Dataset Information

?-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) is an insulinotropic factor made in the gastrointestinal tract that is essential for normal glucose tolerance. Infusion of GLP-1 increases insulin secretion in both diabetic and nondiabetic humans. However, the degree to which people vary in their ?-cell sensitivity to GLP-1 and the factors contributing to this variability have not been reported.The objective was to measure the sensitivity of insulin secretion to GLP-1 in cohorts of lean and obese subjects across a broad range of insulin sensitivity.Insulin secretion was measured during clamped hyperglycemia (7.2 mmol/L) and graded GLP-1 infusion in young, healthy subjects, and GLP-1 sensitivity was computed from the insulin secretion rate (ISR) during progressive increases in plasma GLP-1.All subjects had fasting glucose values <5.2 mm. The obese subjects were insulin resistant compared to the lean group (homeostasis model of assessment 2 for insulin resistance: obese, 2.6 ± 0.5; lean, 0.8 ± 0.1; P < .001). ISR increased linearly in both cohorts with escalating doses of GLP-1, but the slope of ISR in response to GLP-1 was greater in the obese than in the lean subjects (obese, 0.17 ± 0.03 nmol/min/pm; lean, 0.05 ± 0.01 nmol/min/pm; P < .001). There was a significant association of ?-cell GLP-1 sensitivity and insulin resistance (r = 0.83; P < .001), and after correction for homeostasis model of assessment 2 for insulin resistance, the slopes of ISR vs GLP-1 concentration did not differ in the two cohorts (obese, 0.08 ± 0.01; lean, 0.08 ± 0.01; P = .98). However, within the entire study group, ?-cell GLP-1 sensitivity corrected for insulin resistance varied nearly 10-fold.Insulin secretion in response to GLP-1 is proportional to insulin resistance in healthy subjects. However, there is considerable variability in the sensitivity of the ?-cell to GLP-1 that is independent of insulin sensitivity.

SUBMITTER: Aulinger BA

PROVIDER: S-EPMC4454808 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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β-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity.

Aulinger Benedikt A BA Vahl Torsten P TP Wilson-Pérez Hilary E HE Prigeon Ron L RL D'Alessio David A DA

The Journal of clinical endocrinology and metabolism 20150331 6

<h4>Context</h4>Glucagon-like peptide-1 (GLP-1) is an insulinotropic factor made in the gastrointestinal tract that is essential for normal glucose tolerance. Infusion of GLP-1 increases insulin secretion in both diabetic and nondiabetic humans. However, the degree to which people vary in their β-cell sensitivity to GLP-1 and the factors contributing to this variability have not been reported.<h4>Objective</h4>The objective was to measure the sensitivity of insulin secretion to GLP-1 in cohorts ...[more]

PMID: 25825945

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Project description:ObjectiveTo regulate food intake, our brain constantly integrates external cues, such as the incentive value of a potential food reward, with internal state signals, such as hunger feelings. Incentive motivation refers to the processes that translate an expected reward into the effort spent to obtain the reward; the magnitude and probability of a reward involved in prompting motivated behaviour are encoded by the dopaminergic (DA) midbrain and its mesoaccumbens DA projections. This type of reward circuity is particularly sensitive to the metabolic state signalled by peripheral mediators, such as insulin or glucagon-like peptide 1 (GLP-1). While in rodents the modulatory effect of metabolic state signals on motivated behaviour is well documented, evidence of state-dependent modulation and the role of incentive motivation underlying overeating in humans is lacking.MethodsIn a randomised, placebo-controlled, crossover design, 21 lean (body mass index [BMI] < 25 kg/m2) and 16 obese (BMI³ 30 kg/m2) volunteer participants received either liraglutide as a GLP-1 analogue or placebo on two separate testing days. Incentive motivation was measured using a behavioural task in which participants were required to exert physical effort using a handgrip to win different amounts of food and monetary rewards. Hunger levels were measured using visual analogue scales; insulin, glucose, and systemic insulin resistance as assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) were quantified at baseline.ResultsIn this report, we demonstrate that incentive motivation increases with hunger in lean humans (F(1,42) = 5.31, p = 0.026, β = 0.19) independently of incentive type (food and non-food reward). This effect of hunger is not evident in obese humans (F(1,62) = 1.93, p = 0.17, β = -0.12). Motivational drive related to hunger is affected by peripheral insulin sensitivity (two-way interaction, F(1, 35) = 6.23, p = 0.017, β = -0.281). In humans with higher insulin sensitivity, hunger increases motivation, while poorer insulin sensitivity dampens the motivational effect of hunger. The GLP-1 analogue application blunts the interaction effect of hunger on motivation depending on insulin sensitivity (three-way interaction, F(1, 127) = 5.11, p = 0.026); no difference in motivated behaviour could be found between humans with normal or impaired insulin sensitivity under GLP-1 administration.ConclusionWe report a differential effect of hunger on motivation depending on insulin sensitivity. We further revealed the modulatory role of GLP-1 in adaptive, motivated behaviour in humans and its interaction with peripheral insulin sensitivity and hunger. Our results suggest that GLP-1 might restore dysregulated processes of midbrain DA function and hence motivational behaviour in insulin-resistant humans.

Dataset Information

?-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity.

Publications

β-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity.

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