Whole-body Glucose Production Research Articles

Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C-knockout mice.

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a stable isotope approach to simultaneously quantify gluconeogenic and oxidative metabolic fluxes in the liver and kidney. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; KO). 2H/13C isotopes were infused in fasted KO and WT littermate mice, and fluxes were estimated from isotopic measurements of tissue and plasma metabolites using a multicompartment metabolic model. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by coordinated regulation of gluconeogenic flux through PEPCK-C. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multitissue metabolism in various genetic, pathophysiological, physiological, and pharmacological settings.

207-LB: Simultaneous 2H/13C Assessment of Liver and Kidney Metabolic Fluxes Reveals Reciprocal Upregulation of Renal Gluconeogenesis in Hepatic PEPCK-C Knockout Mice

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a novel stable isotope approach to simultaneously quantify hepatic and renal gluconeogenic and oxidative metabolic fluxes. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic PEPCK (KO). Experiments were performed in fasted (~18hr) KO and wild-type (WT) littermate mice (n≥4, per group) fitted with jugular vein and carotid artery catheters. A multi-compartment metabolic model was used to assess fluxes using the isotopic enrichment of plasma and tissue metabolites from mice infused with 2H/13C isotopes. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis of 17 and 30-fold, respectively. This was consistent with a ~2-fold rise in PEPCK-C and mitochondrial PEPCK protein expression in the kidneys. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by regulating gluconeogenic flux through PEPCK-C. This reciprocity creates a layer of redundancy that protects glucose homeostasis in the event that hepatic glucose production is impaired. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multi-tissue metabolism in various genetic, (patho)physiological, and pharmacological settings. Disclosure M. Rahim: None. C. M. Hasenour: Employee; Self; Eli Lilly and Company. T. Bednarski: None. C. C. Hughey: None. D. Wasserman: None. J. Young: Consultant; Self; Pfizer Inc., Stock/Shareholder; Self; Metalytics. Funding National Institutes of Health (R01DK106348, U01CA235508, T32DK101003, U24DK059637)

Cystathionine-\u03b3-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis

BackgroundSepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H2S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease.MethodsThis study is a post hoc analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood 13C6-glucose and expiratory 13CO2/12CO2 isotope enrichment during 13C6-glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections.ResultsSepsis was associated with lactic acidosis (p = 0.004) and AKI (50% fall of creatinine clearance (CrCl), p = 0.019). While both whole-body glucose production (p = 0.004) and oxidation (p = 0.006) were increased, kidney tissue mitochondrial respiration was reduced (p = 0.028), coinciding with decreased CSE (p = 0.003) and PGC1α (p = 0.003) expression. Albumin extravasation (p = 0.011) and nitrotyrosine formation (p = 0.008) were increased in septic kidneys.ConclusionsSepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.

High-Fat-Fed Obese Glutathione Peroxidase 1-Deficient Mice Exhibit Defective Insulin Secretion but Protection from Hepatic Steatosis and Liver Damage

Reactive oxygen species (ROS) such as H2O2 can promote signaling through the inactivation of protein tyrosine phosphatases (PTPs). However, in obesity, the generation of ROS exceeds the antioxidant reserve and can contribute to the promotion of insulin resistance. Glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme that eliminates H2O2. Here, we have used Gpx1(-/-) mice to assess the impact of oxidative stress on glucose homeostasis in the context of obesity. Gpx1(-/-) mice fed an obesogenic high-fat diet for 12 weeks exhibited systemic oxidative stress and hyperglycemia, but had unaltered whole-body insulin sensitivity, improved hepatic insulin signaling, and decreased whole-body glucose production. High-fat-fed Gpx1(-/-) mice also exhibited decreased hepatic steatosis and liver damage accompanied by decreased plasma insulin and decreased glucose-induced insulin secretion. The decreased insulin secretion was associated with reduced islet β cell pancreatic and duodenal homeobox-1 (Pdx1) and insulin content, elevated pancreatic PTP oxidation (including PTPN2 oxidation), and elevated signal transducer and activator of transcription 1 (STAT1) Y701 phosphorylation. Taken together, these results are consistent with H2O2 inactivating pancreatic PTPs (such as the STAT1 phosphatase PTPN2) for the promotion of STAT-1 signaling to suppress Pdx1 expression and differentiation and, consequently, reduce β cell insulin secretion. We propose that the decreased insulin secretion, in turn, results in decreased hepatic lipogenesis and steatosis, attenuates liver damage, and improves hepatic insulin signaling to suppress hepatic glucose production. Limiting insulin secretion may help combat the development of hepatic steatosis and liver damage in diet-induced obesity.

