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  • American Diabetes Association  (5)
  • 2000-2004  (5)
  • 1
    Online Resource
    Online Resource
    Glucagon-Like Peptide 1 Increases Secretory Burst Mass of Pulsatile Insulin Secretion in Patients With Type 2 Diabetes and Impaired Glucose Tolerance
    American Diabetes Association ; 2001
    In:  Diabetes Vol. 50, No. 4 ( 2001-04-01), p. 776-784
    Details
    In: Diabetes, American Diabetes Association, Vol. 50, No. 4 ( 2001-04-01), p. 776-784
    Abstract: The insulinotropic gut hormone glucagon-like peptide (GLP)-1 increases secretory burst mass and the amplitude of pulsatile insulin secretion in healthy volunteers without affecting burst frequency. Effects of GLP-1 on secretory mechanisms in type 2 diabetic patients and subjects with impaired glucose tolerance (IGT) known to have impaired pulsatile release of insulin have not yet been studied. Eight type 2 diabetic patients (64 ± 9 years, BMI 28.9 ± 7.2 kg/m2, HbA1c 7.7 ± 1.3%) and eight subjects with IGT (63 ± 10 years, BMI 31.7 ± 6.4 kg/m2, HbA1c 5.7 ± 0.4) were studied on separate occasions in the fasting state during the continued administration of exogenous GLP-1 (1.2 pmol · kg−1 · min−1, started at 10:00 p.m. the evening before) or placebo. For comparison, eight healthy volunteers (62 ± 7 years, BMI 27.7 ± 4.8 kg/m2, HbA1c 5.4 ± 0.5) were studied only with placebo. Blood was sampled continuously over 60 min (roller-pump) in 1-min fractions for the measurement of plasma glucose and insulin. Pulsatile insulin secretion was characterized by deconvolution, autocorrelation, and spectral analysis and by estimating the degree of randomness (approximate entropy). In type 2 diabetic patients, exogenous GLP-1 at ∼90 pmol/l improved plasma glucose concentrations (6.4 ± 2.1 mmol/l vs. placebo 9.8 ± 4.1 mmol/l, P = 0.0005) and significantly increased mean insulin burst mass (by 68%, P = 0.007) and amplitude (by 59%, P = 0.006; deconvolution analysis). In IGT subjects, burst mass was increased by 45% (P = 0.019) and amplitude by 38% (P = 0.02). By deconvolution analysis, insulin secretory burst frequency was not affected by GLP-1 in either type 2 diabetic patients (P = 0.15) or IGT subjects (P = 0.76). However, by both autocorrelation and spectral analysis, GLP-1 prolonged the period (lag time) between subsequent maxima of insulin concentrations significantly from ∼9 to ∼13 min in both type 2 diabetic patients and IGT subjects. Under placebo conditions, parameters of pulsatile insulin secretion were similar in normal subjects, type 2 diabetic patients, and IGT subjects based on all methodological approaches (P & gt; 0.05). In conclusion, intravenous GLP-1 reduces plasma glucose in type 2 diabetic patients and improves the oscillatory secretion pattern by amplifying insulin secretory burst mass, whereas the oscillatory period determined by autocorrelation and spectral analysis is significantly prolonged. This was not the case for the interpulse interval determined by deconvolution. Together, these results suggest a normalization of the pulsatile pattern of insulin secretion by GLP-1, which supports the future therapeutic use of GLP-1–derived agents.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.50.4.776
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2001
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  • 2
    Online Resource
    Online Resource
    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
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. suppl_3 ( 2004-12-01), p. S220-S224
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. suppl_3 ( 2004-12-01), p. S220-S224
    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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.suppl_3.S220
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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  • 3
    Online Resource
    Online Resource
    Reduced Insulinotropic Effect of Gastric Inhibitory Polypeptide in First-Degree Relatives of Patients With Type 2 Diabetes
    American Diabetes Association ; 2001
    In:  Diabetes Vol. 50, No. 11 ( 2001-11-01), p. 2497-2504
    Details
    In: Diabetes, American Diabetes Association, Vol. 50, No. 11 ( 2001-11-01), p. 2497-2504
    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 (Δ) in insulin (P = 0.0003) and C-peptide concentrations (P & lt; 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects (Δ insulin: P = 0.04; Δ C-peptide: P = 0.016) but significantly higher than in patients with type 2 diabetes (P ≤ 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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.50.11.2497
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2001
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  • 4
    Online Resource
    Online Resource
    Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. 3 ( 2004-03-01), p. 654-662
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. 3 ( 2004-03-01), p. 654-662
    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/m2, 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/m2, 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 & lt; 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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.3.654
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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  • 5
    Online Resource
    Online Resource
    Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. suppl_3 ( 2004-12-01), p. S190-S196
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. suppl_3 ( 2004-12-01), p. S190-S196
    Abstract: The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In ∼50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.suppl_3.S190
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
    detail.hit.zdb_id: 1501252-9
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