Gastric Inhibitory Polypeptide Levels Research Articles

Serum bile acid along with plasma incretins and serum high–molecular weight adiponectin levels are increased after bariatric surgery

Bariatric surgery has been shown to improve glucose tolerance, although the mechanism has not been fully elucidated. Animal studies have suggested important roles of bile acid (BA) as a regulator of energy homeostasis and glucose metabolism. However, little is known about its role in humans. We investigated the longitudinal changes of BA, incretins, and adipokines after significant weight reduction in 34 Japanese adults with morbid obesity who underwent laparoscopic bariatric surgery. In subjects who underwent malabsorptive or restrictive surgery, body mass index had markedly decreased from 43.0 ± 6.5 (SD) to 37.8 ± 5.7 kg/m 2 and from 45.3 ± 11.2 to 41.5 ± 10.5 kg/m 2, respectively, at 1 month after surgery. Glycated hemoglobin decreased from 6.1% ± 1.5% to 5.2% ± 0.4% and from 6.2% ± 1.3% to 5.4% ± 0.7%, and total BA level increased from 3.1 ± 3.5 to 7.2 ± 5.3 μmol/L and from 3.2 ± 2.6 to 9.4 ± 10.0 μmol/L, respectively. At baseline, serum concentration of primary BA was positively correlated with plasma gastric inhibitory polypeptide level ( r = 0.548, P = .001); and change in primary BA level was positively correlated with changes in plasma gastric inhibitory polypeptide ( r = 0.626, P = .001) and serum immunoreactive insulin level ( r = 0.592, P = .002) at 1 month after surgery. Furthermore, plasma glucagon-like peptide–1 and serum high–molecular weight adiponectin levels increased in both surgeries. These hormonal changes might explain the mechanism(s) of improved glucose tolerance after bariatric surgery in morbidly obese subjects.

Resistin-Like Molecule α Decreases Glucose Tolerance during Intestinal Inflammation

Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-alpha at baseline and following an experimental model of colitis. Relm-alpha was readily detected in the serum at baseline (4-5 ng/ml), and its level was regulated by energy uptake. Retnla(-/-) mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla(-/-) mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha was up-regulated, and DSS-treated Retnla(-/-) mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla(-/-) mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.

Hyperglycemia Acutely Lowers the Postprandial Excursions of Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide in Humans

Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acute hyperglycemia reduces the postprandial excursions of gastric inhibitory polypeptide (GIP) and GLP-1, and if so, whether this can be attributed to changes in gastric emptying. Fifteen nondiabetic individuals participated in a euglycemic clamp and a hyperglycemic clamp experiment, carried out over 285 min. A mixed meal was ingested after 45 min. Plasma concentrations of glucose, insulin, C-peptide, glucagon, triglycerides, GIP, and GLP-1 were determined, and gastric emptying was assessed using a (13)C-octanoate breath test. Glucose levels were 160 +/- 1 mg/dl during the hyperglycemic clamp experiments and 83 +/- 3 mg/dl during the euglycemia (P < 0.0001). Glucose infusion rates were higher during hyperglycemia, but meal ingestion led to a decline in glucose requirements in both experiments (P < 0.0001). Insulin and C-peptide levels were higher during the hyperglycemic clamp experiments (P < 0.0001), whereas glucagon levels were higher during euglycemia (P < 0.0001). The postprandial increases in GIP and GLP-1 concentrations were 46 and 52% lower during the experiments with hyperglycemia (P = 0.0017 and P = 0.021). Hyperglycemia also elicited a significant delay in gastric emptying (P < 0.0001). Hyperglycemia acutely reduces the postprandial levels of GIP and GLP-1, possibly through a deceleration of gastric emptying. This supports the concept that reduced incretin levels in some patients with type 2 diabetes are a consequence rather than a cause of type 2 diabetes.

Glucose-induced GIP levels in patients with insulinoma.

