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Baptist Gallwitz - One of the best experts on this subject based on the ideXlab platform.

  • glucagon like peptide 1 and Gastric Inhibitory Polypeptide new advances
    Current Opinion in Endocrinology Diabetes and Obesity, 2016
    Co-Authors: Baptist Gallwitz
    Abstract:

    Purpose of review Glucagon-like peptide-1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP) are gastrointestinal peptides that play an important role as incretin hormones in the regulation of plasma glucose and insulin secretion. GLP-1-based therapies have therefore been implemented as treatment for type 2 diabetes (T2D). The purpose of this review is to summarize novel treatment options for T2D with GLP-1-based therapies. In addition, both peptides have relevant extrapancreatic effects that have been further characterized recently and are summarized in this review. Recent findings Novel findings regarding changes in GLP-1 secretion after bariatric surgery are highlighted, wherein GLP-1 plays a role in promoting body weight loss and diabetes remission. For T2D therapy, novel options with long-acting GLP-1 analogs are summarized that show a good efficacy and safety profile, also in combination with insulin as well as for obesity treatment. As GIP is not suitable for T2D therapy, extrapancreatic effects of GIP, mainly on bone metabolism that have been characterized recently, are described. These show that the activated GIP receptor is important to allow optimal bone mass and structure. Summary This review summarizes new findings on the physiology and pathophysiology of GLP-1 and GIP and novel therapeutic aspects.

  • influence of Gastric Inhibitory Polypeptide on pentagastrin stimulated Gastric acid secretion in patients with type 2 diabetes and healthy controls
    World Journal of Gastroenterology, 2006
    Co-Authors: Juris J Meier, M A Nauck, Jens J Holst, Carolyn F Deacon, W E Schmidt, Bartholomaeus Kask, Baptist Gallwitz
    Abstract:

    AIM: Gastric Inhibitory Polypeptide is secreted from intestinal K-cells in response to nutrient ingestion and acts as an incretin hormone in human physiology. While animal experiments suggested a role for GIP as an inhibitor of Gastric secretion, the GIP effects on Gastric acid output in humans are still controversial. METHODS: Pentagastrin was administered at an infusion rate of 1 µg . kg-1 . h-1 over 300 min in 8 patients with type 2 diabetes (2 female, 6 male, 54 ± 10 years, BMI 30.5 ± 2.2 kg/m2; no history of autonomic neuropathy) and 8 healthy subjects (2/6, 46 ± 6 years., 28.9 ± 5.3 kg/m2). A hyperglycaemic clamp (140 mg/dl) was performed over 240 min. Placebo, GIP at a physiological dose (1 pmol . kg-1 . min-1), and GIP at a pharmacological dose (4 pmol . kg-1 . min-1) were administered over 60 min each. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at the beginning of each infusion period, respectively. Gastric volume, acid and chloride output were analysed in 15-min intervals. Capillary and venous blood samples were drawn for the determination of glucose and total GIP. Statistics were carried out by repeated-measures ANOVA and one-way ANOVA. RESULTS: Plasma glucose concentrations during the hyperglycaemic clamp experiments were not different between patients with type 2 diabetes and controls. Steady-state GIP plasma levels were 61 ± 8 and 79 ± 12 pmol/l during the low-dose and 327 ± 35 and 327 ± 17 pmol/l during the high-dose infusion of GIP, in healthy control subjects and in patients with type 2 diabetes, respectively (P = 0.23 and p 0.99). Pentagastrin markedly increased Gastric acid and chloride secretion (P < 0.001). There were no significant differences in the rates of Gastric acid or chloride output between the experimental periods with placebo or any dose of GIP. The temporal patterns of Gastric acid and chloride secretion were similar in patients with type 2 diabetes and healthy controls (P = 0.86 and P = 0.61, respectively). CONCLUSION: Pentagastrin-stimulated Gastric acid secretion is similar in patients with type 2 diabetes and healthy controls. GIP administration does not influence Gastric acid secretion at physiological or pharmacological plasma levels. Therefore, GIP appears to act as an incretin rather than as an enterogastrone in human physiology.

