Plasma GLP-1 Concentrations Research Articles

Effect of feeding fat or intrajugular infusion of glucagon-like peptide-1 and cholecystokinin on dry matter intake, digestibility, and digesta rate of passage in growing wethers1

A cause and effect relationship between glucagon-like peptide 1 (7, 36) amide (GLP-1) and cholecystokinin (CCK) and DMI regulation has not been established in ruminants. Three randomized complete block experiments were conducted to determine the effect of feeding fat or infusing GLP-1 or CCK intravenously on DMI, nutrient digestibility, and Cr rate of passage (using Cr(2)O(3) as a marker) in wethers. A total of 18 Targhee × Hampshire wethers (36.5 ± 2.5 kg of BW) were used, and each experiment consisted of four 21-d periods (14 d for adaptation and 7 d for infusion and sampling). Wethers allotted to the control treatments served as the controls for all 3 experiments; experiments were performed simultaneously. The basal diet was 60% concentrate and 40% forage. In Exp. 1, treatments were the control (0% added fat) and addition of 4 or 6% Ca salts of palm oil fatty acids (DM basis). Treatments in Exp. 2 and 3 were the control and 3 jugular vein infusion dosages of GLP-1 (0.052, 0.103, or 0.155 µg•kg of BW(-1)•d(-1)) or CCK (0.069, 0.138, or 0.207 µg•kg of BW(-1)•d(-1)), respectively. Increases in plasma GLP-1 and CCK concentrations during hormone infusions were comparable with increases observed when increasing amounts of fat were fed. Feeding fat and infusion of GLP-1 tended (linear, P = 0.12; quadratic, P = 0.13) to decrease DMI. Infusion of CCK did not affect (P > 0.21) DMI. Retention time of Cr in the total gastrointestinal tract decreased (linear, P < 0.01) when fat was fed, but was not affected by GLP-1 or CCK infusion. In conclusion, jugular vein infusion produced similar plasma CCK and GLP-1 concentrations as observed when fat was fed. The effects of feeding fat on DMI may be partially regulated by plasma concentration of GLP-1, but are not likely due solely to changes in a single hormone concentration.

Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man

Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg − 1 min − 1 ) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1 ± 5.2 (saline) to 87.0 ± 11.5 min (PYY3-36), whereas retention at 120 min was 2.5 ± 1.4% for saline, 10.7 ± 4.4 for PYY1-36 and 15.8 ± 4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5 ± 22.6 mm) and decreased prospective consumption (VAS change 39.5 ± 7.7 mm). In conclusion, PYY3-36's reducing effect upon food intake might be mediated by a decreased gastric emptying rate.

Role of viscosity and fermentability of dietary fibers on satiety‐related hormones in rats

The objective of this study was to determine the effect of two dietary fiber characteristics ‐small intestinal contents viscosity and large intestinal fermentability ‐on satiety‐related hormones in rats. Diets contained fiber sources that were either not viscous, somewhat viscous, or highly viscous, and either highly fermentable or non‐fermentable, in a 2 X 3 factorial design. The dietary fiber content was 8% (w/w). Blood was drawn in the fasting state after 35 days. At 42 days, rats were food‐deprived for 15 hours then fed 4 g of their respective diets. Two h later, plasma and small intestinal contents were collected. In the fed state, rats fed non‐fermentable fibers had significantly greater plasma GLP‐1 concentration than fermentable fibers. In the fasted state, among non‐fermentable fibers, viscosity had no effect on GLP‐1 concentration. However, among fermentable fibers, greater viscosity reduced GLP‐1 concentration. In the fed state, rats fed fermentable fibers had a significantly greater plasma ghrelin concentration than non‐fermentable fibers. In the fasted state, ghrelin concentration was influenced by a complex interaction between viscosity and fermentability. Plasma leptin was unaffected by either viscosity or fermentability. In conclusion, fiber fermentability alters short‐acting satiety‐related hormones such that non‐fermentable fibers may increase satiety. (Support by GTC Nutrition)Grant Funding SourceIndustry

Appetite-related gut peptides, ghrelin, PYY, and GLP-1 in obese women with and without binge eating disorder (BED)

