Type 2 diabetic patients may have a mild form of an injury response: a clinical research center study

Arthur P. Richardson and John A. Tayek

Department of Internal Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California 90509


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Patients with type 2 diabetes (DM) demonstrate inadequate insulin release, elevated gluconeogenesis, and diminished nonoxidative glucose disposal. Similar metabolic changes occur during systemic injury caused by infection, trauma, or cancer. Described here are metabolic changes occurring in 16 DM and 11 lung cancer patients (CA) and 13 normal volunteers (NV). After a 10-h overnight fast, all subjects had fasting hormone and substrate concentrations determined, along with rates of glucose production, leucine appearance (LA), and leucine oxidation (LO). Fasting insulin (data not shown) and C-peptide concentrations were elevated in DM and CA compared with weight-matched NV (0.72 ± 0.09 and 0.64 ± 0.08 vs. 0.51 ± 0.03 mg/l, P < 0.05). C-reactive protein concentration was elevated in CA compared with DM and NV (23.3 ± 6.0 vs. 4.2 ± 1.4 and 2.1 ± 0.5 mg/l, P < 0.01). All counterregulatory hormones were normal except for serum cortisol (11.4 ± 1.0 and 12.1 ± 1.0 vs. 8.9 ± 0.7 µg/dl, DM and CA vs. NL, respectively, P < 0.05). Glucose production was increased in DM and CA compared with NV (4.22 ± 0.6 and 3.53 ± 0.3 vs. 2.76 ± 0.2 mg · kg lean body wt-1 · min-1, P < 0.01). LO and LA were increased in DM and CA compared with NV (LO: 27.3 ± 1.5 and 19.7 ± 1.5 vs. 12.5 ± 1.1 mmol · kg lean body wt-1 · min-1, P < 0.05; LA: 91.9 ± 6.6 and 90.7 ± 7.0 vs. 79.1 ± 6.0 mmol · kg lean body wt-1 · min-1, P < 0.01). DM share similar metabolic derangements with CA. The increase in LA may be secondary to an increased glucose production where amino acids are mobilized to provide the liver with adequate substrate to make glucose. The increase in glucose production may also be part of the injury response, or it may represent a form of insulin resistance that exists in both the DM and (non-DM) CA patients.

glucose utilization; cortisol; acute-phase response; C-reactive protein; tumor necrosis factor-alpha ; interleukin-6; growth hormone; free triiodothyronine; metabolic syndrome


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PATIENTS WITH TYPE 2 DIABETES MELLITUS without signs of infection or injury have an elevated C-reactive protein (CRP) (24), possibly a marker of injury. Other acute-phase reactants (serum amyloid A, serum sialic acid, alpha -1 acid glycoprotein), interleukin (IL)-6, and serum cortisol can be elevated in patients with diabetes (24). One of the new glitazones has been shown to reduce acute-phase proteins in diabetes (8). This suggests that the treatment of insulin resistance may be associated with ameliorating the acute-phase response in diabetes. However, it is unclear whether an injury response commonly exists in normal-weight patients with diabetes. If the injury response exists, then it may contribute to an elevated amino acid mobilization, reduced glucose utilization from the skeletal muscle, and a raised glucose production (15).

The purpose of this study was to evaluate the degree of systemic injury, as measured by the serum cortisol, CRP, tumor necrosis factor (TNF)-alpha, IL-6, and/or reduced free triiodothyronine (T3) concentration, in two different disease states, diabetes and cancer. We looked for a relationship between the increased injury response (as measured by serum cortisol and/or reduced T3 concentration) and the rate of amino acid mobilization and glucose production. Earlier reports have demonstrated that cancer patients can have an increased gluconeogenesis (34), reduced nonoxidative glucose utilization (4, 7, 17, 32, 36), and an elevation in plasma insulin and C-peptide concentration (32). To test whether the metabolic abnormalities observed in diabetes were similar to that seen in cancer, we enrolled patients with type 2 diabetes mellitus (DM), patients with lung cancer (CA), and healthy volunteers (NV). We tested the hypothesis that DM patients have an injury response that is similar to the stereotypical response seen in cancer. The paucity of head-to-head comparisons of the injury response between DM and CA patients prompted this study.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study population and patient characteristics. Volunteers were recruited from the outpatient clinics at Harbor-UCLA Medical Center. Sixteen DM patients were compared with 11 CA patients and 13 NV. None of the CA patients or NV had a family history of DM or thyroid disease. None of the patients was participating in any exercise program. None of the volunteers had a history of hypoglycemia. All had normal liver function tests, renal function, and lack of anemia. The non-DM groups had a fasting glucose <126 mg/dl. None of the patients was receiving chemotherapy or radiation therapy, and all were fully ambulatory with a normal Karnofsky Performance Score. The CA patients were recently diagnosed with nonsmall cell lung cancer and had no evidence of liver metastasis. DM subjects had been diagnosed with diabetes mellitus an average of 5.1 ± 1.4 yr (means ± SE) previous, and they had average Hb A1c of 10.1 ± 0.6%. They were free of renal, eye, or neurological complications. Anthropometric data are summarized in Table 1.