  • secretion of incretin hormones and the insulinotropic effect of Gastric Inhibitory Polypeptide in women with a history of gestational diabetes
    Diabetologia, 2005
    Co-Authors: Juris J Meier, Jens J Holst, Kirsten Vollmer, Carolyn F Deacon, Baptist Gallwitz, Wolfgang E Schmidt, M Askenas, M A Nauck
    Abstract:

    The insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg−1 min−1; 30–90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

  • stimulation of insulin secretion by intravenous bolus injection and continuous infusion of Gastric Inhibitory Polypeptide in patients with type 2 diabetes and healthy control subjects
    Diabetes, 2004
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Baptist Gallwitz, Bartholomaeus Kask, Wolfgang E Schmidt, Michael A Nauck
    Abstract:

    A reduced insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is a characteristic of patients with type 2 diabetes. It was the aim of this study to determine the response of insulin secretion to different GIP doses administered by intravenous bolus injection and via continuous infusion in both healthy subjects and patients with type 2 diabetes. Eight patients with type 2 diabetes and eight healthy subjects participated in a 240-min hyperglycemic clamp (140 mg/dl) with intravenous infusion of placebo, GIP at a low dose, and GIP at a high dose, each administered continuously over 60 min. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at 0, 60, and 120 min, respectively. Capillary and venous blood was drawn for glucose, insulin, C-peptide, and GIP. Plasma insulin and C-peptide concentrations were lower in patients than in control subjects during all infusion periods. GIP bolus administration evoked a significant increase in plasma insulin levels in both patients with type 2 diabetes and healthy subjects. In contrast, the continuous GIP infusion led to a weak increase in insulin secretion in both healthy subjects and type 2 diabetic patients. The dose-response relationship for the increase in insulin secretion after GIP bolus administration was similar in both groups, although at different degrees of β-cell function. The stimulation of insulin secretion by GIP is stronger after its bolus administration than during continuous infusion. Even though the insulin secretory capacity is generally impaired in patients with type 2 diabetes, the relative sensitivity of insulin secretion to a bolus administration of GIP is almost preserved. Therefore, the existence of a specific GIP receptor defect in type 2 diabetes appears unlikely.

  • secretion degradation and elimination of glucagon like peptide 1 and Gastric Inhibitory Polypeptide in patients with chronic renal insufficiency and healthy control subjects
    Diabetes, 2004
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Michael A Nauck, Wolfgang E Schmidt, Daniel Kranz, Dirk Gaeckler, Baptist Gallwitz
    Abstract:

    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 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.

Jens J Holst - One of the best experts on this subject based on the ideXlab platform.

  • postmenopausal women with impaired glucose
    2015
    Co-Authors: Hillevi Larsson, Jens J Holst
    Abstract:

    Reduced Gastric Inhibitory Polypeptide but normal glucagon-like peptide 1 response to oral glucose i

  • hyperglycemia acutely lowers the postprandial excursions of glucagon like peptide 1 and Gastric Inhibitory Polypeptide in humans
    The Journal of Clinical Endocrinology and Metabolism, 2009
    Co-Authors: Kirsten Vollmer, Jens J Holst, Husai Gardiwal, Bjoern A Menge, Oliver Goetze, Carolyn F Deacon, W E Schmidt, Juris J Meier
    Abstract:

    Introduction: 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. Patients and Methods: 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 13C-octanoate breath test. Results: 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...

  • reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon like peptide 1 or Gastric Inhibitory Polypeptide in humans
    American Journal of Physiology-endocrinology and Metabolism, 2007
    Co-Authors: Juris J Meier, W E Schmidt, Jens J Holst, Matthias A Nauck
    Abstract:

    Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of Gastric Inhibitory Polypeptide (GIP) and glucagon-like p...

  • influence of Gastric Inhibitory Polypeptide on pentagastrin stimulated Gastric acid secretion in patients with type 2 diabetes and healthy controls
    World Journal of Gastroenterology, 2006
    Co-Authors: Juris J Meier, M A Nauck, Jens J Holst, Carolyn F Deacon, W E Schmidt, Bartholomaeus Kask, Baptist Gallwitz
    Abstract:

