after the meals, whereas an increase of approximately 2 mmol was seen during an optimized insulin treatment. In agreement with the short half-life of the peptide, 2-h postprandial plasma insulin levels were significantly decreased both at day 12 and 14, suggesting that there was not enough GLP-1 left to stimulate endogenous insulin release and compensate for the decrease in the dose of exogenous insulin. Therefore, the effect of GLP-1 was lost before the next meal, resulting in increased preprandial blood glucose values at lunch and dinner. The concentration of VLDL triglycerides decreased already during the 1st week. This decrease persisted during the 2nd week when GLP-1 was included in the treatment. No changes were observed in the levels of LDL and HDL cholesterol. The LDL particle diameter increased from a mean of 22.3 to 22.6 nm (P < 0.01) in response to insulin treatment. A further increment to 22.9 nm (P < 0.05) was seen after GLP-1 treatment. The LDL particle size did not change in the control group. Lipoprotein lipase activity was decreased by 27% and hepatic lipase was reduced by 13% in the GLP-1-treated group. CONCLUSIONS: We confirm the antidiabetogenic effect of GLP-1 in NIDDM patients. This effect was maintained during 7 days, which implies that the patients did not develop tolerance during this treatment period. Intensive insulin treatment, leading to normotriglyceridemia, increased the mean LDL particle diameter, which is likely to lower the risk of future coronary heart disease in patients with NIDDM. Furthermore, an additive effect of GLP-1 is indicated. Hence, this study gives additional evidence that GLP-1 may be useful as an agent for treating NIDDM.

Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet.

OBJECTIVE: Glucagon-like peptide I(7-36) (GLP-I) amide, an endogenous incretin, has been identified as a potential adjunct to the treatment of NIDDM and has been studied following intravenous and subcutaneous injection. A mucoadhesive buccal GLP-I tablet containing 119 nmol has been developed to provide transmucosal absorption as a possible alternative to injection treatment. RESEARCH DESIGN AND METHODS: Eight healthy volunteers received a single tablet under fasting conditions in this randomized double-blind placebo-controlled study. A total GLP-I immunoreactivity was measured using COOH-terminal radioimmunoassay (RIA) (total peptide activity) and NH2-terminal RIA (active, nondegraded peptide). RESULTS: The mean (+/- SE) peak GLP-I concentration was 117 +/- 19 pmol/l and occurred 30 +/- 4 min after application. The mean placebo-adjusted area under curve was 8,145 +/- 873 pmol.min-1.l-1, consistent with a relative bioavailability of 7% versus intravenous injection and 47% versus subcutaneous injection. The levels of active peptide increased in parallel with total GLP-I. Half-life of peptide activity after buccal administration was 27 and 24 min measured with COOH-terminal and NH2-terminal RIA, respectively. Placebo adjusted insulin concentrations increased to a peak of 252 +/- 57 pmol/l, glucose decreased 1.4 +/- 0.2 mmo/l, and glucagon decreased 17 +/- 3 ng/l, consistent with the increase in plasma GLP-I concentrations. CONCLUSIONS: Therapeutic plasma levels of GLP-I in humans were achieved after a single buccal tablet. No increased degradation of GLP-I was found in the buccal mucosa compared to subcutaneous tissue. This alternative treatment form may be feasible in in the future for NIDDM.

Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas.

OBJECTIVE: To investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg-1.min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m2, mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS: GLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 +/- 0.4 and 4.5 +/- 0.1 vs. 6.0 +/- 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 +/- 60 vs. 724 +/- 91 mmol.l-1. min-1, area under the curve [AUC] [-30-180 min], P < 0.02), whereas glibenclamide had no effect (598 +/- 101 mmol.l-1. min-1, AUC [-30-180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 +/- 24 mmol. l-1.min, AUC [-30-180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 +/- 0.4; GLP-I 6.3 +/- 1.6, P < 0.01; glibenclamide 6.8 +/- 2.1, P < 0.01; combination 20.7 +/- 5.0, P < 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50% compared with the control subjects (P < 0.01). CONCLUSIONS: In acute experiments on overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.

The metabolic response to cholecystectomy: insulin resistance after open compared with laparoscopic operation.

