Glucagon-Like Peptide 1 Increases Secretory Burst Mass of Pulsatile Insulin Secretion in Patients With Type 2 Diabetes and Impaired Glucose Tolerance

Ritzel, Robert; Schulte, Miriam; Pørksen, Niels; Nauck, Markus; Holst, Jens J.; Juhl, Claus Bogh; März, Winfried; Schmitz, O.; Schmiegel, Wolff; Nauck, Michael A.

doi:10.2337/diabetes.50.4.776

Cited by 62 publications

(37 citation statements)

References 48 publications

(66 reference statements)

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“…An improved regularity of release pattern was not expected in this study of healthy subjects. In Type II diabetes GLP-1 has, in a preliminary report, also been shown to increase insulin secretion by amplification of the burst mass with no effect on the burst frequency when GLP-1 was given as an overnight infusion [25]. This is similar to the findings in our study.…”

Section: Discussionsupporting

confidence: 91%

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

et al. 2000

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Type II (non-insulin-dependent) diabetes mellitus is among a vast number of abnormalities characterised by disturbed beta-cell function. This includes defects in first-phase and second-phase insulin secretion as well as a deterioration of the highly coordinated pulsatile release pattern seen in healthy subjects [1,2]. The full impact on glucose control of the latter alterations in Type II diabetic patients is not established, but in vivo experiments suggest that pulsatile insulin delivery is important for insulin actions [3±5].Stimulation of insulin secretion has been the principal goal in the treatment of Type II diabetic patients for decades. The impact of pharmacological beta-cell stimulation on insulin pulsatility has not been examined in Type II diabetes, although the nature of the insulin response could be important to shortterm and long-term glucose control. In non-diabetic Diabetologia (2000) 43: 583±588 Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness Abstract Aims/hypothesis. The enteric incretin hormone, glucagon-like peptide-1 (GLP-1), is a potent insulin secretagogue in healthy humans and patients with Type II (non-insulin-dependent) diabetes mellitus. In this study we assessed the impact of short-term GLP-1 infusion on pulsatile insulin secretion in Type II diabetic patients. Methods. Type II diabetic patients (n = 8) were studied in a randomised cross-over design. Plasma insulin concentration time series were obtained during basal conditions and during infusion with saline or GLP-1 (1.2 pmol/l × kg ±1 × min ±1 ) on 2 separate days. Plasma glucose was clamped at the initial concentration by a variable glucose infusion. Serum insulin concentration time series were evaluated by deconvolution analysis, autocorrelation analysis, spectral analysis and approximate entropy. Results. Serum insulin concentrations increased by approximately 100 % during GLP-1 infusion. Pulsatile insulin secretion was increased as measured by secretory burst mass (19.3 ± 3.8 vs 53.0 ± 10.7 pmol/l/ pulse, p = 0.02) and secretory burst amplitude (7.7 ± 1.5 vs 21.1 ± 4.3 pmol/l/min, p = 0.02). A similar increase in basal insulin secretion was observed (3.6 ± 0.9 vs 10.2 ± 2.2 pmol/l/min, p = 0.004) with no changes in the fraction of insulin delivered in pulses (0.50 ± 0.06 vs 0.49 ± 0.02, p = 0.84). Regularity of secretion was unchanged as measured by spectral analysis (normalised spectral power: 5.9 ± 0.6 vs 6.3 ± 0.8, p = 0.86), autocorrelation analysis (autocorrelation coefficient: 0.19 ± 0.04 vs 0.18 ± 0.05, p = 0.66) and the approximate entropy statistic (1.48 ± 0.02 vs 1.51 ± 0.02, p = 0.86). Conclusion/interpretation. Short-term stimulation with GLP-1 jointly increases pulsatile and basal insulin secretion, maintaining but not improving system regularity in Type II diabetic patients. [Diabetologia (2000) 43: 583±588]Keywords GLP-1, Insulin, pulsatility, insulin secretion, time series, Type II diabetes, human.Received: 11 November 1999 and in revise...

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Section: Discussionsupporting

confidence: 91%

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

et al. 2000

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“…It is therefore likely that the phase relationship between cAMP and Ca 2+ signals varies depending on the relative expression levels of different adenylyl cyclases and phosphodiesterases as well as on the type of stimulus (Fridlyand et al, 2007). The coordinated elevations and mutual enhancement of Ca 2+ and cAMP signals observed in GLP-1-stimulated cells should be an exquisite trigger for exocytosis and may explain how the incretin hormone selectively enhances the pulsatile component of insulin release in healthy and diabetic subjects (Pørksen et al, 1998;Ritzel et al, 2001).…”

Section: Cyclic Ampmentioning

confidence: 99%

“…Measurements in the portal vein of dogs and humans have indicated that virtually all insulin (>70-75%) is released in a pulsatile fashion (Pørksen et al, 1995;Pørksen et al, 1997). Early estimates of pulse intervals are somewhat variable due to technical limitations but later data indicate a periodicity of 4-6 min in humans (Storch et al, 1993;Pørksen et al, 1997;Ritzel et al, 2001) and dogs (Pørksen et al, 1996). The insulin-releasing β-cells are located in about 1 million islets of Langerhans distributed within the 25 cm long human pancreas.…”

mentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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“…Insulin secretion occurs in a pulsatile manner, and GLP-1 increases the amplitude of each pulse without changing the pulse frequency [24,25,95]. …”

Section: E the Insulin Secretagogue Action Of Glp-1mentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

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Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing b-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate b-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted. Keywords GLP-1; diabetes mellitus; insulin secretion A. INTRODUCTIONGlucagon-like peptide-1-(7-36)-amide (GLP-1, also known as t-GLP-1 or GLIP) is an intestinally-derived insulinotropic hormone that has attracted considerable attention by virtue of its proven ability to act as a blood glucose lowering agent. The efficacy with which GLP-1 lowers concentrations of blood glucose in type 2 diabetic subjects (adult onset diabetes mellitus) has prompted clinical investigations whereby the therapeutic value of GLP-1 as an antidiabetogenic agent has been substantiated. Earlier studies revealed that © 2003 Bentham Science Publishers Ltd. * Address correspondence to this author at the Department of Physiology and Neuroscience, MSB 442, New York University School of Medicine, 550 First Avenue, NY 10016, New York, USA; Tel: 212-263-5434; Fax: 212-689-9060; holzg01@popmail.med.nyu.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGLP-1 is an ...

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Glucagon-Like Peptide 1 Increases Secretory Burst Mass of Pulsatile Insulin Secretion in Patients With Type 2 Diabetes and Impaired Glucose Tolerance

Cited by 62 publications

References 48 publications

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

Oscillatory control of insulin secretion

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

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