The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- Mayo Clinic
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Change in fasting glucose
研究概览
简要总结
The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets. However, its regulation is at present unknown. Common genetic variation in the TCF7L2 locus (T-allele at rs7903146) arguably confers the greatest genetic risk of T2DM. It is associated with α- and β-cell dysfunction. TCF7L2 (the product of TCF7L2) was first described as the transcription factor necessary for proglucagon expression in intestinal L-cells (which secrete GLP-1). This led to speculation that TCF7L2 confers risk of diabetes via changes in circulating GLP-1. This has turned out to not be the case. This raises the possibility that these diabetogenic effects are mediated via an inability of islet GLP-1 to adapt to rising glycemia. Therefore, this experiment will determine the contribution of islet GLP-1 to the functional abnormalities of the islet associated with the TCF7L2 locus.
详细描述
The investigators recently demonstrated that blockade of Glucagon-Like Peptide-1's (GLP-1) receptor (GLP1R) results in changes in islet function without changes in circulating GLP-1. This supports other evidence (rodents and humans) that through the (inducible) expression of a prohormone convertase (PC-1/3), the α-cell can process proglucagon to intact GLP-1. 'Islet' or 'pancreatic' GLP-1 acts in a paracrine fashion to regulate insulin (basal and 1st phase) and glucagon secretion. These effects are more pronounced in people with early type 2 diabetes (T2DM) in keeping with increased expression of PC-1/3 and GLP-1 that is observed in diabetic islets.
Although pancreatic GLP-1 adapts to support islet function in T2DM, it is unclear if this mechanism is upregulated in prediabetes and whether it contributes to the phenotype(s) observed. There is evidence that α-cell proglucagon processing is subject to paracrine regulation by the β-cell. β-cell secretion of the signaling peptide 14-3-3-Zeta is decreased by GLP1R agonism, stimulating α-cell production of GLP-1. Common genetic variation in the TCF7L2 locus (T-allele at rs7903146) arguably confers the greatest genetic risk of T2DM4. It is associated with α- and β-cell dysfunction. TCF7L2 (the product of TCF7L2) was first described as the transcription factor necessary for proglucagon expression in intestinal L-cells (which secrete GLP-1). Does a relative absence or an inability of islet GLP-1 to adapt to rising glycemia explain the increased risk of T2DM associated with the T-allele at rs7903146? This experiment will determine the contribution of islet GLP-1 to the functional abnormalities of the islet associated with the TCF7L2 locus.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 25 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Subjects with the TT or CC genotype at rs7903146
排除标准
- •Age < 25 or > 70 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose).
- •CT genotype at rs7903146
- •HbA1c > 6.5%
- •Use of any glucose-lowering agents including metformin or sulfonylureas.
- •For female subjects: positive pregnancy test at the time of enrollment or study.
- •History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
- •Active systemic illness or malignancy.
- •Symptomatic macrovascular or microvascular disease.
研究组 & 干预措施
Exendin 9-39
Exendin 9-39 will be infused during fasting and during a hyperglycemic clamp
干预措施: Exendin 9-39 (Biological)
Saline
Saline will be infused during fasting and during a hyperglycemic clamp
干预措施: Saline (Other)
结局指标
主要结局
Change in fasting glucose
时间窗: Change in average glucose concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
comparison of fasting glucose during saline vs. exendin 9-39 infusion
Change in fasting glucagon
时间窗: Change in average glucagon concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day)
comparison of fasting glucagon during saline vs. exendin 9-39 infusion
次要结局
- Change in fasting insulin(Change in average insulin concentration between -30 min and 0 min of each study day (saline day vs. exendin 9-39 day))
- Change in first phase insulin secretion(Change in integrated insulin concentrations (area above baseline) between 0 min and 30 min of each study day (saline day vs. exendin 9-39 day))