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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3005-3010
Copyright © 1997 by The Endocrine Society

Original Studies

Endogenous Glucose Production Following Injury Increases with Age

James M. Watters1, Sonya B. Norris and Susan M. Kirkpatrick

Departments of Surgery and Physiology (J.M.W.), University of Ottawa; and Division of General Surgery and Loeb Institute for Medical Research (J.M.W., S.B.N., S.M.K.), Ottawa Civic Hospital, Ottawa, Canada

Address all correspondence and requests for reprints to: James M. Watters, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada, K1Y 4E9.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
To evaluate the influence of aging on the increase in endogenous glucose production that follows injury, we studied 22 fully resuscitated, clinically stable, previously healthy patients aged <=30 yr or >=60 yr admitted to hospital following injury, and 11 healthy volunteers in the same age groups. Endogenous glucose production was determined using a primed constant infusion of D-glucose-6,6-2d2. Urine cortisol and C-peptide were markedly higher in patients than volunteers (both P < 0.01), and urine C-peptide was lower in older than in younger patients (P < 0.05). Urine cortisol increased as a function of the interaction of age and Injury Severity Score (ISS) (r2 = 0.40, P < 0.001). Intracellular water was markedly lower and extracellular water greater in patients compared with volunteers (both P < 0.001), reflecting the loss of body cell mass and expansion of the extracellular space following injury. Endogenous glucose production (milligrams per minute per liter intracellular water) was best described as a function of ISS and age-ISS interaction (r2 = 0.35, all P < 0.05), and was increased 56% and 78% in younger and older patients, respectively, in comparison with the respective volunteer groups. Endogenous glucose production following injury increases in relation to the severity of injury and patient age. Greater cortisol elaboration and diminished insulin secretion in older patients may contribute to this age effect.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE METABOLIC alterations that follow injury and resuscitation represent a generally predictable set of responses that have been studied extensively in otherwise healthy young and middle-aged individuals. The changes that occur in carbohydrate metabolism include hyperglycemia, accelerated endogenous glucose production (EGP), resistance of normally sensitive tissues to the effects of insulin, and intolerance of glucose loads. There is a net release of amino acids from muscle that provides substrate for accelerated gluconeogenesis and other metabolic pathways, and which derives from net muscle protein breakdown. These patterned responses are presumed to have survival value for the organism but are associated clinically with rapid muscle wasting and cannot be sustained for prolonged periods. Moreover, unlike the metabolic changes that accompany uncomplicated starvation, they are not prevented or reversed simply by the provision of adequate exogenous substrate. The changes in body composition that follow major injury are characterized by the loss of body cell mass and expansion of the extracellular space (1).

Aging is also accompanied by generally predictable changes in body composition: body cell mass declines, accounted for in large part by decreased muscle mass (2). In addition, we have observed in previous studies that hyperglycemia and glucose intolerance following injury are exaggerated in elderly patients, and that insulin responses to glucose loading are markedly impaired (3, 4). Thus the elderly patient is likely to be at a particular metabolic and probably clinical disadvantage following injury, as a result of age effects on glucose metabolism and obligatory net muscle protein catabolism in the face of reduced muscle mass (2). Our purpose in this study was to compare EGP in younger and older trauma patients and healthy volunteers, and to relate differences in EGP to body composition and to insulin and other hormonal responses.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and volunteers

Patients aged 30 yr or less or 60 yr or more who were admitted to hospital following injury and who had been independent, community-dwelling individuals before injury were studied. Patients who were diabetic by history or had other metabolic disease, were pregnant, or were receiving corticosteroids, insulin, or inotropic agents were excluded. Severity of injury was evaluated by Injury Severity Score (ISS), which is based on an anatomic description of an individual’s injuries, and by Glasgow Coma Scale, a functional assessment of neurological status (5, 6). Height and recalled weight before injury were recorded. Healthy, active individuals in the same age groups were studied in comparable fashion in the hospital’s clinical investigation unit following overnight admission. Volunteers were screened by history, physical examination, and blood testing including fasting serum glucose and HbA1c. An ISS value of 0 was assigned to volunteers. The protocol was reviewed and approved by the Research Ethics Committee of the Ottawa Civic Hospital. Written consent was obtained from each patient or next-of-kin and volunteer.

