Endogenous GLP-1 Secretion on Islet Function in People With and Without Type 2 Diabetes

Accumulating evidence suggests that in rodents and humans GLP-1 is synthesized within islets and may act locally in a paracrine fashion. Indeed, mice with genetic loss of intra-islet GLP-1 exhibit decreased insulin secretion and impaired response to metabolic stressors. 'Pancreatic' GLP-1 may contribute to the effects of DPP-4 inhibitors in rodents and humans. Antagonism of GLP1R with exendin-9,39 during fasting impairs the islet cell response to an I.V. glucose challenge. Islet GLP-1 content is increased in T2DM and in islets from non-diabetic humans exposed to hyperglycemia and Free Fatty Acids. These observations imply that paracrine GLP-1 secretion supports islet function in the presence of glucolipotoxicity. In this experiment we will examine the role of endogenous GLP-1 secretion in people with and without T2DM and during β-cell stress induced by FFA elevation.

• Saline (Biological): Saline infused during the study
• Exendin-9,39 (Biological): Exendin-9,39 infused during the study
• Saline + Intralipid/Heparin (Biological): Saline infused during acute insulin resistance
• Exendin-9,39 + Intralipid/Heparin (Biological): Exendin-9,39 infused during acute insulin resistance

Primary outcomes

• Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 [Average concentration over the -30 to 0 minutes of study]: Concentrations of glucagon Measured by immunoassay over the -30 to 0 minutes of study. On one study day subjects received saline, on the other exendin-9,39. The infusion commenced at -120 minutes.

Sex: All, ages: 25 Years to 65 Years, accepts healthy volunteers

Inclusion criteria - non-diabetic subjects:

* Weight-stable, non-diabetic subjects

Exclusion Criteria - non-diabetic subjects:

* Age < 25 or > 65 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 glucose-lowering agents.
* 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.

Inclusion criteria - diabetic subjects:

* Weight-stable, diabetic subjects treated with diet and lifestyle alone or with metformin monotherapy

Exclusion Criteria - diabetic subjects:

* Age < 25 or > 65 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).
* Use of any glucose-lowering agent other than metformin.
* 2 or more fasting glucose values > 250mg/dl on medication or after medication withdrawal.
* Unwillingness or inability to withdraw medication for three weeks prior to, and for the duration of the study.
* 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.

Participant flow

Outcome results

• Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 (Primary), Mean, pmol/l: No Diabetes 7.4 +/- 1.2; Type 2 Diabetes 7.9 +/- 0.3

Adverse events

Time frame: The 3 months of participation

Other adverse events by term

• Results publication: Welch AA, Farahani RA, Egan AM, Laurenti MC, Zeini M, Vella M, Bailey KR, Cobelli C, Dalla Man C, Matveyenko A, Vella A. Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans. J Clin Invest. 2023 Nov 15;133(22):e173495. doi: 10.1172/JCI173495. PMID 37751301

• Study Protocol and Statistical Analysis Plan (PDF, 2022-01-10)

• Adrian Vella, Principal investigator, Mayo Clinic

NIH grants: R01DK126206