To determine whether physiological changes in plasma glucagon concentrations are important in regulating basal adipose tissue lipolysis, FFA flux ([1-14C]palmitate) was measured in response to increases and decreases in plasma glucagon. Eight volunteers with insulin-dependent diabetes mellitus (IDDM) and nine healthy nondiabetic volunteers were studied using the pancreatic clamp technique to control plasma insulin, GH, and glucagon concentrations at desired levels. Palmitate flux at the chosen euglucagonemic hormone infusion rates was similar to baseline values (1.73 +/- 0.12 vs. 1.75 +/- 0.23 and 1.35 +/- 0.18 vs. 1.35 +/- 0.16 mumol/kg.min, respectively, in IDDM and nondiabetic subjects). No significant changes in palmitate flux occurred in response to glucagon withdrawal or mild (nondiabetic volunteers) or high physiological (IDDM volunteers) hyperglucagonemia. Thus, under conditions of normal FFA availability, changes in plasma glucagon concentrations within the physiological range have little or no effect on adipose tissue lipolysis.