    AIM: Gastric Inhibitory Polypeptide is secreted from intestinal K-cells in response to nutrient ingestion and acts as an incretin hormone in human physiology. While animal experiments suggested a role for GIP as an inhibitor of Gastric secretion, the GIP effects on Gastric acid output in humans are still controversial. METHODS: Pentagastrin was administered at an infusion rate of 1 µg . kg-1 . h-1 over 300 min in 8 patients with type 2 diabetes (2 female, 6 male, 54 ± 10 years, BMI 30.5 ± 2.2 kg/m2; no history of autonomic neuropathy) and 8 healthy subjects (2/6, 46 ± 6 years., 28.9 ± 5.3 kg/m2). A hyperglycaemic clamp (140 mg/dl) was performed over 240 min. Placebo, GIP at a physiological dose (1 pmol . kg-1 . min-1), and GIP at a pharmacological dose (4 pmol . kg-1 . min-1) were administered over 60 min each. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at the beginning of each infusion period, respectively. Gastric volume, acid and chloride output were analysed in 15-min intervals. Capillary and venous blood samples were drawn for the determination of glucose and total GIP. Statistics were carried out by repeated-measures ANOVA and one-way ANOVA. RESULTS: Plasma glucose concentrations during the hyperglycaemic clamp experiments were not different between patients with type 2 diabetes and controls. Steady-state GIP plasma levels were 61 ± 8 and 79 ± 12 pmol/l during the low-dose and 327 ± 35 and 327 ± 17 pmol/l during the high-dose infusion of GIP, in healthy control subjects and in patients with type 2 diabetes, respectively (P = 0.23 and p 0.99). Pentagastrin markedly increased Gastric acid and chloride secretion (P < 0.001). There were no significant differences in the rates of Gastric acid or chloride output between the experimental periods with placebo or any dose of GIP. The temporal patterns of Gastric acid and chloride secretion were similar in patients with type 2 diabetes and healthy controls (P = 0.86 and P = 0.61, respectively). CONCLUSION: Pentagastrin-stimulated Gastric acid secretion is similar in patients with type 2 diabetes and healthy controls. GIP administration does not influence Gastric acid secretion at physiological or pharmacological plasma levels. Therefore, GIP appears to act as an incretin rather than as an enterogastrone in human physiology.

  • secretion of incretin hormones and the insulinotropic effect of Gastric Inhibitory Polypeptide in women with a history of gestational diabetes
    Diabetologia, 2005
    Co-Authors: Juris J Meier, Jens J Holst, Kirsten Vollmer, Carolyn F Deacon, Baptist Gallwitz, Wolfgang E Schmidt, M Askenas, M A Nauck
    Abstract:

    The insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg−1 min−1; 30–90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

W Creutzfeldt - One of the best experts on this subject based on the ideXlab platform.

  • binding specificity and signal transduction of receptors for glucagon like peptide 1 7 36 amide and Gastric Inhibitory Polypeptide on rinm5f insulinoma cells
    Journal of Molecular Endocrinology, 1993
    Co-Authors: Baptist Gallwitz, W Creutzfeldt, M Witt, U R Folsch, W E Schmidt
    Abstract:

    Glucagon-like peptide-1(7-36)amide (GLP-1(7-36) amide) and Gastric Inhibitory Polypeptide (GIP), peptides of the glucagon family, stimulate insulin secretion in vitro and in vivo. They possess high N-terminal sequence homology. Binding studies with 125I-labelled GIP and 125I-labelled GLP-1(7-36)amide were performed in RINm5F insulinoma cells to investigate receptor specificity and to compare both receptors directly. Both binding sites were highly ligand-specific: GIP did not bind to the GLP-1(7-36)amide receptor and vice versa. Both peptides increased intracellular cyclic AMP levels; GLP-1(7-36)amide was 100-fold more potent in stimulating cyclic AMP production when compared with GIP. At ranges of 1-10 nmol GLP-1(7-36)amide/l and 0.1-10 nmol GIP/l, corresponding to submaximal binding concentrations, the hormones showed an additive effect on cyclic AMP production. The N-terminal portion of GIP was important for binding, as GIP(1-30) showed almost full binding and biological activity. GIP(17-42) bound in a concentration-dependent manner with approximately 500-fold lower potency than GIP. At concentrations of up to 10 mumol GIP(17-42)/l no stimulation of cyclic AMP was observed.