Methods

Patients were studied 48–96 h following admission and any surgical procedure and were fully resuscitated and clinically stable. All glucose-containing iv fluids or feedings were stopped on the evening before study, and patients and volunteers were fasted overnight. Studies were conducted beginning early in the morning, under as quiet and undisturbed conditions as obtainable. Arterialized blood was obtained using a dorsal hand vein catheter and the heated hand technique unless an arterial line was in place, e.g. in patients in an intensive care unit (7).

Total body water (TBW) was determined by dilution of deuterium oxide and extracellular water (ECW) as corrected bromide space, using corrections for nonextracellular distribution, Donnan equilibrium, and plasma water (8, 9, 10). Deuterium oxide (>=99 atoms percent excess; MSD Isotopes, Pointe Claire, Quebec) 10 g accurately measured, and sodium bromide 15 mg/kg (3%, 0.5 ml/kg body weight) were given iv. Blood was obtained before tracer administration and 4 h later for serum determinations of deuterium enrichment and bromide concentration by isotope ratio mass spectrometry (VG MM 602C, Environmental Isotope Laboratory, University of Waterloo, Waterloo, Ontario) and high performance liquid chromatography (Varian Star 9001–9050, Varian Canada, Mississauga, Ontario), respectively. Intracellular water (ICW) was calculated as the difference between TBW and ECW.

EGP was determined using a primed constant infusion of deuterated glucose (D-glucose-6,6-2d2, >=99 atoms percent excess, MSD Isotopes), maintained for 2 h (prime 22.4 µmol/kg, infusion 0.28 µmol/kg·min) (11). Blood was obtained for determination of isotope enrichment before deuterated glucose infusion and after 90, 100, 110, and 120 min of constant infusion. Deuterium enrichment of the trifluoracetyl derivative of glucose was determined by gas chromatograph-mass spectrometer (Hewlett-Packard 5890 GC-Kratof Concept II H MS, Department of Chemistry, University of Ottawa). EGP was taken as the rate of appearance of glucose calculated using the steady state Steele equation.

Glucose was determined by glucose oxidase methodology (Glucose Analyzer 2, Beckman Instruments, Palo Alto, California), and insulin, C-peptide, cortisol, and glucagon by RIA (Euro/DPC, Witney, UK) in serum obtained immediately before and during the final 10 min of deuterated glucose infusion. Cortisol and C-peptide determinations were also carried out on 4-h urine collections obtained following voiding just before body water tracer administration and including the 2-h period of labeled glucose infusion.

Data are expressed as mean ± SEM and were analyzed by ANOVA for age group and injury status effects with Tukey’s HSD post hoc, and by multivariate techniques using standard software (SystatFPU 5.2.1, Systat Inc., Evanston, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Fourteen young and eight older trauma patients were studied. Mean and median ISS scores (25 and 27, respectively) were the same in younger and older patient groups. ISS ranged from 7–43 in younger patients and 10–34 in older patients (Fig. 1Go). Glasgow Coma Scale scores ranged from 6–15 (median 15) in both patient groups. ISS were similar in males and females. Trauma was blunt in nature in 13 younger and all older patients, and penetrating in 1 young patient. The most common mechanism of injury was a motor vehicle crash in both groups (including motorcycle and snowmobile crashes in young patients). Five young and 6 older healthy volunteers were studied. The mean ages of young patients and volunteers were similar, as were those of the older groups (Table 1Go). Sex distribution, body weight, and body mass index did not differ among groups. Narcotic administration in the young patients during the 4 h before study was 7 ± 1 mg morphine equivalents/4 h, and in older patients was 3 ± 2 mg morphine equivalents/4 h (P < 0.05) (12).



