What Impact of Weight on GLP-1-stimulated Insulin Secretion?
The size of the incretin effect among healthy subjects may vary up to 2-fold, suggesting differences in ß-cell sensitivity to GLP-1. Does BMI play a role in this variability?
The body's insulin response to oral glucose can be reduced by 30% to 40% by blocking the action of endogenous glucagon-like polypeptide-1 (GLP-1) but the effect on insulin secretion is widely variable. The magnitude of the incretin effect has also been shown to vary 1.5-2-fold among healthy subjects. Both observations suggest interindividual differences in Ã-cell sensitivity to GLP-1. The slides above summarize a recent study that was based on the hypothesis that insulin secretion would be less sensitive to stimulation by GLP-1 in obese vs lean subjects who were healthy.The authors were surprised by the results. Find out why.
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in response to blood glucose concentrations. Agents that block GLP-1 reduce insulin secretion, but the magnitude can vary among individuals suggesting differences in β-cell sensitivity.
Magnitude of variability in β-cell sensitivity and factors that may influence variation have not been studied. Objective: “To measure the sensitivity of insulin secretion to GLP-1 in cohorts of lean and obese subjects across a broad range of insulin sensitivity.” Possible clinical implications. Individual GLP-1 sensitivity may explain variation in response to GLP-1 receptor agonist therapy, guide patient selection.
Study subjects: healthy, aged 19 to 36 years; no family history of diabetes; lean and obese, normal fasting glucose. 10 lean, 8 obese patients admitted for intervention after overnight 10-hour fast. Subjects underwent clamped hyperglycemia and graded GLP-1 infusion, increased every 25 mins. GLP-1 sensitivity computed from insulin secretion rate (ISR).
All participants had linear increases in ISR with increasing doses of GLP-1. Insulin resistance (via HOMA2-IR) was significantly higher in obese subjects compared with lean: 2.6 vs 0.8; P
B-cell GLP-1 sensitivity and insulin resistance were significantly associated. However, after correction for HOMA2-IR: ISR slopes compared with GLP-1 concentration did not differ between obese and lean individuals. Across participants, there was a 10-fold difference for β-cell GLP-1 sensitivity between the maximum and minimum slope.
“Among our cohort GLP-1 [infusion] enhanced insulin release in proportion to the degree of insulin resistance, a finding most apparent in obese subjects who had a wide range of insulin sensitivity. When the β-cell sensitivity to GLP-1 was corrected for insulin sensitivity, healthy lean and obese subjects have GLP-1-ISR relationships that are essentially identical, refuting our initial hypothesis.”
“The positive relationship between the sensitivity to GLP-1 and insulin resistance raises the possibility that this is a mechanism whereby β-cells adapt to increasing demand for insulin. The wide variation in β-cell GLP-1 sensitivity across our cohorts support this parameter as one that could provide insights into the susceptibility for developing impaired glucose tolerance and diabetes, or for responding to GLP-1-based medications in the presence of these conditions.”
