Glucagon physiology and aging: Evidence for enhanced hepatic sensitivity

Abstract

Summary.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 58young, 21middle-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/1 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/1 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/1) and glucose (0.33 + 0.11 versus 0.50 + 0.11 mmol/1) 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 mlkg-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 (/x = 1.t7 + 0.11 versus 0.67 +0.06 mmol/1, p<0.01). Basal glucose production in older subjects (0.t 3 _+ 0.01 mmol-kg-l, rain-1) was slightly less than in the young (0.15+0.01mmol.kg -1. rain-l). 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) a 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.Key words: Glucagon, aging, glucose tolerance, insulin clamp, hyperglycaemic clamp.The decline in glucose tolerance with advancing age is well established [1][2][3][4][5], but the mechanisms underlying this deterioration are unclear. Recently, both Berger et al. [6] and Marco et al. [7] have reported, in preliminary studies, higher fasting glucagon levels in healthy subjects over the age of 60 years compared to subjects in their twenties. Marco et al. [7] also documented imp...

Insulin sensitivity and secretion in healthy elderly human subjects with ‘abnormal’ glucose tolerance

“…Thus it may be postulated that the increased hepatic insulin sensitivity could be a protective mechanism to limit blood glucose rise, as the elderly have less liver mass with which to take up glucose and therefore endogenous glucose production must be shut off more completely. This is in contrast to other studies of glucagon in normal elderly subjects which have shown no difference [37] or elevation [I41 of plasma glucagon levels both basally and during euglycaemic glucose clamps. The younger subjects had higher glucagon levels basally and throughout the glucose clamp.…”

Mechanisms of Age-Related Glucose Intolerance

“…This profile also argues against a significant role for changes in glucagon metabolism in age-related glucose intolerance, because the most likely expression of such a mechanism would be either an impaired decline or an actual rise in HGO. However, with regard to plasma glucagon levels, it is nevertheless of interest that, although we failed to observe a fall after glucose ingestion (12), a normal decline has been reported during euglycemic (13) and hyperglycemic insulin clamps (28). Finally, this analysis and the recent study by Lefebvre et al (29) together suggest that impaired hepatic glucose uptake plays little or no role in age-related glucose intolerance, because these workers, with [ 1] C]glucose and positron-emission tomography, found that liver was not the major site of early glucose disposition after glucose ingestion.…”

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

“…The imputed results were compared with the "all available" data qualitatively and were found to be in agreement. In addition to change in EGP, the incremental area (or baseline subtracted) under the EGP profile over the 180-min infusion period and the estimated glucagon sensitivity (incremental area under the EGP profile over 180 min divided by the mean glucagon concentration) were used as measures of glucagon action (38).…”