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  		Figure 1. Distribution of ISS in younger (darker segments) and older (lighter segments) patients.

 

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  		Table 1. Patient and volunteer demographics

 
Basal serum glucose, insulin, C-peptide, glucagon, cortisol, and creatinine were not significantly different among younger and older patient and volunteer groups (Table 2Go). Basal serum insulin varied to a limited extent (r2 = 0.19, P < 0.05) with serum glucose (P = 0.06) and (inversely) age (P < 0.05). Serum C-peptide was slightly lower (808 ± 59 vs. 709 ± 49 pmol/L, P < 0.01) at the end of the 2-h deuterated glucose infusion, whereas serum glucose, insulin, and glucagon did not change. The change in serum C-peptide was unrelated to injury status or age group. Serum cortisol declined during the study period in volunteers (535 ± 42 vs. 307 ± 33 nmol/L, P < 0.01) but not in patients. Urine cortisol and C-peptide were markedly higher in patients than volunteers, both being P < 0.01 (Table 3Go). Urine C-peptide was lower in older compared with younger patients (P < 0.05) (Fig. 2Go) and was most strongly predicted by injury status and injury-age group interaction (r2 = 0.39, all P < 0.05). Urine cortisol increased as a function of the interaction of age and ISS (r2 = 0.40, P < 0.001). Deuterium enrichment of plasma glucose did not vary during the 90–120-min period of stable isotope-labeled glucose infusion (P > 0.7).


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  		Table 2. Basal serum biochemistry

 

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  		Table 3. Urine biochemistry

 


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  		Figure 2. Urine C-peptide (4-h collections) in younger and older volunteers and patients.

 
Body weight and TBW were not different among groups (Table 4Go), but were greater in males than in females (both P <= 0.001). ECW was substantially increased and ICW decreased in patients compared with volunteers (both P <= 0.001). ECW and ICW were both lower in females than males (both P < 0.05) but neither was a function of age group. The ratio ICW/TBW was a function of injury severity and sex (r2 = 0.78, all P < 0.05) but was not related to age or age group.


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  		Table 4. Body water compartments

 
When expressed without reference to body size (i.e. as milligrams glucose per minute) or as a function of body weight or body surface area, differences in EGP between patients and volunteers did not reach statistical significance (all P = 0.08) (Table 5Go). EGP was significantly greater in patients than volunteers when expressed in terms of TBW (P < 0.05) or ICW (EGPicw) (P = 0.001) (Fig. 3Go). When trauma was considered as a dichotomous variable (i.e. trauma patient or volunteer), age group effects on EGP did not reach statistical significance. However, the severity of injuries sustained ranged from mild to severe in both age groups, and when trauma was expressed in terms of ISS, ISS was a significant predictor of EGPicw (r2 = 0.25, P < 0.01), with the strongest predictor being age-ISS interaction (r2 = 0.34, P < 0.001). EGP expressed as a function of body weight was also most closely related to age-ISS interaction (r2 = 0.16, P < 0.05), although less strongly so than EGPicw. EGPicw was 56% greater in young patients than young volunteers and 78% greater in older patients compared with older volunteers. EGPicw was related to urine cortisol (r2 = 0.29, P < 0.01) in patients and volunteers, to urine C-peptide among volunteers but not patients (r2 = 0.42, P < 0.05), and not to peripheral serum insulin.


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  		Table 5. Endogenous glucose production

 


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  		Figure 3. EGP rates in younger and older volunteers and patients.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The elderly population is heterogeneous, and we chose to study community-dwelling individuals who were active in physical and other spheres, and who were representative of a substantial population who may suffer serious injury and require acute hospital care. We excluded institutionalized or frail individuals, but potential coexisting illness in the older individuals who were studied was minimized only by screening using routine clinical means. Individuals in the older groups were presumably selected to some degree as survivors by virtue of their having obtained an advanced age, but the study question mandated such a cross-sectional design. Patient and volunteer groups were similar in terms of body weight, body surface area, and body mass index, i.e. conventional clinical measures of metabolic body size. The younger and older patients whom we studied had sustained injuries of similar nature and anatomic severity by similar mechanisms. Patterns of injury resulting from a given physical insult are known to vary to some extent with age, and mortality to increase with age for a given mechanism and anatomic severity of injury (13).

