The same dose (1 mg) of intravenous glucagon, administered in two consecutive pulses, demonstrates that insulin and C-peptide secretory responses in obese patients exceed those of normal weight subjects. The analysis of the molar ratio of serum immunoreactive C-peptide (IRCP) to serum immunoreactive insulin (IRI) which revealed significant differences between obese and control groups suggests that higher plasma insulin levels in obesity may result not only from a greater response to glucagon loads and from an impaired sensitivity to endogenous insulin by target tissues, but also from a decreased hepatic removal and destruction of the hormone. Perhaps an anomaly in the hepatic handling of insulin exists in obese subjects and thus a greater amount of the hormone reaches the periphery contributing to hyperinsulinemia, as observed in hyperglycemic and hyperinsulinemic obese (ob/ ob) mice.