Altered glucose kinetics occurs with aging: a new outlook on metabolic flexibility

Abstract

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios [RER = carbon dioxide production (V̇co₂)/oxygen consumption (V̇o₂)] during a 2-h 75-g oral glucose tolerance test (OGTT). After an 12-h overnight fast, 28 participants, 15 young (21-35 yr; 7 men and 8 women) and 13 older (60-80 yr; 7 men and 6 women), received venous primed-continuous infusions of [6,6-²H]glucose and [3-¹³C]lactate with a [Formula: see text] bolus. After a 90-min metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 min post glucose consumption, peaked at 60 min, and remained elevated. As assessed by rates of appearance (Ra) and disposal (Rd) and metabolic clearance rate (MCR), glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population after the oral glucose challenge. Finally, there were no differences in 12-h fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population after a glucose challenge. Furthermore, those physiological deficits are not detected from changes in RER during an OGTT.NEW & NOTEWORTHY To determine metabolic flexibility in response to an OGTT, we studied healthy young and older men and women to determine glucose kinetics and changes in RER. Compared to young subjects, glucose kinetics were suppressed in older healthy individuals during an OGTT. Surprisingly, the age-related changes in glucose flux were not reflected in RER measurements; thus, RER measurements do not give a complete view of metabolic flexibility in healthy individuals.

Keywords: OGTT; euglycemia; fractional gluconeogenesis; sex; tracer.

Graphical abstract

Figure 1.

Changes in arterialized blood glucose concentration ([glucose]) over the course of an oral glucose tolerance test (OGTT) for young (solid line, n = 15) and older (dashed line, n = 13) subjects. Values are means ± SE. #Significantly different from baseline values (P ≤ 0.05), $significantly different from peak glucose concentration (P ≤ 0.05), *significantly different from older individuals (P ≤ 0.05), +trended to be different from older individuals (P ≤ 0.10). Sampling time 0 represents an average of values determined 75 and 90 min after the initiation of isotope tracer infusion. The 5 min and subsequent sampling times represent the time after consumption of 75 g of D-glucose. Arterialized [glucose] increases more in older than young adults during an OGTT.

Figure 2.

Glucose rate of appearance (Ra) before and after an oral glucose tolerance test (OGTT) for young (solid line, n = 15) and older (dashed line, n = 13) subjects. Values are means ± SE. #Significantly different from baseline (P ≤ 0.05), *significantly different from older individuals (P ≤ 0.05), ^trended to be different from baseline (P ≤ 0.10), +trended to be different from older individuals (P ≤ 0.10). Glucose Ra is suppressed in aging during an OGTT.

Figure 3.

Glucose rate of disappearance (Rd) before and after an oral glucose tolerance test (OGTT) for young (solid line, n = 15) and older (dashed line, n = 13) subjects. Values are means ± SE. #Significantly different from baseline (P ≤ 0.05), *significantly different from older individuals (P ≤ 0.05), ^trended to be different from baseline (P ≤ 0.10), +trended to be different from older individuals (P ≤ 0.10). Glucose Rd is suppressed in aging during an OGTT.

Figure 4.

Glucose metabolic clearance rate (MCR) before and after an oral glucose tolerance test (OGTT) for young (solid line, n = 15) and older (dashed line, n = 13) subjects. Values are means ± SE. #Significantly different from baseline (P ≤ 0.05), *significantly different from older individuals (P ≤ 0.05), ^trended to be different from baseline (P < 0.10). Glucose MCR is suppressed in aging during an OGTT.

Figure 5.

The rate of lactate conversion to glucose (GNG) before and after an oral glucose tolerance test (OGTT) for young (solid line, n = 13) and older (dashed line, n = 13) subjects. Values are means ± SE. #Significantly different from baseline (P ≤ 0.05), ^trended to be different from baseline (P ≤ 0.10). Fasting lactate conversion to glucose before a glucose challenge is suppressed in aging. *Significantly different from older individuals.

Figure 6.

Fractional gluconeogenesis (fGNG; %) before and after an oral glucose tolerance test (OGTT) for young (solid bar, n = 13) and older (dashed bar, n = 13) subjects. Values are means ± SE. #Significantly different from baseline (P ≤ 0.05), *significantly different from older individuals (P ≤ 0.05), +trended to be different from older individuals (P ≤ 0.10). Elevated fGNG persists during an OGTT in older persons.

Figure 7.

Respiratory exchange ratio (RER) before and after an oral glucose tolerance test (OGTT) for young (solid line, n = 13) and older (dashed line, n = 13) subjects. Values are means ± SE. *Significantly different from older individuals (P ≤ 0.05), #significantly different from baseline (P ≤ 0.05). No differences in RER-measured energy substrate partitioning between young and older individuals during fasting and after an oral glucose challenge.