  • additive insulinotropic effects of exogenous synthetic human Gastric Inhibitory Polypeptide and glucagon like peptide 1 7 36 amide infused at near physiological insulinotropic hormone and glucose concentrations
    The Journal of Clinical Endocrinology and Metabolism, 1993
    Co-Authors: Michael A Nauck, Eckart Bartels, Cathrine Orskov, R Ebert, W Creutzfeldt
    Abstract:

    Gastric Inhibitory Polypeptide (GIP) and glucagon-like peptide-1-(7-36) amide (GLP-1) are glucose-dependent insulinotropic gut hormones that may explain the greater insulin secretory response with oral compared to i.v. glucose (incretin effect). To study their individual and combined contributions, in eight healthy volunteers, on separate occasions, synthetic human GIP (1 pmol/kg.min) and/or GLP-1 (0.3 pmol/kg.min) or placebo were infused i.v. (-30 to 120 min), while at 0 min, a glucose infusion "isoglycemic" to the profile after an oral glucose load of 50 g/400 mL was started. After the administration of 50 g oral glucose, immunoreactive GIP rose several-fold to 337 +/- 43 pmol/L, while there was only a transient (10-30 min) and moderate increment in immunoreactive GLP-1 (from basal, 25-30, to 41 +/- 4 pmol/L). Isoglycemic i.v. glucose infusions led to smaller B-cell responses (estimated incretin effect, 41 +/- 5%). With single infusions of GIP or GLP-1 (circulating concentrations, 464 +/- 73 and 54 +/- ...

  • additive insulinotropic effects of exogenous synthetic human Gastric Inhibitory Polypeptide and glucagon like peptide 1 7 36 amide infused at near physiological insulinotropic hormone and glucose concentrations
    The Journal of Clinical Endocrinology and Metabolism, 1993
    Co-Authors: Michael A Nauck, Eckart Bartels, Cathrine Orskov, R Ebert, W Creutzfeldt
    Abstract:

    Gastric Inhibitory Polypeptide (GIP) and glucagon-like peptide-1-(7-36) amide (GLP-1) are glucose-dependent insulinotropic gut hormones that may explain the greater insulin secretory response with oral compared to i.v. glucose (incretin effect). To study their individual and combined contributions, in eight healthy volunteers, on separate occasions, synthetic human GIP (1 pmol/kg.min) and/or GLP-1 (0.3 pmol/kg.min) or placebo were infused i.v. (-30 to 120 min), while at 0 min, a glucose infusion "isoglycemic" to the profile after an oral glucose load of 50 g/400 mL was started. After the administration of 50 g oral glucose, immunoreactive GIP rose several-fold to 337 +/- 43 pmol/L, while there was only a transient (10-30 min) and moderate increment in immunoreactive GLP-1 (from basal, 25-30, to 41 +/- 4 pmol/L). Isoglycemic i.v. glucose infusions led to smaller B-cell responses (estimated incretin effect, 41 +/- 5%). With single infusions of GIP or GLP-1 (circulating concentrations, 464 +/- 73 and 54 +/- 3 pmol/L, respectively), B-cell responses were significantly augmented compared to i.v. glucose alone and were no longer significantly different from those after oral glucose. The combination of GIP and GLP-1 led to B-cell responses that were significantly higher than those with either hormone alone (additive mode of cooperation). Plasma GIP concentrations were similar after endogenous secretion (oral glucose) and i.v. infusion, while exogenously administered GLP-1 led to plasma levels that were maintained at an elevated level for a longer period during exogenous infusion than after stimulation by oral glucose. When, in seven volunteers, a lower dose (0.15 pmol/kg.min) of GLP-1 was infused during isoglycemic glucose infusion experiments only for the duration of elevated plasma levels in the oral glucose challenges (0-30 min), a significant, but transient, increment in insulin and C-peptide concentrations was observed, which was equivalent to 26 +/- 10% of the estimated incretin effect. Therefore, in conclusion, circulating GIP seems to make a major contribution to the incretin effect after oral glucose, and GLP-1 appears to mediate a smaller proportion. GIP and GLP-1 can interact in an additive manner in normal man.