OBJECTIVE: To study the changes in insulin sensitivity and plasma concentrations of interleukin-6 (IL-6) after open compared with laparoscopic cholecystectomy. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: 12 otherwise healthy patients undergoing either open (n = 6) or laparoscopic (n = 6) cholecystectomy. MAIN OUTCOME MEASURE: Relative insulin sensitivity (compared with preoperative) on the day after operation. Changes in IL-6 concentrations postoperatively. RESULTS: The mean (SEM) relative reduction in insulin sensitivity was significantly smaller after laparoscopic (18 (5)%) compared with the open operation, (58 (4)%) (p < 0.01). There was a significant increase in plasma concentrations of IL-6 postoperatively, but there was no difference between the groups. CONCLUSION: Insulin sensitivity is less affected 24 hours after laparoscopic than after open cholecystectomy, which in this study was not accompanied by a simultaneous difference in the IL-6 response. The small postoperative reduction of insulin sensitivity may be a contributing factor to the clinical benefit of improved wellbeing observed after laparoscopic surgery.

Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM.

OBJECTIVE: To investigate the effect of subcutaneously injected glucagon-like peptide 1 (GLP-1) (7-36)amide on postprandial plasma glucose, insulin, and C-peptide levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) and a secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: GLP-1 (25 nmol) was injected subcutaneously into either the abdominal wall or the gluteal region at a standardized depth and speed. The injection device was guided by the ultrasound determination of the depth of the fat layer. The peptide was given 5 min before a standard meal. Plasma concentrations of glucose, C-peptide, insulin, glucagon, and GLP-1 were followed during 240 min after the injection. RESULTS: In control experiments, a significant hyperglycemia was attained after the meal. GLP-1 given into the abdominal wall not only virtually abolished the post-prandial blood glucose rise but significantly decreased glucose concentrations, with a nadir at approximately 25 min after the injection. A rapid rise of C-peptide and insulin levels was observed 10-15 min after the injection of GLP-1. The stimulatory effect of GLP-1 was transient, and, at 45 min after the meal, both insulin and C-peptide levels were almost identical in GLP-1 and control experiments. Significantly lower glucagon concentrations were observed 35-65 min after the peptide injection. GLP-1 concentration in plasma increased from 10 pM to a peak concentration (Cmax) of 70 pM at Tmax 30 min after injection. Then GLP-1 levels rapidly decreased to 25 pM at 95 min and returned to basal at 215 min. The gluteal injection of GLP-1 had similar effects compared with the abdominal administration on plasma levels of glucose, insulin, C-peptide, and glucagon. CONCLUSIONS: GLP-1 is promptly absorbed from the subcutaneous tissue. It exerts a significant blood glucose lowering effect when administered before meals in overweight patients with NIDDM.

Glucose infusion instead of preoperative fasting reduces postoperative insulin resistance.

In severe catabolic states, such as burn injury, sepsis and accidental injury, a state of marked insulin resistance is encountered. Insulin resistance is also present after elective surgical treatment, more pronounced with increasingly greater magnitude of operation performed. Results of recent animal experiments have shown that even short periods of food deprivation, reducing carbohydrate reserves, alter responses to stress. This notion resulted in our questioning the rationale of carbohydrate depletion associated with overnight preoperative fasting. Twelve patients undergoing elective open cholecystectomy were randomly given no infusion (control group) or 5 milligrams per kilogram per minute of glucose infusion (glucose group) during preoperative overnight fasting. Insulin sensitivity (M value, milligram per kilogram per minute) was determined using the hyperinsulinemic normoglycemic clamp (plasma insulin level, 65 microunits per milliliter and blood glucose level, 4.5 millimoles per liter) before and the first postoperative day. Preoperative insulin sensitivity was similar in the two groups. Postoperatively, M values decreased by 55 +/- 3 percent (control group) and by 32 +/- 4 percent (glucose group) (p < 0.01). Plasma levels of insulin, c-peptide, glucagon, growth hormone, catecholamines and cortisol in connection with clamps were similar in both groups preoperatively and postoperatively. The present results indicate that active preoperative carbohydrate preservation may improve postoperative metabolism because postoperative occurrence of insulin resistance was reduced with preoperative glucose infusion.