Body composition tends to change in a predictable manner through adult life. Weight remains more or less stable, whereas fat mass tends to increase and lean body mass to decrease (1, 2). Hydration of the lean body mass is not a function of age, and lean body mass is reflected in TBW (14). Lean body mass is comprised of the body cell mass (the size of which is reflected in the volume of ICW) and extracellular mass. Body cell mass generally declines with age, both in absolute terms and as a proportion of lean body mass (1, 2), although differences in ICW and ICW/TBW ratio between young and older groups were not significant in the limited number of volunteers we studied. Changes in body composition following injury and other forms of surgical illness have been studied by a number of investigators, the classic description by Moore et al. (1, 9, 15) being of a progressive fall in the ICW/TBW ratio, reflecting the loss of body cell mass and expansion of extracellular mass. We observed substantially lower ICW/TBW and greater ECW/ICW in injured patients, fully consistent with such concepts.

The body cell mass is considered to be the work-performing, energy-consuming tissue compartment, and hypermetabolism following injury is held to be a generalized phenomenon of the body cell mass, involving muscle and the viscera to comparable extents (1, 16). We have observed in previous work that age effects on the increases in energy expenditure and urinary nitrogen losses that follow major elective surgery can be accounted for in large part by differences in body composition (17, 18). Expression of metabolic variables, including EGP, as a function simply of body weight would fail to take into account the considerable changes in body composition that are known to occur with both aging and injury. For this reason, we evaluated EGP in this study as a function of ICW, a correlate of body cell mass. Such referencing of metabolic activity in terms of body composition (specifically lean body mass) rather than body weight has also been used by others to examine age and gender effects on insulin resistance (19).

Increases in EGP, assessed by a variety of techniques, are characteristic of the metabolic responses to injury and acute surgical illness (20, 21, 22, 23). Substrate flux studies have demonstrated that the increase in glucose produced can be related in large part to increased utilization by insulin-independent inflammatory and healing tissues of the wound (24). Increases in EGP of 50% or more have been observed in burn patients compared with healthy volunteers (21). Even greater increases in patients with burn wounds that have become infected suggest a relationship between EGP and the severity of the injury or stress. The differences in EGP between volunteer and injured groups that we observed (when expressed per kilogram of body weight for purposes of comparison with other reports) are less pronounced than in previous studies. However, the average severity of the injuries is almost certainly less in the present study, and we observed a dose-response relationship between injury severity and EGP. EGP was most strongly related to the interaction of age and injury severity, being similar in the younger and older volunteers and increasing as a function of both age and injury severity among patients. If amino acids such as alanine derived from net skeletal muscle breakdown are as important a substrate for glucose production in the elderly trauma patient as in young patients (21), then it is likely that the preexisting lesser muscle mass of the elderly patient will be catabolized at a disproportionately rapid rate. The ability of the elderly patient to sustain the accelerated activity of the metabolic pathways that use such amino acids may be compromised, and the strength of respiratory and other muscles may fall below critical clinical thresholds. We have previously observed that the strength of older patients following major surgery is substantially lower than that of young patients, and that the recovery of strength in older patients is impaired (18).