BED is characterized by overeating with a loss of control. The primary aim of the study was to measure plasma concentrations of three key gut peptides influencing hunger (ghrelin) and satiety (PYY, GLP-1) to ascertain potential abnormalities in BED. The participants were 10 obese BED and 9 obese nonBED premenopausal women. They did not differ in age, 30.1 ± 8.1 SD, BMI, 36.2 ± 5.9, or % body fat, 43.3 ± 5.7. Following a13-h overnight fast, blood was drawn (− 15, 0, 5, 15, 30, 60, 90, 120 min) for measurement of total plasma concentrations of ghrelin, PYY and GLP-1, pre and post ingestion of a nutritionally complete liquid meal (1256 kJ) at 9 am (0–5 min). Ratings of hunger and fullness preceded each blood draw. Ghrelin was significantly lower premeal at − 15 min ( P = .05) and postmeal at 90 min ( P = .027) and 120 min ( P = .025) in the BED group as compared to the nonBED group. Ghrelin also declined less postprandially in the BED group ( P = .019) with a longer time to the nadir value ( P = .004). However, fasting and meal-related changes in levels of PYY and GLP-1 did not differ between the groups nor did ratings of hunger and fullness. Following a randomized cognitive behavior and dietary intervention, the ghrelin values in BED normalized. Prior to treatment, the lower fasting ghrelin in BED may be a consequence of down regulation by overeating. The lack of differences in the satiety promoting hormones, PYY and GLP-1, makes them unlikely contributors to the binge eating in BED.

Abomasal infusion of casein, starch and soybean oil differentially affect plasma concentrations of gut peptides and feed intake in lactating dairy cows

The effects of specific nutrients on secretion and plasma concentrations of gut peptides (glucagon-like peptide-1 (7–36) amide (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin-8 (CCK)) differ across species, but are not reported for cattle. Our objective was to determine acute (hours) and chronic (1 week) effects of increased abomasal supply of protein, carbohydrate, or fat to the small intestine on dry matter intake (DMI) and plasma concentrations of GLP-1, GIP, CCK, and insulin. Four mid-lactation Holstein cows were used in a 4 × 4 Latin square design experiment. Treatments were 7-day abomasal infusions of water, soybean oil (500 g/d), corn starch (1100 g/d), or casein (800 g/d). Jugular vein plasma was obtained over 7 h at the end of the first and last day of infusions. Oil infusion decreased DMI on day 7, but total metabolizable energy (ME) supply (diet plus infusate) did not differ from water infusion. Casein and starch infusion had no effect on feed DMI; thus, ME supply increased. Decreased DMI on day 7 of oil infusion was accompanied by increased plasma GLP-1 concentration, but decreased plasma CCK concentration. Increased plasma GIP concentration was associated with increased ME supply on day 7 of casein and starch infusion. Casein infusion tended to increase plasma CCK concentration on both days of sampling, and increased plasma GLP-1 and insulin concentration on day 1 of infusion. The present data indicate a sustained elevation of plasma concentration of GLP-1, but not CCK, may contribute to the reduced DMI observed in dairy cows provided supplemental fat.

Plasma concentrations of glucagon-like peptide-1 and cholecystokinin in sheep are altered by the amount of dry matter intake and the addition of fat to the diet

Dry matter intake (DMI) regulation is important in ruminants as DMI is a major determinant of milk and meat production. It is known that the gut peptides glucagon-like peptide-17, 36 amide (GLP-1) and cholecystokinin-8 (CCK) can reduce DMI in nonruminants (Walsh, 1994). In ruminants, there is little information on the function or effects of diet on plasma concentrations of these peptides. Previous studies have shown that supplemental dietary fat (Relling and Reynolds, 2007b) increases plasma concentrations of GLP-1 and CCK and decreases DMI. In contrast, increased metabolizable energy intake (MEI) in early lactation also increases GLP-1 and CCK concentration in dairy cows (Relling and Reynolds, 2007a). Therefore, our objective was to determine if plasma concentrations of GLP-1 and CCK are affected by supplemental fat, and if the response differs for ad libitum versus restricted DMI.

Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats

Long-term treatment with dipeptidyl peptidase IV inhibitors (DPPIV-I) or glucagon-like peptide (GLP)-1 analogs may potentially affect intestinal growth by down- or upregulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12-wk administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg bid sc), or DPPIV-I (NN-7201, 10 mg/kg qd orally) in GK rats. Some animals were observed additionally for 9 wk after the end of treatment. Both treatments lowered glycated hemoglobin A1c at wk 12 vs. control (Ex-4, -0.8%; DPPIV-I, -0.4%). Body weight was reduced by Ex-4 compared with control (361 +/- 4 vs. 399 +/- 5 g; P < 0.001) because of reduced food intake, whereas neither parameter was affected by DPPIV-I. Linear bone growth was unaffected by either treatment. After treatment end, food intake in Ex-4 animals increased, and, by wk 21, body weight was identical in all groups. The small intestine of Ex-4-treated animals was larger at wk 12 compared with control (length, 135.6 +/- 1.6 vs. 124.5 +/- 2.3 cm, P < 0.001; absolute weight, 8.4 +/- 0.2 vs. 6.4 +/- 0.4 g, P < 0.001), being most pronounced proximally, where the absolute cross-sectional area related to body weight increased by 24% because of increased mucosal thickness. These effects were reversible, and 9 wk after the end of treatment, no differences between Ex-4 and control were apparent. Plasma GLP-2 concentrations were unaltered by either treatment, and Ex-4 had no agonistic or antagonistic effects on the transfected GLP-2 receptor. DPPIV-I had no intestinal effects. In conclusion, the continued presence of Ex-4 is necessary to maintain weight loss in GK rats. Effective antihyperglycemic treatment with Ex-4 increases intestinal mass reversibly, whereas DPPIV-I lacks intestinal effects.

Feeding Rumen-Inert Fats Differing in Their Degree of Saturation Decreases Intake and Increases Plasma Concentrations of Gut Peptides in Lactating Dairy Cows

Our objective was to determine the effect of feeding rumen-inert fats differing in their degree of saturation on dry matter intake (DMI), milk production, and plasma concentrations of insulin, glucagon-like peptide 1 (7-36) amide (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) in lactating dairy cows. Four midlactation, primiparous Holstein cows were used in a 4×4 Latin square experiment with 2-wk periods. Cows were fed a control mixed ration ad libitum, and treatments were the dietary addition (3.5% of ration dry matter) of 3 rumen-inert fats as sources of mostly saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), or polyunsaturated fatty acids (PUFA). Daily DMI, milk yield, and composition were measured on the last 4 d of each period. Jugular vein blood was collected every 30min over a 7-h period on d 12 and 14 of each period for analysis of plasma concentrations of hormones, glucose, and nonesterified fatty acids. Feeding fat decreased DMI, and the decrease tended to be greater for MUFA and PUFA compared with SFA. Plasma concentration of GLP-1 increased when fat was fed and was greater for MUFA and PUFA. Feeding fat increased plasma glucose-dependent insulinotropic polypeptide and CCK concentrations and decreased plasma insulin concentration. Plasma CCK concentration was greater for MUFA and PUFA than for SFA and was greater for MUFA than PUFA. Decreases in DMI in cows fed fat were associated with increased plasma concentrations of GLP-1 and CCK and a decreased insulin concentration. The role of these peptides in regulating DMI in cattle fed fat requires further investigation.

