Healthy, Type 2 Diabetes
Conditions
Brief summary
GLP-1 is a hormone made by the body that promotes the production of insulin in response to GLP-1 is produced within the islets expressing prohormone convertase 1/3eating. However, there is increasing evidence that this hormone might help support the body's ability to produce insulin when diabetes develops. The purpose of this study is to determine the effect of endogenous GLP-1 secretion on insulin secretion in people with and without type 2 diabetes.
Detailed description
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.
Interventions
BIOLOGICALSaline
Saline infused during the study
BIOLOGICALExendin-9,39
Exendin-9,39 infused during the study
BIOLOGICALSaline + Intralipid/Heparin
Saline infused during acute insulin resistance
BIOLOGICALExendin-9,39 + Intralipid/Heparin
Exendin-9,39 infused during acute insulin resistance
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Adrian Vella
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| No Diabetes Subjects without Diabetes | 12 |
| Type 2 Diabetes Subjects with Type 2 Diabetes | 11 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Type 2 Diabetes | Total | No Diabetes |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 5 | 56 years STANDARD_DEVIATION 7 | 54 years STANDARD_DEVIATION 8 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 11 participants | 23 participants | 12 participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 1 / 11 | 1 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39
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.
Time frame: Average concentration over the -30 to 0 minutes of study
Population: 1 patient with type 2 diabetes did not complete one study secondary to loss of IV access
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| No Diabetes | Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 | Saline | 7.4 pmol/l | Standard Error 1.2 |
| No Diabetes | Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 | Exendin 9-39 | 7.8 pmol/l | Standard Error 1.1 |
| Type 2 Diabetes | Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 | Saline | 7.9 pmol/l | Standard Error 0.3 |
| Type 2 Diabetes | Change in Fasting Glucagon in the Presence or Absence of Exendin-9,39 | Exendin 9-39 | 10.2 pmol/l | Standard Error 0.3 |