The Effect of a Short Sprint on Postexercise Whole-Body Glucose Production and Utilization Rates in Individuals with Type 1 Diabetes Mellitus

Recently we showed that a 10-sec maximal sprint effort performed before or after moderate intensity exercise can prevent early hypoglycemia during recovery in individuals with type 1 diabetes mellitus (T1DM). However, the mechanisms underlying this protective effect of sprinting are still unknown. The objective of the study was to test the hypothesis that short duration sprinting increases blood glucose levels via a disproportionate increase in glucose rate of appearance (Ra) relative to glucose rate of disappearance (Rd). SUBJECTS AND EXPERIMENTAL DESIGN: Eight T1DM participants were subjected to a euglycemic-euinsulinemic clamp and, together with nondiabetic participants, were infused with [6,6-(2)H]glucose before sprinting for 10 sec and allowed to recover for 2 h. In response to sprinting, blood glucose levels increased by 1.2 ± 0.2 mmol/liter (P < 0.05) within 30 min of recovery in T1DM participants and remained stable afterward, whereas glycemia rose by only 0.40 ± 0.05 mmol/liter in the nondiabetic group. During recovery, glucose Ra did not change in both groups (P > 0.05), but glucose Rd in the nondiabetic and diabetic participants fell rapidly after exercise before returning within 30 min to preexercise levels. After sprinting, the levels of plasma epinephrine, norepinephrine, and GH rose transiently in both experimental groups (P < 0.05). A sprint as short as 10 sec can increase plasma glucose levels in nondiabetic and T1DM individuals, with this rise resulting from a transient decline in glucose Rd rather than from a disproportionate rise in glucose Ra relative to glucose Rd as reported with intense aerobic exercise.

Increased postabsorptive and exercise-induced whole-body glucose production in patients with chronic obstructive pulmonary disease

Skeletal muscle biopsy studies have consistently shown a decreased oxidative phenotype in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Limited information is available regarding potential adaptations or abnormalities in anaerobic metabolism and glucose homeostasis. Whole-body glucose production was assessed at rest and during exercise in COPD patients with moderate disease severity (forced expiratory volume in 1 second, 52% ± 3%), prestratified into normal-weight (n = 7; body mass index [BMI], 27.5 ± 0.9 kg·m −2) and underweight subjects (n = 6; BMI, 20.6 ± 0.7 kg·m −2), and in 8 healthy controls matched for age and BMI with the normal-weight COPD group. Glucose tolerance was normal in all subjects. Rate of appearance ( R a) of glucose at rest and during submaximal cycling exercise was measured in postabsorptive state by infusion of stable isotope tracer [6,6- 2H 2]glucose. Resting glucose R a was significantly enhanced in underweight COPD patients compared with controls (16.7 ± 0.3 vs 15.1 ± 0.4 μmol·kg fat-free mass −1·min −1, P < .05) and was inversely related to fat-free mass ( r = −0.75, P < .01). Furthermore, the exercise-induced increase in glucose R a was enhanced in COPD patients (81.9% ± 3.4% vs 72.1% ± 2.0%, P = .05), resulting in elevated end-of-exercise glucose output. Differences were most pronounced in underweight patients, who were also characterized by enhanced plasma catecholamine levels and decreased insulin concentrations (all, P < .05). In normal-weight patients, there was evidence for decreased insulin sensitivity assessed by homeostatic modeling technique. Whole-body glucose production is increased in underweight COPD patients with normal glucose tolerance. It is hypothesized that lowered body weight in COPD has unique effects on glucose uptake despite reduced skeletal muscle oxidative capacity, relative hypoxemia, and sympathetic activation.

Comparing the glucose kinetics of adolescent girls and adult women during pregnancy