Insulin resistance after abdominal surgery.

A study was carried out to determine the time course and degree of postoperative insulin resistance in patients undergoing elective abdominal surgery. Mean(s.e.m.) insulin sensitivity was determined before and on the first (n = 10), fifth, ninth and 20th (n = 5) days after elective open cholecystectomy using the normoglycaemic (4.7(0.1) mmol/l), hyperinsulinaemic (402(12)pmol/l) glucose clamp technique. Preoperative insulin sensitivity expressed as the M value varied from 2.3 to 8.2 mg per kg per min. The relative reduction in insulin sensitivity was most pronounced on the first day after surgery, at a mean(s.e.m.) of 54(2) per cent. Thereafter, a large variation between individuals was found during the course of recovery, and insulin sensitivity returned to normal 20 days after operation. On the first day after surgery, plasma concentrations of glucose, C peptide, noradrenaline and glucagon were slightly but significantly higher than before operation (P < 0.05), whereas insulin, growth hormone, cortisol and adrenaline levels were unaltered. Marked insulin resistance thus develops after elective upper abdominal surgery and persists for at least 5 days after operation. Factors other than simultaneous changes in levels of the hormones studied seem to regulate the maintenance of postoperative insulin resistance.

Development of postoperative insulin resistance is associated with the magnitude of operation.

OBJECTIVE: To study the development of insulin resistance and changes in stress hormone concentrations in patients undergoing elective operations of different magnitude. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: 12 otherwise healthy patients, undergoing elective surgery for cholecystectomy (n = 6) and inguinal hernia repair (n = 6). INTERVENTIONS: Insulin sensitivity was measured by the normoglycaemic, hyperinsulinaemic glucose clamp technique before operation (control) and on the first postoperative day. MAIN OUTCOME MEASURE: Relative insulin sensitivity (compared with preoperative) on the day after each operation. Changes in stress hormone concentrations in relation to the relative change in insulin sensitivity. RESULTS: After hernia repair, mean (SEM) insulin sensitivity was reduced by 32 (4)%, p < 0.05 compared with baseline, and after open cholecystectomy by 56 (3)%, (p < 0.05). The difference between the two groups was highly significant (p < 0.01). The changes in concentrations of catecholamines, glucagon, cortisol and growth hormone after operation were only small, and did not correlate with the relative changes in insulin sensitivity. CONCLUSIONS: Insulin resistance develops even after a minor elective operation, (inguinal hernia repair). The degree of postoperative insulin resistance was more pronounced after open cholecystectomy. The alteration in insulin sensitivity could not be related to simultaneous changes in the hormones studied.

Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.

BACKGROUND: Glucagon-like peptide-1 (7-36) amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known. METHODS: We compared the effect of an infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the effect of GLIP on insulin sensitivity. RESULTS: In the normal subjects, the infusion of GLIP significantly lowered the meal-related increases in the blood glucose concentration (P less than 0.01) and the plasma concentrations of insulin and glucagon (P less than 0.05 for both comparisons). The insulinogenic index (the ratio of insulin to glucose) increased almost 10-fold, indicating that GLIP had an insulinotropic effect. In the patients with NIDDM, the infusion of GLIP reduced the mean (+/- SE) calculated isoglycemic meal-related requirement for insulin from 17.4 +/- 2.8 to 2.0 +/- 0.5 U (P less than 0.001), so that the integrated area under the curve for plasma free insulin was decreased (P less than 0.05) in spite of the stimulation of insulin release. In the patients with IDDM, the GLIP infusion decreased the calculated isoglycemic meal-related insulin requirement from 9.4 +/- 1.5 to 4.7 +/- 1.4 U. The peptide decreased glucagon and somatostatin release in both groups of patients. In the normoglycemic-clamp studies in the patients with IDDM, the GLIP infusion significantly increased glucose utilization (saline vs. GLIP, 7.2 +/- 0.5 vs. 8.6 +/- 0.4 mg per kilogram of body weight per minute; P less than 0.01). CONCLUSIONS: GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM: