The effect of ghrelin on insulin sensitivity and beta-cell function after sleeve gastrectomy

Sleeve gastrectomy (SG) leads to substantial weight loss and improvement in type 2 diabetes, but the underlying mechanisms remain incompletely understood. Given that circulating ghrelin concentrations are reduced after SG, we hypothesized that lower ghrelin levels may contribute to enhanced insulin sensitivity and β-cell function after SG. This was a human, placebo-controlled, randomized, crossover study. We investigated the effect of elevating ghrelin by an intravenous ghrelin infusion on β-cell function and insulin sensitivity using the "Botnia-clamp" (intravenous glucose tolerance test combined with hyperinsulinemic-euglycemic clamp), compared with saline coinfusion. Twelve SG-operated [aged 51 ± 10.9 yr, BMI 32.1 ± 4.6 kg/m² (means ± SD)], and 10 sex-, age-, and body mass index (BMI)-matched unoperated controls without diabetes were included. Outcomes were peripheral insulin sensitivity (M/I) and β-cell function, assessed as the disposition index (DI), calculated as first phase insulin secretion × M/I. Ghrelin infusion significantly reduced peripheral insulin sensitivity (M/I) by 25% following SG and 29% in controls compared with saline infusion. Beta-cell function was significantly impaired with a 37% and 29% reduced first phase insulin secretion, and a 49% and 48% reduction in DI, respectively. No group differences were observed. Ghrelin infusion impairs insulin sensitivity and β-cell function in individuals who have undergone SG as well as in matched control. However, the present findings do not provide evidence that the lower circulating ghrelin concentrations following SG are directly responsible for improvements, as it remains unclear whether this relationship reflects a simple and reversible mechanism.NEW & NOTEWORTHY In a randomized, placebo-controlled crossover study, intravenous ghrelin infusion impaired insulin sensitivity and β-cell function in individuals with previous sleeve gastrectomy as well as in matched controls. Ghrelin reduced peripheral insulin sensitivity by 25%-29% and decreased β-cell function (disposition index) by 48%-49%. These findings suggest that the postoperative reduction in circulating ghrelin following sleeve gastrectomy may contribute to improved glucose metabolism, while underscoring the complex role of ghrelin in human glucose homeostasis.