Glucagon physiology and aging: Evidence for enhanced hepatic sensitivity

To evaluate the role of abnormal glucagon physiology in the glucose intolerance of aging, we have examined: (1) basal glucagon concentration, (2) suppression of plasma glucagon by hyperglycaemia and hyperinsulinaemia, (3) plasma glucagon response to intravenous alanine, (4) glucagon kinetics, and (5) hepatic sensitivity to glucagon (3 ng·kg^-1·min^-1 for 3 h) using 3-³H-glucose in young (24±1 years), middleaged (41±2 years), and older (62±2 years) subjects. Fasting plasma glucagon levels in 58 young, 21 middle-aged, and 32 older subjects were 89±10, 91±12, and 96±21 pg/ml, respectively (p=NS). Following elevation of plasma glucose to 2.2-6.9 mmol/l above basal for 2 h (hyperglycaemic clamp technique), young, middle-aged, and older subjects showed similar depressions in plasma glucagon levels during all three studies. Elevation of the plasma insulin concentration to approximately 100 mU/l while maintaining euglycaemia (insulin clamp technique) also resulted in a similar decline in plasma glucagon levels in both young and older subjects (by 25±3 and 27±3 pg/ml respectively). Following intravenous alanine infusion, the increase in plasma glucagon was not significantly different in young compared with older subjects (65±16 versus 38±7 pg/ml). Plasma insulin (7±1 versus 8±1 mU/l) and glucose (0.33±0.11 versus 0.50±0.11 mmol/l) responses were comparable in young and older subjects. During continuous glucagon infusion, the steady-state plasma glucagon concentration (267±32 versus 252±12 pg/ml) and the metabolic clearance rate of glucagon (16±1 versus 15±1 ml· kg^-1·min^-1) were similar in young and older subjects. However, the increase in plasma glucose concentration was significantly greater in the older than young subjects (Δ=1.17±0.11 versus 0.67±0.06 mmol/l, p<0.01). Basal glucose production in older subjects (0.13 ±0.01 mmol·kg^-1·min^-1) was slightly less than in the young (0.15±0.01 mmol·kg^-1· min^-1). However, the rise in glucose production following glucagon was significantly greater in older than young subjects (31±5 versus 18±4%, p<0.05). In conclusion, (1) basal glucagon levels are not consistently elevated in older subjects, (2) glucagon suppression by both hyperglycaemia and hyperinsulinaemia is similar in young and older subjects, (3) α cell sensitivity to alanine is not affected by age, (4) the metabolic clearance rate of glucagon is similar in young and older subjects, and (5) hepatic sensitivity to a physiological increment in plasma glucagon is increased in older subjects.