Effect of age on hepatic glucose production

During the post-prandial state stable plasma glucose levels are maintained by a coordinated balance between hepatic glucose production (HGP) and glucose uptake by peripheral tissues (primarily muscle). The role of the liver in the maintenance of plasma glucose level has been best evaluated with the euglycaemic clamp. Dose—response relationships between plasma insulin level and HGP clearly demonstrate that in normal tolerant individuals, the liver is exquisitely sensitive to insulin and HGP is completely suppressed at insulin levels well below the commonly used insulin dose (240pmol'm~2'min71). Additionally, as demonstrated in Fig. 4, there is no difference in either the basal HGP or in the dose—response curve of its suppression by insulin between young

FIG. 4. Dose—response curves for suppression of hepatic glucose output by insulin in young and old participants.

and old individuals. HGP is suppressed over 90% in aged individuals with insulin levels of 240 pmol/l (40mU/ml) (Meneilly et al 1987). The half-maximal effect is approximately 150 pmol/l (25 mU/ml). This finding is in general agreement with findings of other investigators in both young and elderly volunteers (DeFronzo 1979, Fink et al 1983, Rizza et al 1981). In our studies (Meneilly et al 1987), we have also observed that with low dose insulin infusions, HGP is more rapidly suppressed in the elderly. We have attributed this to a delayed suppression of endogenous insulin release in the elderly individuals (as assessed with C-peptide levels). Thus, early in the study, the liver is exposed to a greater insulin level in the old than in the young. The liver is exquisitely sensitive to portal insulin concentration and an increase of 30—60 pmol/l (* 5 mU/ml) reduces HGP by 50% (DeFronzo et al 1983). Thus, although total suppression of HGP does not differ with age, reduction of HGP by insulin occurs more rapidly in the elderly at physiological levels. The European Group for the Study of Insulin Resistance (EGIR, described in more detail below) has reported their analysis of HGP in 344 non-diabetic subjects (212 men and 132 women) during a euglycaemic clamp (240pmol'm—2'min71) (Natali et al 2000). They ranged in age from 18—85 years and in BMI from 15—55 kg/m2. Basal HGP showed a large variability and was strongly related to lean body mass (LBM) (r = 0.63). HGP was 23% higher in men than in women, which is entirely due to higher LBM in men and no longer different when HPG is adjusted for LBM. Similarly HGP was also positively related to BMI and percentage fat and again these associations were no longer different when adjusted for LBM. There was a tendency for HGP to decline with increasing age ( — 1.1 0.7 mmol'm—1 per year) which was not significant (P = 0.10) and any significance was completely lost when adjusted for LBM (0.002 mmolm71' kg LBM —1 per year). Therefore the variability of basal HGP is due to differences of LBM which also explains the differences of HGP due to age, sex and BMI. Additionally, independent of LBM and fasting plasma insulin, peripheral insulin resistance is associated with higher HGP. The latter suggests that regulation of peripheral glucose uptake and HGP are coupled.

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