  • lack of effect of synthetic human Gastric Inhibitory Polypeptide and glucagon like peptide 1 7 36 amide infused at near physiological concentrations on pentagastrin stimulated Gastric acid secretion in normal human subjects
    Digestion, 1992
    Co-Authors: M A Nauck, Eckart Bartels, Cathrine Orskov, R Ebert, W Creutzfeldt
    Abstract:

    Gastric Inhibitory Polypeptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1) are glucose-dependent insulinotropic gut hormones. Under experimental conditions, both have been shown to reduce stimulated Gastric acid secretion. To study their individual and combined effects on pentagastrin-stimulated (0.1 μg/kg/h from – 90 to 120 min) Gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/ kg/min) or placebo (0.9% NaCl with 1 % albumin) were infused intravenously (from – 30 to 120 min) in 9 healthy volunteers. At 0 min, a glucose infusion was started that mimicked the glycemic profile after an oral glucose load of 50 g/400 ml and allowed for the glucose-dependent insulinotropic action of GIP and GLP-1 [7-36 amide]. Pentagastrin stimulated acid output significantly, but neither GIP nor GLP-1 [7-36 amide] either alone or in combination, reduced pentagastrin-stimulated Gastric acid secretion. The circulating concentrations of GIP and GLP-1 [7-36 amide] obtained at steady state during exogenous administration of synthetic peptides were similar to or higher than those reached after oral glucose (endogenous secretion). In conclusion, (penta) gastrin-stimulated Gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role as enterogastrone.

Juris J Meier - One of the best experts on this subject based on the ideXlab platform.

  • hyperglycemia acutely lowers the postprandial excursions of glucagon like peptide 1 and Gastric Inhibitory Polypeptide in humans
    The Journal of Clinical Endocrinology and Metabolism, 2009
    Co-Authors: Kirsten Vollmer, Jens J Holst, Husai Gardiwal, Bjoern A Menge, Oliver Goetze, Carolyn F Deacon, W E Schmidt, Juris J Meier
    Abstract:

    Introduction: 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. Patients and Methods: 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 13C-octanoate breath test. Results: 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...

  • reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon like peptide 1 or Gastric Inhibitory Polypeptide in humans
    American Journal of Physiology-endocrinology and Metabolism, 2007
    Co-Authors: Juris J Meier, W E Schmidt, Jens J Holst, Matthias A Nauck
    Abstract:

    Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of Gastric Inhibitory Polypeptide (GIP) and glucagon-like p...

  • influence of Gastric Inhibitory Polypeptide on pentagastrin stimulated Gastric acid secretion in patients with type 2 diabetes and healthy controls
    World Journal of Gastroenterology, 2006
    Co-Authors: Juris J Meier, M A Nauck, Jens J Holst, Carolyn F Deacon, W E Schmidt, Bartholomaeus Kask, Baptist Gallwitz
    Abstract:

    AIM: Gastric Inhibitory Polypeptide is secreted from intestinal K-cells in response to nutrient ingestion and acts as an incretin hormone in human physiology. While animal experiments suggested a role for GIP as an inhibitor of Gastric secretion, the GIP effects on Gastric acid output in humans are still controversial. METHODS: Pentagastrin was administered at an infusion rate of 1 µg . kg-1 . h-1 over 300 min in 8 patients with type 2 diabetes (2 female, 6 male, 54 ± 10 years, BMI 30.5 ± 2.2 kg/m2; no history of autonomic neuropathy) and 8 healthy subjects (2/6, 46 ± 6 years., 28.9 ± 5.3 kg/m2). A hyperglycaemic clamp (140 mg/dl) was performed over 240 min. Placebo, GIP at a physiological dose (1 pmol . kg-1 . min-1), and GIP at a pharmacological dose (4 pmol . kg-1 . min-1) were administered over 60 min each. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at the beginning of each infusion period, respectively. Gastric volume, acid and chloride output were analysed in 15-min intervals. Capillary and venous blood samples were drawn for the determination of glucose and total GIP. Statistics were carried out by repeated-measures ANOVA and one-way ANOVA. RESULTS: Plasma glucose concentrations during the hyperglycaemic clamp experiments were not different between patients with type 2 diabetes and controls. Steady-state GIP plasma levels were 61 ± 8 and 79 ± 12 pmol/l during the low-dose and 327 ± 35 and 327 ± 17 pmol/l during the high-dose infusion of GIP, in healthy control subjects and in patients with type 2 diabetes, respectively (P = 0.23 and p 0.99). Pentagastrin markedly increased Gastric acid and chloride secretion (P < 0.001). There were no significant differences in the rates of Gastric acid or chloride output between the experimental periods with placebo or any dose of GIP. The temporal patterns of Gastric acid and chloride secretion were similar in patients with type 2 diabetes and healthy controls (P = 0.86 and P = 0.61, respectively). CONCLUSION: Pentagastrin-stimulated Gastric acid secretion is similar in patients with type 2 diabetes and healthy controls. GIP administration does not influence Gastric acid secretion at physiological or pharmacological plasma levels. Therefore, GIP appears to act as an incretin rather than as an enterogastrone in human physiology.

