Overview
We 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. At present it is unknown if these abnormalities develop in prediabetes and whether they contribute to the phenotypes observed. In this experiment we will use blockade of GLP1R to probe the contribution of endogenous GLP-1 secretion to the regulation of fasting glucose and islet function in prediabetes.
Description
We 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 and glucagon secretion. These effects are more pronounced in people with early type 2 diabetes (T2DM). 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. Abnormal α-cell responsivity to glucose, measured using G50, is associated with Impaired Fasting Glucose (IFG); β-cell dysfunction is associated with Impaired Glucose Tolerance (IGT). Does IGT (or IFG) represent selective failure of intra-islet GLP-1 to support islet function? In this experiment we will use blockade of GLP1R to probe the contribution of endogenous GLP-1 secretion to the regulation of fasting glucose and islet function in prediabetes
Eligibility
Inclusion Criteria:
- People with stable weight and no history of diabetes.
- Fasting glucose \< 126 mg/dL
- 2hr glucose after 75g OGTT \< 200 mg/dL
Exclusion Criteria:
- 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).
- 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.