Gastric inhibitory polypeptide (GIP) levels during an oral glucose tolerance test (OGTT) have been determined in eight patients suffering from a single benign beta-cell adenoma. GIP hypersecretion and an absent correlation between the insulin: glucose ratio and plasma GIP concentration have been observed. Our data show that the insulinotropic effect of GIP is almost abolished in insulinoma patients. This finding may help explain blood glucose levels and the inappropriate plasma insulin response to oral glucose often observed in these patients.

High saturated-fat diet induces apoptosis in rat enterocytes and blunts GIP and insulin-secretive response to oral glucose load

Lipoapoptosis has been described in many organs and tissues, but never in enterocytes. We hypothesized that a high saturated-fat diet can induce duodenal enterocyte apoptosis and impair gastric inhibitory polypeptide (GIP) secretion. Forty male Wistar rats, approximately 4 months old, were randomized on standard laboratory or purified tripalmitin-based high-fat diet (59% calories). An oral-glucose tolerance test was performed after 30 and 90 days of diet to measure plasma glucose, insulin and GIP. Duodena were processed for histology and immunohistochemistry by transferase-mediated dUTP nick end-labeling (TUNEL) method. Apoptosis was confirmed by enzyme-linked immunosorbent assay. Glycemic response was significantly higher (P < 0.01 vs controls) in rats after 90 days. Insulin curve was markedly increased at 30 days, while it was blunted at 90 days. GIP area under the curve was 425.6 +/- 67.6 ng ml(-1) at 30 days vs 150.2 +/- 33.4 ng ml(-1) in controls (P < 0.001) and dropped to 53.8 +/- 25.8 ng ml(-1) at 90 days (P < 0.0001). TUNEL-positive nuclei were 66.08+/-26.19 at 30 days 57 (34.58+/-17 in controls, P < 0.05) and 216.99 +/- 129.42 nuclei per mm(3) at 90 days (38.75 +/- 18.36 in controls, P < 0.0001). A high saturated-fat diet stimulates GIP secretion but with time induces apoptosis of duodenal villi epithelium, showing for the first time that enterocytes are also prone to lipoapoptosis. The reduction of circulating GIP levels might contribute to hypoinsulinemia and hyperglycemia.

The islet enhancer vildagliptin: mechanisms of improved glucose metabolism

Vildagliptin is a potent, selective and reversible inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). GLP-1 and GIP are important for the maintenance of normal glucose homeostasis as they enhance the sensitivity of insulin (beta-cell) and glucagon (alpha-cell) secretion to glucose. The delicate balance that is achieved by the incretin hormones is disturbed in type 2 diabetes mellitus (T2DM). Mechanistic studies of vildagliptin performed to characterise the effects of DPP-4 inhibition on pancreatic islet function and glucose metabolism have found that vildagliptin produces dose-dependent reductions in DPP-4; these result in persistent levels of active GLP-1 and GIP in the circulation leading to improved beta-cell sensitivity to glucose and glucose-dependent insulin secretion, and improved alpha-cell sensitivity to glucose and reduction in inappropriate glucagon secretion. These islet effects in turn lead to a reduction of the inappropriate endogenous glucose production and glucose utilisation during meals, resulting in improved glucose tolerance, and to a reduction of the inappropriate endogenous glucose production during the postabsorptive period that contributes to a reduced fasting hyperglycaemia. These islet effects are associated with improved insulin sensitivity and reduced meal-related hypertriglyceridaemia. In contrast, the GLP-1 effect of significantly delaying gastric emptying was not evident with vildagliptin treatment. The metabolic benefits of vildagliptin observed in T2DM are also evident in subjects with impaired glucose tolerance. Hence, vildagliptin improves glucose metabolism mainly by improving islet function.

Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.