Plasma Concentrations of Gut Peptides in Dairy Cattle Increase after Calving

Effects of transition from late gestation to early lactation on plasma concentrations of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1-(7-36) amide (GLP-1), and cholecystokinin (CCK) have not been reported in cattle. The objective of the present study was to measure plasma concentrations of GLP-1, GIP, CCK, insulin, glucose, and nonesterified fatty acids in blood plasma obtained from the coccygeal vein of 32 Holstein cows at an average of 11 d before, and 5, 12, and 19 d after calving. Feed dry matter intake (DMI) averaged 14.4, 17.7, and 19.9 kg/d on d 5, 12, and 19 of lactation, respectively, as milk yield increased (30.6, 36.6, and 39.7 kg/d, respectively). Plasma concentrations of insulin and glucose were lower postpartum than prepartum, but did not differ among samples collected after calving. In contrast, plasma concentration of gut peptides increased linearly after calving, perhaps as a consequence of increased feed intake and nutrient absorption; however, the increases in plasma concentrations of GIP and GLP-1 as lactation progressed were not associated with increased DMI per se, and likely reflect the endocrine and metabolic adaptations of lacto-genesis. In contrast, increased concentration of CCK was related both to increasing days in milk and DMI. By 19 d postpartum, concentrations of GLP-1, GIP, and CCK increased by 2.3-, 1.8-, and 2.8-fold, respectively, compared with values at 11 d before calving. Although these peptides have direct and indirect effects that reduce appetite and DMI in other species (including increased insulin secretion), these may be glucose- or insulin-dependent functions, and insulin and glucose concentrations were reduced in early lactation.

A Possible Role of GLP-1 in the Pathophysiology of Early Dumping Syndrome

Exaggerated plasma concentrations of GLP-1 precede reactive hypoglycemia after oral glucose in gastrectomy patients, resulting in late dumping syndrome. Recently, we showed that GLP-1 elicits the activation of sympathetic outflow. Because sympathetic activation is thought to be a cause of early dumping, we hypothesized that exaggerated GLP-1 may contribute to the pathophysiology of early dumping syndrome. In 11 patients after gastrectomy and 14 controls, blood pressure, heart rate, and plasma concentrations of norepinephrine, epinephrine, GLP-1, glucagon, insulin, and glucose were measured after oral glucose. In gastrectomy patients, GLP-1, norepinephrine, and heart rate peaked 15 to 30 min after oral glucose. Significant positive correlations were found among GLP-1, norepinephrine, and heart rate at 30 min, and these parameters at 30 min were significantly higher in patients with early dumping syndrome. These results suggest that GLP-1 is involved in the pathophysiology of early dumping syndrome.

α‐Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon‐like peptide 1 (7–36 amide) and to delay gastric emptying in Type 2 diabetic patients

Acarbose is able to enhance GLP-1 release and delay gastric emptying in normal subjects. The effect of alpha-glucosidase inhibition on GLP-1 has been less evident in Type 2 diabetic patients. The aim of this study was to investigate the possible influence of acarbose on GLP-1 release and gastric emptying in Type 2 diabetic patients after a mixed test meal. Ten Type 2 diabetic patients were tested with 100 mg acarbose or placebo served with a mixed meal that was labelled with 100 mg 13C-octanoic acid. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1 and GIP were determined over 6 h. Gastric emptying was measured by determining breath 13CO2 using infrared absorptiometry. Statistics repeated-measures anova. Gastric emptying rates (t1/2: 162 +/- 45 vs. 163 +/- 62 min, P = 0.65) and plasma concentrations (increasing from approximately 12 to approximately 25 pmol/l, P = 0.37) and integrated responses of GLP-1 (P = 0.37) were not changed significantly by acarbose treatment. Postprandial plasma glucose concentrations (P < 0.0001) and their integrated responses were lowered by acarbose (by 64%; P = 0.016). The plasma concentrations of insulin and C-peptide were reduced (P = 0.007 and 0.057, respectively) by acarbose, while glucagon was not changed (P = 0.96). GIP plasma concentrations (increasing with placebo from approximately 10 to approximately 85 pmol/l and with acarbose to approximately 55 pmol/l (P < 0.0001) and their integrated responses were significantly lowered (by 43%) by acarbose (P = 0.021). After 2 weeks of acarbose treatment (50 mg t.i.d. for the first and 100 mg t.i.d. for the second week, n = 6), similar results were found. In hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a mixed test meal failed to enhance GLP-1 release and did not influence gastric emptying.