Fetal energy demands are met mostly from oxidation of maternally supplied glucose. In pregnant adults this increased glucose requirement is met by an increase in gluconeogenesis. It is not known, however, whether, like their adult counterparts, pregnant adolescent girls can increase gluconeogenesis-hence, glucose production. Our objective was to measure glucose kinetics in 8 pregnant adolescents and 8 adult women. We measured glucose kinetics after an overnight fast by using a primed-constant 6-h U-(13)C-glucose infusion at the end of trimester 1 and early trimester 3. From trimester 1 to trimester 3, whole-body glucose production increased significantly in both groups (P < 0.01). However, whereas the weight-specific rate in adults increased by 18.2%, it increased by only 14.3% in adolescents. In adults, the increase in whole-body glucose production was largely due to a significant increase (P < 0.01) in the rate of gluconeogenesis, but in adolescents there was no change in whole-body gluconeogenesis, and weight-specific gluconeogenesis actually decreased by 11.7%. In both groups, the rate of whole-body glycogenolysis increased significantly (P < 0.05) in trimester 3, and in adolescents, it increased by 95%. These findings suggest that, in the fasted state in late pregnancy, pregnant adolescents cannot increase weight-specific glucose production by the same magnitude as their adult counterparts. Furthermore, whereas adult women increase glucose production primarily through gluconeogenesis, adolescents do so through glycogenolysis.

Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects

We tested the hypothesis that NEFA concentrations are higher in obese subjects with fatty liver than in obese subjects without fatty liver. We recruited 22 obese (BMI>30 kg/m(2)) men aged 42-64 years, in whom liver fat was assessed by ultrasound and classified into categories of no, mild to moderate and severe fatty liver by two independent radiologists. Regional and visceral abdominal fat were assessed by dual-energy X-ray absorptiometry and magnetic resonance imaging, and endogenous glucose production, whole-body glucose disposal during an insulin clamp, and NEFA concentrations were measured, along with NEFA suppression (percent (%) suppression and insulin sensitivity index for NEFA during an OGTT). Seven subjects had no evidence of fatty liver, nine had mild or moderate fatty liver and six had severe fatty liver. The amount of visceral fat was not associated with the degree of fatty liver. Whole-body glucose disposal was inversely associated with fatty liver (38.4, 26.5 and 23.9 mumol kg(-1) min(-1) for the groups with no fatty liver, mild to moderate fatty liver and severe fatty liver, respectively, p=0.004). NEFA suppression during the OGTT was decreased (62.5, 50.8 and 41%, p=0.03, for no, mild to moderate, and severe fatty liver, respectively) and the insulin sensitivity index for NEFA was decreased (0.80, 0.40 and 0.34, p<0.0001). Regression modelling suggested that NEFA concentrations were associated with fatty liver independently of whole-body glucose production and disposal measurements. In obese men, NEFA concentrations during an OGTT are associated with fatty liver independently of classic measures of insulin sensitivity determined by the hyperinsulinaemic clamp. The contribution to this association by factors regulating NEFA concentrations requires further study.

Whole-body and adipose tissue glucose metabolism in response to short-term fasting in lean and obese women

Alterations in glucose metabolism during early fasting may be an important trigger of the hormonal and metabolic responses to fasting. The purpose of this study was to determine whether glucose metabolism in response to brief starvation differs in lean and abdominally obese women. We evaluated whole-body glucose metabolism by use of stable-isotope tracer methods and glucose uptake in subcutaneous abdominal adipose tissue by use of arteriovenous balance in 7 lean [58 +/- 2 kg; body mass index (BMI; in kg/m(2)): 21 +/- 5] and 6 abdominally obese (96 +/- 2 kg; BMI: 36 +/- 1) women after 14 and 22 h of fasting. Between 14 and 22 h of fasting, whole-body glucose production and disposal declined in both groups (P < 0.05), but the reduction was 50% greater in lean than in obese women (P < 0.05). The decline in glucose uptake at 22 h of fasting was also lower in obese (0.11 +/- 0.04 micromol*100 g(-1) x min(-1)) than in lean (0.26 +/- 0.03 micromol x 100 g(-1) x min(-1)) women (P < 0.05). Decreases in plasma insulin and leptin concentrations between 14 and 22 h of fasting were also lower in obese than in lean women (insulin: 20 +/- 3% and 32 +/- 5%; leptin: 18 +/- 3% and 37 +/- 6%; both P < 0.05). The normal decline in glucose production and uptake that occurs during early fasting is blunted in women with abdominal obesity. These alterations in glucose metabolism are associated with a blunted decline in circulating concentrations of both insulin and leptin, which may explain some of the differences in the metabolic response to fasting observed between lean and abdominally obese persons.