Predictors of Incretin Concentrations in Subjects With Normal, Impaired, and Diabetic Glucose Tolerance

Defects in glucagon-like peptide 1 (GLP-1) secretion have been reported in some patients with type 2 diabetes after meal ingestion. We addressed the following questions: 1) Is the quantitative impairment in GLP-1 levels different after mixed meal or isolated glucose ingestion? 2) Which endogenous factors are associated with the concentrations of GLP-1? In particular, do elevated fasting glucose or glucagon levels diminish GLP-1 responses? Seventeen patients with mild type 2 diabetes, 17 subjects with impaired glucose tolerance, and 14 matched control subjects participated in an oral glucose tolerance test (75 g) and a mixed meal challenge (820 kcal), both carried out over 240 min on separate occasions. Plasma levels of glucose, insulin, C-peptide, glucagon, triglycerides, free fatty acids (FFAs), gastric inhibitory polypeptide (GIP), and GLP-1 were determined. GIP and GLP-1 levels increased significantly in both experiments (P < 0.0001). In patients with type 2 diabetes, the initial GIP response was exaggerated compared with control subjects after mixed meal (P < 0.001) but not after oral glucose ingestion (P = 0.98). GLP-1 levels were similar in all three groups in both experiments. GIP responses were 186 +/- 17% higher after mixed meal ingestion than after the oral glucose load (P < 0.0001), whereas GLP-1 levels were similar in both experiments. There was a strong negative association between fasting glucagon and integrated FFA levels and subsequent GLP-1 concentrations. In contrast, fasting FFA and integrated glucagon levels after glucose or meal ingestion and female sex were positively related to GLP-1 concentrations. Incretin levels were unrelated to measures of glucose control or insulin secretion. Deteriorations in glucose homeostasis can develop in the absence of any impairment in GIP or GLP-1 levels. This suggests that the defects in GLP-1 concentrations previously described in patients with long-standing type 2 diabetes are likely secondary to other hormonal and metabolic alterations, such as hyperglucagonemia. GIP and GLP-1 concentrations appear to be regulated by different factors and are independent of each other.

Altered distribution of adiponectin isoforms in children with Prader–Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones

Prader-Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones. We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11.35 years, body mass index (BMI) Z-score 2.15] and 14 BMI-matched controls (median age 11.97 years, BMI Z-score 2.34). Despite comparable BMI Z-scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA-IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z-score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0.05), HOMA-IR (P < 0.01), BMI Z-score (P < 0.05), insulin (P < 0.01) and leptin (P < 0.05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls. Relative to controls of similar age and BMI Z-score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI-matched controls.

Entero-Endocrine Changes After Gastric Bypass in Diabetic and Nondiabetic Patients: A Preliminary Study

Alterations in entero-endocrine signaling may play a role in improvements in satiety and glucose tolerance after Roux-en-Y gastric bypass (RYGB). We report our findings of gut hormone secretion in a cohort of diabetic and nondiabetic morbidly obese patients. Ten morbidly obese subjects who underwent uncomplicated RYGB were studied: 5 were diabetic and 9 were female. Nonfasting plasma levels of glucagon-like peptide-1 (GLP-1), insulin, desacyl ghrelin, active ghrelin, neuropeptide Y (NPY), and gastric inhibitory polypeptide (GIP) were determined preoperatively and 6 months postoperatively. Mean patient age was 42 +/- 11 years, and the mean preoperative body mass index was 50 +/- 6 kg/m(2). At 6 months mean BMI fell to 33 +/- 5 kg/m(2) (P < 0.0001), and there were no differences between diabetics and nondiabetics with respect to amount of weight loss. In non-diabetics, compared to preoperative levels, there were significant increases in GLP-1 and desacyl-ghrelin in the nondiabetic patients (P = 0.046 and P = 0.016, respectively); no change in plasma insulin, active ghrelin, NPY, or GIP was demonstrated. In contrast, when compared to preoperative levels, there were no significant changes in entero-endocrine hormone levels in the diabetic cohort postoperatively. At 6 months postoperation, RYGB significantly alters the hormone levels for GLP-1 and desacyl-ghrelin in morbidly obese nondiabetic patients. No significant change was noted in a matched cohort of diabetic patients. Weight loss was similar in diabetics and nondiabetics, suggesting that GLP-1 and ghrelin are not the only mechanisms producing weight loss after RYGB.

Effective surgical treatment of obesity may be mediated by ablation of the lipogenic gut hormone gastric inhibitory polypeptide (GIP): evidence and clinical opportunity for development of new obesity-diabetes drugs?

