A Pilot Study Investigating the Influence of Glucagon-Like Peptide-1 Receptor Single Nucleotide Polymorphisms on Gastric Emptying Rate in Caucasian Men

Abstract Context: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. Main Objective: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. Design: This was a randomized, double-blind, crossover study. Subjects: Subjects included normal human volunteers and patients with GH deficiency. Intervention: Intervention included saline or ghrelin (10 pmol/kg·min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. Main Outcome Measures: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. Results: The emptying rate was significantly faster for ghrelin (1.26 ± 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 ± 2.2 and 26.5 ± 3.8 min) and half-emptying time (49.4 ± 3.9 and 75.6 ± 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. Conclusion: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

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Intron-specific Single Nucleotide Polymorphisms of Fat Mass and Obesity- Associated Gene in Obese and Overweight Individuals of the Indian Adult Population- A Pilot Study

Current Diabetes Reviews ◽

10.2174/2542591901666181126144449 ◽

2019 ◽

Vol 16 (1) ◽

pp. 84-94

Author(s):

Aakash Reddy ◽

Katari Venkatesh ◽

Sayani Sahu ◽

Pallavi Sinha Roy ◽

Konkona Datta ◽

...

Keyword(s):

Pilot Study ◽

Single Nucleotide Polymorphisms ◽

Fat Mass ◽

Indian Population ◽

Detection System ◽

Adult Population ◽

Genotypic Frequency ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Increased Risk

Background: The Fat mass and obesity-associated gene (FTO) and its involvement in weight gain and obesity is well-known. However, no reports have been published on the Indian population regarding the relationship between single nucleotide polymorphisms (SNPs) in its intronic region and obesity. The aim of this pilot study was to evaluate the frequency and association of SNPs in intron-1 of the FTO gene in obese and overweight Indian adults. Methods: This study group consisted of 80 adults, aged 23.5 ± 8.9 yr, with a mean BMI of 28.8 ± 6.2 kg/m2. Genomic DNA was isolated, exons1-3 & intron1 of FTO were amplified using polymerase chain reaction and sequenced by ABI sequencing detection system. The reported SNPs rs1420185, rs8050136, rs1121980 and rs55872725 were checked for their presence or absence in this group of the adult Indian population. Results: No mutations were found in the exonic sequence of FTO, however, the association of rs1420185, rs8050136, rs1121980 and rs55872725 SNPs was identified in this population. The genotypic frequency at FTO rs8050136 was 32.2% for C>A, at rs55872725 it was 45.7% for C>T, at rs1420185 it was 27.1% for T>C and at rs1121980 it was 30.5% for G>A. All four SNPs in combination were observed in 6 participants (10.2%), all of whom were found to be either obese or overweight. Conclusion: These findings indicate that Indians with these SNPs are most likely to be at increased risk of obesity.

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Effects of gastric emptying on the postprandial ghrelin response

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00238.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. E389-E395 ◽

Cited By ~ 34

Author(s):

Wendy A. M. Blom ◽

Anne Lluch ◽

Sophie Vinoy ◽

Annette Stafleu ◽

Robin van den Berg ◽

...

Keyword(s):

Gastric Emptying ◽

Intravenous Infusion ◽

Indirect Measurement ◽

Gastric Emptying Rate ◽

Total Ghrelin ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Ghrelin Secretion ◽

Single Blind

Distension and chemosensitization of the stomach are insufficient to induce a ghrelin response, suggesting that postgastric feedback is required. This postgastric feedback may be regulated through insulin. We investigated the relation between gastric emptying rate and the postprandial ghrelin response as well as the role of insulin and other hormones possibly mediating this response. Fifteen healthy men [BMI 21.6 kg/m2 (SD 1.9), age 20.5 yr (SD 2.5)] were studied in a single-blind, crossover design. Subjects received two treatments separated by 1 wk: 1) a dairy breakfast in combination with a 3-h intravenous infusion of glucagon-like peptide-1 (GLP-1), which delays gastric emptying, and 2) a dairy breakfast in combination with a 3-h intravenous infusion of saline. Blood samples were drawn before breakfast and during the infusion. Postprandial ghrelin (total) responses were lower following the saline infusion compared with the GLP-1 infusion ( P < 0.05). Acetaminophen concentrations, an indirect measurement of gastric emptying rate, were inversely correlated with total ghrelin concentrations (saline r = −0.76; 95% CI = −0.90, −0.49, GLP-1 r = −0.47; 95% CI = −0.76, −0.04). Ghrelin concentrations were only weakly correlated with insulin concentrations (saline r = −0.36; 95% CI = −0.69, 0.09; GLP- 1 r = −0.42; 95% CI = −0.73, 0.03), but strongly inversely correlated with GIP concentrations (saline r = −0.74; 95% CI= −0.89, −0.45; GLP-1 r = −0.63; 95% CI = −0.84, −0.27). In conclusion, our results support the hypothesis that ghrelin requires postgastric feedback, which may not be regulated through insulin. Conversely, our data suggest a role of glucose-dependent insulinotropic polypeptide in ghrelin secretion.

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Minireview: Signal Bias, Allosterism, and Polymorphic Variation at the GLP-1R: Implications for Drug Discovery

Molecular Endocrinology ◽

10.1210/me.2013-1116 ◽

2013 ◽

Vol 27 (8) ◽

pp. 1234-1244 ◽

Cited By ~ 27

Author(s):

Cassandra Koole ◽

Emilia E. Savage ◽

Arthur Christopoulos ◽

Laurence J. Miller ◽

Patrick M. Sexton ◽

...

Keyword(s):

Drug Discovery ◽

Cell Mass ◽

Current Understanding ◽

Receptor Protein ◽

Insulin Biosynthesis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Downstream Signaling ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1% or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.

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