  • secretion of incretin hormones and the insulinotropic effect of Gastric Inhibitory Polypeptide in women with a history of gestational diabetes
    Diabetologia, 2005
    Co-Authors: Juris J Meier, Jens J Holst, Kirsten Vollmer, Carolyn F Deacon, Baptist Gallwitz, Wolfgang E Schmidt, M Askenas, M A Nauck
    Abstract:

    The insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg−1 min−1; 30–90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

  • stimulation of insulin secretion by intravenous bolus injection and continuous infusion of Gastric Inhibitory Polypeptide in patients with type 2 diabetes and healthy control subjects
    Diabetes, 2004
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Baptist Gallwitz, Bartholomaeus Kask, Wolfgang E Schmidt, Michael A Nauck
    Abstract:

    A reduced insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is a characteristic of patients with type 2 diabetes. It was the aim of this study to determine the response of insulin secretion to different GIP doses administered by intravenous bolus injection and via continuous infusion in both healthy subjects and patients with type 2 diabetes. Eight patients with type 2 diabetes and eight healthy subjects participated in a 240-min hyperglycemic clamp (140 mg/dl) with intravenous infusion of placebo, GIP at a low dose, and GIP at a high dose, each administered continuously over 60 min. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at 0, 60, and 120 min, respectively. Capillary and venous blood was drawn for glucose, insulin, C-peptide, and GIP. Plasma insulin and C-peptide concentrations were lower in patients than in control subjects during all infusion periods. GIP bolus administration evoked a significant increase in plasma insulin levels in both patients with type 2 diabetes and healthy subjects. In contrast, the continuous GIP infusion led to a weak increase in insulin secretion in both healthy subjects and type 2 diabetic patients. The dose-response relationship for the increase in insulin secretion after GIP bolus administration was similar in both groups, although at different degrees of β-cell function. The stimulation of insulin secretion by GIP is stronger after its bolus administration than during continuous infusion. Even though the insulin secretory capacity is generally impaired in patients with type 2 diabetes, the relative sensitivity of insulin secretion to a bolus administration of GIP is almost preserved. Therefore, the existence of a specific GIP receptor defect in type 2 diabetes appears unlikely.

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  • stimulation of insulin secretion by intravenous bolus injection and continuous infusion of Gastric Inhibitory Polypeptide in patients with type 2 diabetes and healthy control subjects
    Diabetes, 2004
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Baptist Gallwitz, Bartholomaeus Kask, Wolfgang E Schmidt, Michael A Nauck
    Abstract:

    A reduced insulinotropic effect of Gastric Inhibitory Polypeptide (GIP) is a characteristic of patients with type 2 diabetes. It was the aim of this study to determine the response of insulin secretion to different GIP doses administered by intravenous bolus injection and via continuous infusion in both healthy subjects and patients with type 2 diabetes. Eight patients with type 2 diabetes and eight healthy subjects participated in a 240-min hyperglycemic clamp (140 mg/dl) with intravenous infusion of placebo, GIP at a low dose, and GIP at a high dose, each administered continuously over 60 min. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at 0, 60, and 120 min, respectively. Capillary and venous blood was drawn for glucose, insulin, C-peptide, and GIP. Plasma insulin and C-peptide concentrations were lower in patients than in control subjects during all infusion periods. GIP bolus administration evoked a significant increase in plasma insulin levels in both patients with type 2 diabetes and healthy subjects. In contrast, the continuous GIP infusion led to a weak increase in insulin secretion in both healthy subjects and type 2 diabetic patients. The dose-response relationship for the increase in insulin secretion after GIP bolus administration was similar in both groups, although at different degrees of β-cell function. The stimulation of insulin secretion by GIP is stronger after its bolus administration than during continuous infusion. Even though the insulin secretory capacity is generally impaired in patients with type 2 diabetes, the relative sensitivity of insulin secretion to a bolus administration of GIP is almost preserved. Therefore, the existence of a specific GIP receptor defect in type 2 diabetes appears unlikely.