Roux-en-Y bypass surgery is increasingly used for treatment of gross obesity due to the general inability of lifestyle change and existing drug treatments to counter the obesity epidemic. This common form of bariatric surgery involves bypass of the small intestine with significant reduction of body of weight that is independent of malabsorption. Strikingly, obesity-related diabetes is also cured by the procedure but prior to body weight loss. This is due to rapid improvement of insulin resistance and associated pancreatic beta-cell function. Several hypotheses have been proposed to account for this phenomenon, but the most attractive concerns surgical ablation of gastric inhibitory polypetide (GIP)-secreting intestinal K-cells. Thus, circulating GIP levels are decreased after Roux-en-Y bypass surgery and GIP is known to play a key role in lipid metabolism and fat deposition. Further, both genetic and chemical ablation of GIP in animal models has been shown to protect against obesity and associated metabolic disturbances. These observations in animals and man suggest that GIP receptor antagonism may afford an alternative therapeutic option for treatment of obesity-diabetes.

P195: Entero-endocrine effects of Roux-en-Y gastric bypass for morbid obesity

Introduction: Alterations in entero-endocrine signaling may play a role in improvements in appetite and glucose tolerance after Roux-en-Y gastric bypass (RYGB). We report our findings of gut hormone secretion in a cohort of diabetic and non-diabetic morbidly obese patients. Methods: 10 morbidly obese subjects who underwent uncomplicated RYGB were studied: 5 were diabetic and 9 were female. Non-fasting plasma levels of GLP-1, insulin, deacyl ghrelin, active ghrelin, neuropeptide YY (NPY), and gastric inhibitory polypeptide (GIP) were determined preoperatively and 6 months postoperatively. Paired t-test was used to compare hormone levels with p value <0.05 (** in table) considered significant. Results The patient age was 41.9 ± 10.8 years, and the preoperative BMI was 49.5 ± 5.9 kg/m2. The 6 month BMI fell to 32.6 ± 4.7 kg/m2 (p<0.0001), and there were no differences between diabetics and non-diabetics with respect to amount of weight loss. There were significant increases, compared to preoperative levels, for GLP-1 and deacyl-ghrelin in non-diabetics (p=0.046 & p=0.016, respectively). Insulin, active ghrelin, NPY, and GIP demonstrated no change after RYGB. There were no significant changes in entero-endocrine hormone levels for diabetic patients. Conclusions: At 6 months postoperation, RYGB significantly alters the hormone levels for GLP-1 and deacyl-ghrelin in nondiabetics but there were no significant changes in diabetics. Weight loss was similar in diabetics and non-diabetics, suggesting that GLP-1 and ghrelin are not the only mechanisms producing weight loss after RYGB. Tabled 1 BMI GLP-1 Insulin Deacyl Ghrelin Active Ghrelin NPY GIP Nondiabetics (n=5) Preop 49.7 1.0 660 11 3.4 28 38 Postop 31.9** 1.8** 960 18** 14 26 41 Diabetics (n=5) Preop 49.0 1.0 11000 28 9.0 31 43 Postop 33.3** 1.3 1200 30 0.88 28 42 Open table in a new tab

The gastroenteroinsular response to glucose ingestion during postexercise recovery

This study examined gastrointestinal hormone and peptide responses when glucose was ingested after prolonged exercise. Six endurance-trained male athletes ran on a treadmill for 2 h at 60% VO2 max. Immediately after the run, the athletes consumed 75 g of glucose in 250 ml of water (ExGLU) or flavored water as a placebo control (ExPL). On a separate visit, the athletes rested for 2 h and then consumed glucose (ConGLU). During the first 60 min of recovery from exercise alone (ExPL), plasma vasoactive intestinal peptide (VIP), gastrin, and glucagon-like peptide-1 (GLP-1) all increased significantly, whereas glucose, insulin, and gastric inhibitory polypeptide (GIP) were unchanged from the immediate postexercise value. When glucose was ingested after exercise (ExGLU), glucose, insulin, VIP, gastrin, GLP-1, and GIP were all increased (P < 0.01). However, when glucose was ingested after resting for 2 h (ConGLU), VIP levels were unaffected, although glucose, insulin, gastrin, GLP-1, and GIP levels increased (P < 0.05). The plasma glucose response was greater (P < 0.03) and the plasma insulin response lower (P < 0.004) during ExGLU compared with ConGLU. There was a significantly higher (P < 0.01) VIP response during the initial period of recovery in ExGLU than there was with both ExPL and ConGLU. Plasma VIP showed a modest negative correlation with circulating glucose (r = -0.35, P < 0.03) and insulin (r = -0.37, P < 0.03) during the ExGLU recovery period. In summary, when glucose is ingested after prolonged exercise, there is mild insulin resistance and a corresponding rapid transitory increase in plasma VIP. These data suggest that VIP may play an important glucoregulatory role when glucose is ingested during the immediate postexercise recovery period.