Weight loss and elevated gluconeogenesis from alanine in lung cancer patients

The role of gluconeogenesis from protein in the pathogenesis of weight loss in lung cancer is unclear. Our aim was to study gluconeogenesis from alanine in lung cancer patients and to analyze its relation to the degree of weight loss. In this cross-sectional study, we used primed-constant infusions of [6,6-(2)H(2)]-D-glucose and [3-(13)C]-L-alanine to assess whole-body glucose and alanine turnover and gluconeogenesis from alanine in weight-losing (WL, n = 9) and weight-stable (WS, n = 10) lung cancer patients and healthy control (n = 15) subjects. Energy intake and plasma alanine concentrations did not differ significantly among the subject groups. Mean (+/-SEM) whole-body glucose production was significantly higher in WL than in WS and control subjects (0.74 +/- 0.06 compared with 0.55 +/- 0.04 and 0.51 +/- 0.04 mmol*kg(-)(1)*h(-)(1), respectively, P < 0.01). Alanine turnover was significantly elevated in WL compared with WS and control subjects (0.57 +/- 0.04 compared with 0.42 +/- 0.05 and 0.40 +/- 0.03 mmol*kg(-)(1)*h(-)(1), respectively, P < 0.01). Gluconeogenesis from alanine was significantly higher in WL than in WS and control subjects (0.47 +/- 0.04 compared with 0.31 +/- 0.04 and 0.29 +/- 0.04 mmol*kg(-)(1)*h(-)(1), respectively, P < 0.01). The degree of weight loss was positively correlated with glucose and alanine turnover and with gluconeogenesis from alanine (r = 0.45 for all, P < 0.01). Aberrant glucose and alanine metabolism occurred in WL lung cancer patients. These changes were related to the degree of weight loss and not to the presence of lung cancer per se.

Hepatic sugar phosphate levels reflect gluconeogenesis in lung cancer: simultaneous turnover measurements and 31P magnetic resonance spectroscopy in vivo

Stable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as observed by (31)P magnetic resonance (MR) spectroscopy, reflect elevated whole-body glucose turnover and gluconeogenesis from alanine. Patients with advanced non-small-cell lung cancer without liver metastases (n=24; weight loss 0-24%) and healthy control subjects (n=13) were studied after an overnight fast. (31)P MR spectra of the liver in vivo were obtained, and glucose turnover and gluconeogenesis from alanine were determined simultaneously using primed-constant infusions of [6, 6-(2)H(2)]glucose and [3-(13)C]alanine. Liver PME concentrations were 6% higher in lung cancer patients compared with controls (not significant); PME levels in patients with >/=5% weight loss were significantly higher than in patients with <5% weight loss (P<0.01). PDE levels did not differ between the groups. In lung cancer patients, whole-body glucose production was 19% higher (not significant) and gluconeogenesis from alanine was 42% higher (P<0. 05) compared with healthy subjects; turnover rates in lung cancer patients with >/=5% weight loss were significantly elevated compared with both patients with <5% weight loss and healthy subjects (P<0. 05). PME levels were significantly correlated with glucose turnover and gluconeogenesis from alanine in lung cancer patients (r=0.48 and r=0.48 respectively; P<0.05). In conclusion, elevated PME levels in lung cancer patients appear to reflect increased glucose flux and gluconeogenesis from alanine. These results are consistent with the hypothesis that elevated PME levels are due to contributions from gluconeogenic intermediates.

Role of glutamine in human carbohydrate metabolism in kidney and other tissues

Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Until recently, the understanding of many aspects of glutamine metabolism was based on animal and in vitro data. However, recent studies using isotopic and balance techniques have greatly advanced the understanding of glutamine metabolism in humans and its role in glucose metabolism in the kidney and other tissues. There is now evidence that in postabsorptive humans, glutamine is an important glucose precursor and makes a significant contribution to the addition of new carbon to the glucose carbon pool. The importance of alanine for gluconeogenesis, viewed in terms of the addition of new carbons, is less than previously assumed. It appears that glutamine is predominantly a renal gluconeogenic substrate, whereas alanine gluconeogenesis is essentially confined to the liver. As shown recently, renal gluconeogenesis contributes 20 to 25% to whole-body glucose production. Moreover, glutamine has been shown not only to stimulate net muscle glycogen storage but also to stimulate gluconeogenesis in normal humans. Finally, in humans with type II diabetes, conversion of glutamine to glucose is increased (more so than that of alanine). The available evidence on the hormonal regulation of glutamine gluconeogenesis in kidney and liver and its alterations under pathological conditions are discussed.

Parenteral glutamine infusion alters insulin-mediated glucose metabolism.