EGP in health is closely regulated by the counterbalancing effects of insulin and glucagon. We observed markedly higher urine C-peptide excretion in patients compared with volunteers, consistent with increased pancreatic insulin secretion. Peripheral serum insulin concentrations are typically normal or elevated following injury and insulin clearance increased, whereas hepatic and skeletal muscle sensitivity to insulin are diminished (25). Insulin clearance is known to be reduced in healthy elderly individuals (26), and we observed a weak inverse relationship between basal peripheral serum insulin concentration and age in the present study. However, following injury, urine C-peptide was substantially lower in older compared with younger individuals, suggesting that the increased pancreatic secretion of insulin typical of the posttraumatic state is impaired in the elderly. These observations are consistent with observations of lower serum insulin levels following major surgery in older compared with younger individuals, of markedly reduced insulin responses during hyperglycemic glucose clamp or nutritional support following injury in older patients, and of an age-related decline in the serum insulin responses to total parenteral nutrition in a heterogeneous group of medical and surgical patients (4, 17, 27, 28). Thus, although an age effect on peripheral serum insulin concentrations is modest in these data, the urine C-peptide values suggest that pancreatic insulin secretion and portal insulin levels were substantially lower in older patients, potentially contributing to the age-related increase in EGP. Increases in EGP in response to physiological increments in plasma glucagon have been shown to be somewhat greater in healthy older compared with younger subjects (29), but serum glucagon values, although rather variable among patients, were not different between younger and older groups.

Hypercortisolemia plays a major role in the changes in glucose homeostasis that follow injury, including accelerated EGP and insulin resistance (30). More pronounced, prolonged, and variable elevations in plasma cortisol have been described in the elderly following trauma, and we observed a significant direct relationship between age and urine cortisol (3, 31). Thus greater cortisol elaboration in older patients, as reflected in urine values, would offer an additional explanation for their increased EGP, although serum values were variable and not different among groups (32). Greater elevations in circulating glucocorticoids would be expected to result in more marked insulin resistance and enhanced insulin secretion, rather than the apparent reduction that we observed in the older patients (33).

The use of very high doses of iv morphine have been accompanied by modest increases in hepatic glucose production, hyperglycemia, and marked increases in circulating cortisol, catecholamines, and insulin in canine models (34, 35). However, such doses are much higher than used in our patients, particularly those not in an intensive care unit, and any such effects would be negligible in this study. Young patients received greater quantities of narcotics, consistent with previous observations (18). Even if relevant to glucose homeostasis, this difference would have tended to increase EGP in younger patients and to obscure the higher values that we observed in older patients.

Increases in energy expenditure, and presumably other metabolic processes, that occur following injury are believed to be a generalized phenomenon of the body cell mass (1, 24, 36). This concept is based in part on observations of splanchnic and extremity oxygen consumption in burn-injured patients and controls; glucose turnover has been shown to be related to whole-body oxygen consumption in such patients (37). However the body cell mass is not homogeneous, and its composition varies with age: in particular, with the marked decline in muscle mass with aging, visceral mass represents an increasing proportion of the body cell mass. Changes in resting energy expenditure (REE) that accompany aging can be accounted for in large part by changes in body composition (17, 38). REE per unit body cell mass is higher in older subjects, because the size of the muscle mass (which has relatively low REE) is reduced in relation to the body cell mass in the elderly. If increases in metabolic activity following injury are more a function of the viscera than muscle, then the greater elevation of EGP per unit body cell mass in older patients could be accounted for by the diminished contribution of muscle to their body cell mass. A further possible explanation for the apparently greater EGP in older patients is that the determination of ICW is falsely low, as might occur if cellular permeability to bromide was increased in this group and not in younger patients. There is no obvious basis on which to postulate an age effect on permeability or change in intracellular penetrance of bromide (1, 9, 39).

In summary, EGP following injury (expressed in terms of ICW, representing body cell mass) is increased as a function of the interaction of age and injury severity. This age effect may be accounted for by greater cortisol elaboration and diminished pancreatic insulin secretion in older patients following injury.


   Footnotes
 
1 Supported by Medical Research Council of Canada Grant MT-10030 and Career Scientist Award, Ontario Ministry of Health. Back

Received February 3, 1997.

Revised June 2, 1997.

Accepted June 9, 1997.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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