CONTEXT:

The aim of this analysis was to evaluate glucagon and c-peptide concentrations in two scenarios: euglycemic hyperinsulinemia and hyperglycemic hyperinsulinemia. We postulated that worsening obesity and insulin resistance will be reflected as an up-regulated (less suppressible) islet secretion profile.

METHODS:

Eighty-two [34 obese with normal glucose tolerance (NGT), 30 obese with impaired glucose tolerance (IGT), and 18 nonobese with NGT] subjects underwent a euglycemic-hyperinsulinemic clamp (EHC) and a hyperglycemic clamp. C-peptide and glucagon were evaluated at basal and steady-state (SS) conditions.

RESULTS:

Basal glucagon was significantly elevated in obese insulin-resistant and obese IGT subjects as was basal c-peptide. SS glucagon and c-peptide levels during the EHC were lower in the lean and obese insulin-sensitive subjects compared with the obese insulin-resistant subjects with NGT or IGT. Fasting glucagon was the only significant determinant (β = 0.66, P < 0.001) of SS glucagon during the EHC (R(2) = 0.57). In a longitudinal follow-up of a subsample, those who converted from normal to IGT significantly increased their fasting glucagon concentration in comparison with those who remained with NGT.

CONCLUSIONS:

Islet up-regulation manifesting as basal elevated glucagon and c-peptide secretion that determines the suppressive effects of hyperinsulinemia appears early in the course of deteriorating glucose tolerance.