Nutrient-stimulated GLP-1 Release in Normal-weight Men and Women

The aim of the present study was to investigate the effect of a monosaccharide/fiber preload (galactose/guar gum) in combination with a standard breakfast (GG) on plasma GLP-1, insulin, glucose, free fatty acid concentrations, and appetite ratings (satiety, hunger, fullness and desire to eat) in 30 normal-weight subjects. GG was compared to water in combination with the standard breakfast (W). We also tested for differences in GLP-1 release in the described conditions between genders. In women, postprandial plasma GLP-1 concentrations after GG were significantly increased compared to W (p < 0.05). The area under the curve (AUC) for DeltaGLP-1 after GG was related to body fat (%BF) in women (r = 0.48; p = 0.02), but not in men. The rise in plasma insulin was delayed, and plasma glucose concentration was blunted after GG. Deltasatiety was significantly related to DeltaGLP-1 (W). In conclusion, galactose with guar gum increased and extended the GLP-1 release due to breakfast in women, but not in men. This may be partly explained by %BF, which is higher in women than in men since GLP-1 release appears to be related to %BF.

Effects of an Olive Oil–Enriched Diet on Plasma GLP-1 Concentration and Intestinal Content, Plasma Insulin Concentration, and Glucose Tolerance in Normal Rats

The present study aims mainly at measuring, in normal rats, the GLP-1 response to oral intake of an olive oil-enriched diet (OO), and at assessing the long-term effects of such a diet on the GLP-1 content of the intestinal tract, as well as the plasma D-glucose, insulin, and GLP-1 pattern during an oral glucose tolerance test. In meal-trained rats, the mean increment in plasma GLP-1 concentration at min 10 and 20 was 1.39 +/- 0.23 ng/mL higher (p < 0.001) in the rats given access to the OO diet rather than control diet. Relative to the initial value (d 0), the gain in body weight at d 50 was also higher in the animals fed the OO rather than control diet. At d 50, the GLP-1 content of the jejunum, ileum, colon, and cecum were not significantly different in the two groups of rats. At d 19 and 36, the increment in both plasma insulin concentration and paired ratio between plasma insulin and D-glucose concentrations were again higher, during an oral glucose tolerance test conducted in overnight fasted animals, in the rats otherwise fed the OO, as distinct from control, diet. The intake of an olive oil-enriched diet thus increases, in normal rats, GLP-1 release, this coinciding during long-term exposure to the OO diet with higher body weight gain, increased secretory response of insulin-producing cells to oral glucose administration, and, after 36 d, improved glucose tolerance.

Syrian Golden hamster - A model forExamining Metabolic Effects of Volitional Training.

1747 The Syrian Golden hamster is commonly used as a model of dietary induced insulin resistance. Fat metabolism in hamsters closely resembles that in humans and this animal is known to exercise voluntarily. PURPOSE: To explore the metabolic effects of volitional training on young, healthy Syrian hamsters. METHODS: Male, 24- day old, hamsters with initial weight of 46.6 ± 0.83g (mean ± SEM), were randomly divided into sedentary (n = 8) and trained (n = 8) groups. The training group had 24-hour access to running wheels over 4 weeks of study. Food consumption, body weight and running distance were recorded daily and blood glucose was measured once per week. Non-fasted animals were euthanized by decapitation under CO2 anaesthesia and blood and tissues were collected for analysis. Plasma leptin, insulin, GLP-1, glucagon and amylin concentrations were measured in 10ul of serum using a Rat/Mouse Endocrine Panel (Linco Research, Inc.). RESULTS: The distance ran increased during the training period from 12.8 ± 1.11km/day at week 1 to 20.3 ± 0.82km/day at week 4. By the second week, food consumption was significantly higher (p<0.01) in trained (9.6 ± 0.2g/day) than in sedentary (6.48 ± 0.13g/day) animals. Although both groups gained weight, there was no difference in body mass between groups at any time point. Right visceral fat pad was larger (p<0.001) in sedentary (0.72 ± 0.04g) than in trained (0.24 ± 0.02g) animals. There was no difference in the blood glucose over the duration of the study between the trained and sedentary controls (4.6 ± 0.08mM/L vs 4.8 ± 0.1mM/L respectively). Leptin levels in sedentary hamsters were higher (p<0.05) than in trained hamsters (92.2 ± 15.7pM vs 35.5 ± 6.17pM, respectively). No significant difference was seen between the trained and sedentary animals in plasma insulin (284 ± 50.6pM vs 291.6 ± 49.7pM) nor GLP-1 (14.57 ± 3.9pM vs 10.93 ± 1.4pM) levels. Plasma glucagon and amylin were not detectible in sufficient animals to allow for comparison between groups. CONCLUSION: Our observations reveal that the extremely high volume of exercise exhibited by the animals, as well as their metabolic profile, may make this animal model particularly useful for the study of physiological effects of heavy endurance type training on metabolism.