Biologic actions and therapeutic potential of the proglucagon-derived peptides

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.

Vildagliptin, a Dipeptidyl Peptidase-IV Inhibitor, Improves Model-Assessed β-Cell Function in Patients with Type 2 Diabetes

The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function. This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors. Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P < 0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P < 0.0001) relative to placebo. Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 ± 9.7 [mean ± SD] years) and body mass index (BMI; 26.0 ± 4.0 kg/m 2) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 ± 0.17 [mean ± SEM] v 1.75 ± 0.23 nmol/L in NGT; P = .018) and lower OGIS (397 ± 21 v 463 ± 12 mL/min/m 2; P = .005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 ± 51 v 774 ± 91 nmol/min/m 2, P = .001). This measure correlated inversely to the 2-hour glucose level ( r = −0.71; P < .001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 ± 2.4 v 20.0 ± 2.0 nmol/L; P = .035). Hepatic insulin extraction correlated linearly with OGIS ( r = 0.71; P < .001), but was not significantly different between the groups although there was a trend with lower extraction in IGT ( P = .055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT ( P = .036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.

Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects.

Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important factors in the pathogenesis of type 2 diabetes and have a promising therapeutic potential. Alterations of their secretion, in vivo degradation, and elimination in patients with chronic renal insufficiency (CRI) have not yet been characterized. Ten patients with CRI (aged 47 +/- 15 years, BMI 24.5 +/- 2.2 kg/m(2), and serum creatinine 2.18 +/- 0.86 mg/dl) and 10 matched healthy control subjects (aged 44 +/- 12 years, BMI 24.9 +/- 3.4 kg/m(2), and serum creatinine 0.89 +/- 0.10 mg/dl) were included. On separate occasions, an oral glucose tolerance test (75 g), an intravenous infusion of GLP-1 (0.5 pmol. kg(-1). min(-1) over 30 min), and an intravenous infusion of GIP (1.0 pmol. kg(-1). min(-1) over 30 min) were performed. Venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1 (total and intact), and GIP (total and intact; specific immunoassays). Plasma levels of GIP (3-42) and GLP-1 (9-36 amide) were calculated. Statistics were performed using repeated-measures and one-way ANOVA. After the oral glucose load, plasma concentrations of intact GLP-1 and intact GIP reached similar levels in both groups (P = 0.31 and P = 0.87, respectively). The concentrations of GIP (3-42) and GLP-1 (9-36 amide) were significantly higher in the patients than in the control subjects (P = 0.0021 and P = 0.027, respectively). During and after the exogenous infusion, GLP-1 (9-36 amide) and GIP (3-42) reached higher plasma concentrations in the CRI patients than in the control subjects (P < 0.001 and P = 0.0033, respectively), whereas the plasma levels of intact GLP-1 and GIP were not different between the groups (P = 0.29 and P = 0.27, respectively). Plasma half-lives were 3.4 +/- 0.6 and 2.3 +/- 0.4 min for intact GLP-1 (P = 0.13) and 5.3 +/- 0.8 and 3.3 +/- 0.4 min for the GLP-1 metabolite (P = 0.029) for CRI patients vs. healthy control subjects, respectively. Plasma half-lives of intact GIP were 6.9 +/- 1.4 and 5.0 +/- 1.2 min (P = 0.31) and 38.1 +/- 6.0 and 22.4 +/- 3.0 min for the GIP metabolite (P = 0.032) for CRI patients vs. healthy control subjects, respectively. Insulin concentrations tended to be lower in the patients during all experiments, whereas C-peptide levels tended to be elevated. These data underline the importance of the kidneys for the final elimination of GIP and GLP-1. The initial dipeptidyl peptidase IV-mediated degradation of both hormones is almost unaffected by impairments in renal function. Delayed elimination of GLP-1 and GIP in renal insufficiency may influence the pharmacokinetics and pharmacodynamics of dipeptidyl peptidase IV-resistant incretin derivatives to be used for the treatment of patients with type 2 diabetes.

