Lower GIP and glucagon responses in metabolically healthy but obese (MHO) subjects in comparison with at risk obese individuals

Background and aims: Obesity is widely acknowledged as a crucial risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardio- metabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero-insular axis. Materials and methods: We studied 129 obese and 24 non-obese subjects. Obese participants were defined as MHO or at risk obese, according to the HOMA-IR index (MHO: lower tertile of HOMA-IR, n=43; at risk: upper tertile of HOMA-IR index, n=41). We investigated insulin, glucagon and incretin responses after a 120’ oral glucose tolerance test (75g- OGTT). Results: During OGTT, MHO individuals showed in comparison with at risk subjects: lower glucose, insulin and C-peptide fasting plasma levels and responses during the OGTT; higher disposition index; lower fasting (p=0.004) and at 30’(p=0.01) plasma glucose-dependent insulinotropic polypeptide (GIP) levels; lower AUC (0-30) for GIP (p=0.008); higher glucagon-like peptide-1 (GLP-1) plasma levels at 90’(p=0.02) and 120’(p=0.02); lower glucagon plasma levels at baseline (p=0.04) and at 30’(p=0.03); appropriate glucagon suppression after the oral glucose load. Conclusion: Metabolically healthy but obese subjects show, as well as normal weight individuals, a lower diabetogenic profile by virtue of higher disposition index and unaffected entero-insular axis. At risk obese individuals present increased GIP levels that might play a role in determining increased glucagon secretion and inappropriate glucagon responses after glucose load, thus contributing to impaired glucose homeostasis.