Syrian Golden hamster - A model forExamining Metabolic Effects of Volitional Training.

1747 The Syrian Golden hamster is commonly used as a model of dietary induced insulin resistance. Fat metabolism in hamsters closely resembles that in humans and this animal is known to exercise voluntarily. PURPOSE: To explore the metabolic effects of volitional training on young, healthy Syrian hamsters. METHODS: Male, 24- day old, hamsters with initial weight of 46.6 ± 0.83g (mean ± SEM), were randomly divided into sedentary (n = 8) and trained (n = 8) groups. The training group had 24-hour access to running wheels over 4 weeks of study. Food consumption, body weight and running distance were recorded daily and blood glucose was measured once per week. Non-fasted animals were euthanized by decapitation under CO2 anaesthesia and blood and tissues were collected for analysis. Plasma leptin, insulin, GLP-1, glucagon and amylin concentrations were measured in 10ul of serum using a Rat/Mouse Endocrine Panel (Linco Research, Inc.). RESULTS: The distance ran increased during the training period from 12.8 ± 1.11km/day at week 1 to 20.3 ± 0.82km/day at week 4. By the second week, food consumption was significantly higher (p<0.01) in trained (9.6 ± 0.2g/day) than in sedentary (6.48 ± 0.13g/day) animals. Although both groups gained weight, there was no difference in body mass between groups at any time point. Right visceral fat pad was larger (p<0.001) in sedentary (0.72 ± 0.04g) than in trained (0.24 ± 0.02g) animals. There was no difference in the blood glucose over the duration of the study between the trained and sedentary controls (4.6 ± 0.08mM/L vs 4.8 ± 0.1mM/L respectively). Leptin levels in sedentary hamsters were higher (p<0.05) than in trained hamsters (92.2 ± 15.7pM vs 35.5 ± 6.17pM, respectively). No significant difference was seen between the trained and sedentary animals in plasma insulin (284 ± 50.6pM vs 291.6 ± 49.7pM) nor GLP-1 (14.57 ± 3.9pM vs 10.93 ± 1.4pM) levels. Plasma glucagon and amylin were not detectible in sufficient animals to allow for comparison between groups. CONCLUSION: Our observations reveal that the extremely high volume of exercise exhibited by the animals, as well as their metabolic profile, may make this animal model particularly useful for the study of physiological effects of heavy endurance type training on metabolism.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients

The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose. After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans.

Fatty acids affect insulin secretion in vivo, but little is known about the effects of specific fatty acids. Our aim was to investigate differential effects of acutely increased plasma monounsaturated, polyunsaturated and saturated fatty acids on glucose-stimulated insulin secretion in healthy humans. A new experimental protocol was used to increase plasma monounsaturated (MUFA test), polyunsaturated (PUFA test) or saturated (SFA test) non-esterified fatty acids for 2 h by repeated oral fat feeding and continuous intravenous heparin infusion. This was followed by a hyperglycaemic clamp (10 mmol/l) to test insulin secretion in response to a prior plasma NEFA increase. Total plasma NEFA concentrations were increased during the fat tests compared to the control visit (1.7-fold increase for MUFA and SFA tests and 1.4-fold increase for PUFA test; p<0.001). Exaggerated responses in plasma insulin, C-peptide and proinsulin concentrations were seen during the hyperglycaemic clamp after increasing plasma NEFA concentrations compared with the control (p<0.01). The effects were greatest for the MUFA test followed by the PUFA test and SFA test (p<0.01). Plasma GLP-1 concentrations increased during fat feeding, with a higher response during the MUFA test compared to PUFA and SFA tests (p<0.01). Increasing plasma NEFA concentrations by oral fat feeding with heparin infusion augments glucose-stimulated insulin secretion with the greatest effect for monounsaturated fatty acids and the lowest effect for saturated fatty acids. Monounsaturated fatty acids also increase GLP-1 more than saturated fatty acids. Therefore, the exaggerated insulin concentrations could be due to both NEFA and GLP-1.

Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome.

Rapid gastric emptying and exaggerated plasma concentrations of the insulinotropic hormone GLP-1 precede reactive hypoglycemia after oral glucose in gastrectomy patients. We suspected that the plasma volume drop associated with rapid gastric emptying (early dumping) would be accompanied by elevated plasma concentrations of norepinephrine. In order to study any relationship between postprandial norepinephrine, the enteroinsular axis, and plasma glucose, twelve patients with dumping syndrome and nine controls were studied. The plasma concentrations of norepinephrine, GLP-1, GIP, glucagon, insulin, and glucose were measured following a 1.5 g/kg lean body mass glucose meal. The early (0-30 min) integrated norepinephrine concentration was significantly higher in dumpers (22.1 +/- 3.8 nmol/ml/min) compared to controls (14.7 +/- 3.1 nmol/ml/min; P < 0.001) and correlated closely with the postprandial hematocrit increment (r = 0.71; P < 0.05). Early immunoreactivities of GLP-1, GIP, and glucagon peaked 30 min after glucose ingestion and were significantly higher in dumpers. Insulin peaked after 60 min and correlated with early GLP-1. In 11 of the patients glucose fell below baseline after a median interval of 120 min. Glucose at 120 min, when most of the nadirs occurred was lowest in patients with high early GLP-1 concentrations (r = 0.78; P < 0.001). Gel filtration chromatography of the dumpers' plasma revealed that pancreatic glucagon was detectable at time 0 and after 20 min, but not after 120 min. It is concluded that in dumpers pancreatic glucagon is augmented in the early postprandial period, probably through stimulation by catecholamines. At 120 min, when most of the hypoglycemias are encountered, pancreatic glucagon is no longer detectable, probably through inhibition by GLP-1.

Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon

BACKGROUNDThe glucagon-like peptides (GLP) 1 and 2 are secreted postprandially from L cells located mainly in the ileum. Both hormones prolong intestinal transit and GLP-2 is intestinotrophic in rodents. Patients...

Effect of glucagon on carbohydrate‐mediated secretion of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (7–36 amide) (GLP‐1)

Background The insulinotropic hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–36 amide) (GLP-1), regulate insulin secretion to nutrient intake and constitute the endocrine arm of the entero-insular axis. Glucagon has been implicated in the pathophysiology of conditions characterised by abnormal glucose tolerance such as obesity and diabetes mellitus although its effect on the entero-insular axis is not fully understood. Materials and methods We investigated the effect of exogenous glucagon on the entero-insular axis and its relation to gastric emptying in six healthy men aged [mean (±S.E.M.)] 23.6 (0.9) years with a body mass index of 24.0 (1.5) kg/m2. Plasma glucose, GIP, GLP-1, insulin and paracetamol concentrations were measured before and after a 100 g oral carhohydrate load containing 1.5 g of paracetamol for 6 h during intravenous infusion of either glucagon or saline. Results When compared to the saline infusion, peak and integrated insulin and glucose concentrations were higher (p<0.05) following glucagon infusion. After 60 min paracetamol concentrations were lower (p<0.05) following glucagon infusion. Integrated responses for GIP and GLP-1 were markedly reduced following glucagon infusion. Conclusions Exogenous glucagon in addition to its well-documented action of increasing glucose and insulin concentrations and delaying gastric emptying also markedly reduces GIP and GLP-1 secretion. The inhibition of GLP-1 soon after commencement of glucagon infusion supports a direct effect of glucagon on intestinal L-cells. We speculate that the marked inhibition of postprandial GLP-1 secretion by glucagon may be of importance in the pathogenesis of relative insulinopenia in Type 2 diabetes and in the development of reduced satiety in obesity and diabetes. Copyright © 1999 John Wiley & Sons, Ltd.