The entero-insular axis in type 2 diabetes--incretins as therapeutic agents.

The search for intestinal factors regulating the endocrine secretion of the pancreas started soon after the discovery of secretin, i.e. nearly 100 years ago. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels have been named incretins. Of the known gut hormones only gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1 [7-36] amide) fulfill this definition.--The incretin effect (i.e. the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion) is markedly diminished in patients with type 2 diabetes mellitus, while the plasma levels of GIP and GLP-1 and their responses to nutrients are in the normal range. Therefore, a reduced responsiveness of the islet B-cells to incretins has been postulated. This insensitivity of the diabetic B-cells towards incretins can be overcome by supraphysiological (pharmacological) concentrations of GLP-1 [7-36], however not of GIP. Accordingly, fasting and postprandial glucose levels can be normalized in patients with type 2 diabetes by infusions of GLP-1 [7-36]. Further studies revealed that this is partially due to the fact that GLP-1 [7-36]--in addition to its insulinotropic effect--also inhibits glucagon secretion and delays gastric emptying. These three antidiabetic effects qualify GLP-1 [7-36] as an interesting therapeutic tool, mainly for type 2 diabetes. However, because of its short plasma half life time natural GLP-1 [7-36] is not suitable for subcutaneous application. At present methods are being developed to improve the pharmacokinetics of GLP-1 by inhibition of the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or by synthesis of DPP-IV resistant GLP-1 analogues. Also naturally occurring GLP-1 analogues (for instance exendin-4) with a much longer half life time than GLP-1 [7-36] are being tested.--Thus, after 100 years of speculations and experimentations, incretins and their analogues are emerging as new antidiabetic drugs.

The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia.

We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 +/- 0.4 years; BMI 27.7 +/- 1.7 kg/m2). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 +/- 11% by trimethaphan (P = 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (deltaglucose = -1.27 +/- 0.5 [with saline] vs. 0.1 +/- 0.4 mmol/l [with trimethaphan]; P = 0.008). This reduction at 25-60 min in glucose levels correlated significantly to the 10-min insulin response (r = 0.65, P = 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 +/- 9% (P = 0.045), which was lower than the reduction with trimethaphan (P = 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.

Misoprostol-Inhibited Rat Gastric Emptying Is Independent of Gastric Inhibitory Polypeptide Release

We studied the effects of orally or intraperitoneally administrated misoprostol on rat gastric emptying and looked what was the role of gastric inhibitory polypeptide (GIP) in this emptying. The rats initially received oral misoprostol at doses of 1, 10, 50, and 100 μg/kg. Another group of rats received misoprostol intraperitonally at doses of 10, 50, 250, and 500 μg/kg. Using an oral radiochromium motility marker, the liquid gastric emptying was measurement 30 min after misoprostol treatment. The plasma GIP levels were measured by a home-made radioimmunoassay kit. Oral treatments at the doses of 1 and 10 μg/kg did not influence emptying, whereas other doses delayed emptying (p < 0.01). Except the 10- μg/kg injection, other doses exhibited a dose-dependent inhibition in emptying (p < 0.01). Neither oral feeding nor intraperitoneal injection changed plasma GIP levels. We conclude that liquid gastric emptying is disturbed after various routes of misoprostol treatment; GIP appears less important in the misoprostol-mediated gastric emptying.