Glutamine is a conditionally essential amino acid that is critical for many basic cellular processes. Its supplementation has been found to be beneficial during several critical illnesses. This study examines the effects of increased glutamine availability on insulin-mediated glucose homeostasis in vivo in multicatheterized conscious canines (n = 5). Two weeks before the study, catheters were placed in the femoral artery and the portal, hepatic, femoral, and renal veins for blood sampling and in the splenic vein for intraportal infusion of insulin and glucagon. Doppler probes were placed to measure blood flow. The metabolic study consisted of equilibration, basal, and experimental periods during which [3-3H]glucose was infused to measure glucose kinetics. During the 5-hour experimental period, a hyperinsulinemic-euglycemic clamp was performed by infusing somatostatin, basal glucagon, fivefold basal insulin, and glucose to maintain euglycemia. The experimental period was divided evenly into two subperiods performed in random order: (1) i.v. glutamine infusion (0.72 mmol kg(-1) h(-1)) and (2) i.v. saline infusion. With glutamine, the glucose required to maintain euglycemia was increased 46% over saline (6.8 +/- 1.0 to 9.9 +/- 1.7 mg kg(-1) min(-1). In addition, whole-body glucose production and utilization were increased by 1.4 and 4.6 mg kg(-1) min(-1), respectively. Finally, the increase in whole-body glucose utilization was manifested by increased hepatic and hindlimb glucose utilization. Increased glutamine availability blunted insulin's action on glucose production and enhanced insulin-mediated glucose utilization with the changes in utilization being threefold greater than the changes in production. Thus parenteral glutamine has potential benefit as a nutrient adjuvant during clinical situations associated with insulin resistance.

GLUCOSE PRODUCTION RATES IN INFANTS WITH CONGENITAL HIV INFECTION. 702

Congenital human inmunodeficiency virus infection (HIV) can lead to brain damage in utero. Because the CNS utilizes the majority of circulating glucose in the normal infant, we explored the use of whole-body glucose production rate (GPR) to detect prenatal brain damage using (6,6-2H2) glucose tracer. We performed 20 studies in 16 patients, weight range 790-3714 g, between 2 and 35 days of age, born to mothers with HIV disease. Final HIV status is known in 14 patients, two are pending results. At follow up at 3 to 34 months, 2 infants have died, one of HIV and the other with severe brain damage not related to HIVinfection. The two infants who are HIV positive were premature; however, the HIV negative infants include 2 prematures (25%). The GPR of HIV positive babies was 5.4mg/kg/min, not significantly different from HIV negative infants, GPR 4.75mg/kg/min. One infant who developed hydrocephaly and spastic quadriparesis, not related to HIVstatus, had a low GPR of 3.5mg/kg/min. We conclude that GPR of infants exposed to HIV in utero is similar to that of normal babies.

Role of cortisol in the metabolic response to stress hormone infusion in the conscious dog

The role of cortisol in directing the metabolic response to a combined infusion of glucagon, epinephrine, norepinephrine, and cortisol (stress hormones) was investigated. Chronically catheterized, conscious fasted dogs were studied before hormone infusion and after a 70-hour stress hormone infusion containing glucagon, epinephrine, norepinephrine, and cortisol (n = 11) or containing all these hormones except cortisol (n = 5). Combined stress hormone infusion increased arterial plasma glucagon, cortisol, epinephrine, and norepinephrine approximately sixfold. Whole-body glucose production (R a), glycogenolysis, and gluconeogenesis were assessed using tracer and arteriovenous-difference techniques. The absence of an increase in cortisol during stress hormone infusion attenuated the increase in arterial plasma glucose concentration and R a (Δ 81 ± 16 v 24 ± 3 mg/dL and 1.7 ± 0.3 v 0.8 ± 0.4 mg/kg/min, respectively). However, it did not alter the increase in net hepatic glucose output (Δ 0.7 ± 0.3 v 0.8 ± 0.4 mg/ kg/ min). When the increase in cortisol was absent, the increase in net hepatic gluconeogenic precursor uptake was attenuated (Δ 0.7 ± 0.3 v 0.1 ± 0.3 mg glucose/kg/min) due to a decrease in gluconeogenic precursor levels. The efficiency of gluconeogenesis increased to a greater extent (Δ 0.19 ± 0.07 v 0.31 ± 0.11) when cortisol was not infused. The absence of an increase in cortisol also led to marked glycogen depletion in the liver (10 ± 4 v 55 ± 10 mg/g liver). Cortisol thus plays a pivotal role in the metabolic response to stress hormone infusion by sustaining gluconeogenesis through a stimulatory effect on hepatic gluconeogenic precursor supply and by maintaining hepatic glycogen availability.