  • secretion degradation and elimination of glucagon like peptide 1 and Gastric Inhibitory Polypeptide in patients with chronic renal insufficiency and healthy control subjects
    Diabetes, 2004
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Michael A Nauck, Wolfgang E Schmidt, Daniel Kranz, Dirk Gaeckler, Baptist Gallwitz
    Abstract:

    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 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.

  • similar insulin secretory response to a Gastric Inhibitory Polypeptide bolus injection at euglycemia in first degree relatives of patients with type 2 diabetes and control subjects
    Metabolism-clinical and Experimental, 2003
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, W E Schmidt, Nina Siepmann, Michael A Nauck, Michael Greulich, Baptist Gallwitz
    Abstract:

    Abstract Insulin secretion following the intravenous infusion of Gastric Inhibitory Polypeptide (GIP) is diminished in patients with type 2 diabetes and at least a subgroup of their first-degree relatives at hyperglycemic clamp conditions. Therefore, we studied the effects of an intravenous bolus administration of GIP at normoglycemic conditions in the fasting state. Ten healthy control subjects were studied with an intravenous bolus administration of placebo, and of 7, 20, and 60 pmol GIP/kg body weight (BW), respectively. Forty-five first-degree relatives of patients with type 2 diabetes and 33 matched control subjects were studied with (1) a 75-g oral glucose tolerance test (OGTT) and (2) an intravenous bolus injection of 20 pmol GIP/kg BW with blood samples drawn over 30 minutes for determination of plasma glucose, insulin, C-peptide, and GIP. Statistical analysis applied repeated-measures analysis of variance (ANOVA) and Duncan's post hoc tests. Insulin secretion was stimulated after the administration of 20 and of 60 pmol GIP/kg BW in the dose-response experiments ( P P P = .64 and P = .87, respectively). Also expressed as increments over baseline, no differences were apparent (Δ insulin , 7.6 ± 1.2 and 7.6 ± 1.6 mU/L, P = .99; Δ C-peptide , 0.35 ± 0.06 and 0.38 ± 0.08 ng/mL, P = .75). Integrated insulin and C-peptide responses after GIP administration significantly correlated with the respective insulin and C-peptide responses after glucose ingestion (insulin, r = 0.78, P r = 0.35, P = .0015). We conclude that a reduced insulinotropic effect of GIP in first-degree relatives of patients with type 2 diabetes cannot be observed at euglycemia. Therefore, a reduced GIP-induced insulin secretion in patients with type 2 diabetes and their first-degree relatives at hyperglycemia is more likely due to a general defect of B-cell function than to a specific defect of the GIP action.

  • Gastric Inhibitory Polypeptide the neglected incretin revisited
    Regulatory Peptides, 2002
    Co-Authors: Juris J Meier, W E Schmidt, Michael A Nauck, Baptist Gallwitz
    Abstract:

    After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings.

  • reduced insulinotropic effect of Gastric Inhibitory Polypeptide in first degree relatives of patients with type 2 diabetes
    Diabetes, 2001
    Co-Authors: Juris J Meier, Jens J Holst, Carolyn F Deacon, Katrin Hucking, Wolff Schmiegel, Michael A Nauck
    Abstract:

    In patients with type 2 diabetes, Gastric Inhibitory Polypeptide (GIP) has lost much of its insulinotropic activity. Whether this is similar in first-degree relatives of patients with type 2 diabetes is unknown. A total of 21 first-degree relatives, 10 patients with type 2 diabetes, and 10 control subjects (normal oral glucose tolerance) were examined. During a hyperglycemic "clamp" (140 mg/dl for 120 min), synthetic human GIP (2 pmol. kg(-1). min(-1)) was infused intravenously (30-90 min). With exogenous GIP, patients with type 2 diabetes responded with a lower increment (Delta) in insulin (P = 0.0003) and C-peptide concentrations (P < 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects (Delta insulin: P = 0.04; Delta C-peptide: P = 0.016) but significantly higher than in patients with type 2 diabetes (P < or = 0.05). The responses over the time course were below the 95% CI derived from control subjects in 7 (insulin) and 11 (C-peptide) of 21 first-degree relatives of patients with type 2 diabetes. In conclusion, a reduced insulinotropic activity of GIP is typical for a substantial subgroup of normoglycemic first-degree relatives of patients with type 2 diabetes, pointing to an early, possibly genetic defect.