                              
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Table 1.   Patient characteristics and anthropometric data

Study location and dietary intake. All subjects were admitted to the General Clinical Research Center at Harbor-UCLA Medical Center under Institutional Review Board approval. All subjects were advised to consume a 200-g carbohydrate diet for 24 h before the study. Actual carbohydrate intakes were calculated as DM 290 ± 40, CA 240 ± 40, and NV 247 ± 40 g/day. Body water was determined by bioelectrical impedance using a BIA monitor (RJL Systems, Clinton, MI). Body water was used to estimate lean body mass.

Infusion protocol. After a 10-h overnight fast at 6:00 AM, all volunteers received a primed, continuous (25 µCi, 15 µCi/h) 3-h infusion of [6-3H]glucose (100% pure by HPLC, New England Nuclear, Boston, MA) and [1-14C]leucine (4 µCi, 1.7 µCi/h). Plasma specific activity for [3H]glucose and [14C]leucine were at steady state between 120 and 180 min of the 3-h radioactive infusion period (data not shown).

Blood samples. Plasma glucose and leucine enrichment, as well as plasma insulin, C-peptide, glucose, glucagon, growth hormone, cortisol catecholamines, and amino acids were determined at time 0 and every 20 min between 120 and 180 min. One volunteer's insulin concentration was elevated greater than five standard deviations from the mean, and this data point was excluded from the mean and data analysis. Free T3 and free thyroxine (T4) were determined by equilibrium dialysis. The sensitive CRP was determined with a tubormetric method using latex particles coated with antibodies to CRP (Wako Chemicals, Osaka, Japan). Intra-assay precision was 5.9%, and interassay precision was 8.4%. IL-6 and TNF-alpha were determined using an ultrasensitive enzyme immunoassay (R&D Systems, Minneapolis, MN). The interassay for IL-6 was 14.2% and the intra-assay was 6.8%. The interassay for TNF-alpha was 11.3% and the intra-assay 9.7%. All hormones and substrates were measured as previously described (33). Amino acids were measured with a Beckman Gold amino acid analyzer. Serum proteins and liver function tests were measured in the hospital clinical chemistry laboratory. Glucose was measured with an Abbot ABA-100 analyzer (South Pasadena, CA) by a glucose oxidase method.

Data analysis. Data analysis was performed using ANOVA. A three-way ANOVA was performed with the three groups, DM, CA, and NV. Simple linear regression analysis and multiple-step regression analysis were performed by the method of least squares. Significance was defined as P <=  0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Concentrations of hormones and acute-phase reactants. The DM and CA groups both had a significant increase in fasting cortisol, insulin, C-peptide, and other hormone concentrations (Table 2). Both DM and CA groups had a reduced free T3 concentration with a normal total T3 and other thyroid hormones. All three groups had normal concentrations of plasma growth hormone, epinephrine, and norepinephrine (data not shown). Only the CA group had significant elevations in CRP and IL-6. In the non-CA groups (both DM and NV), obesity was associated with a higher CRP concentration (9.4 ± 2.1 vs. 4.2 ± 0.3 mg/ml, P < 0.01). Body mass index was also weakly correlated with CRP concentrations (r = 0.419, P < 0.05).

                              
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Table 2.   Fasting hormonal and acute phase reactant profile

Plasma glucose and glucose production. Fasting glucose concentration at 6:00 AM was increased in the DM group (207 ± 15 mg/dl) and mildly increased in the CA patients (110 ± 4 vs. 95 ± 2 mg/dl, P < 0.05). Glucose production (GP) was significantly elevated in both the DM and the CA groups compared with NV (4.22 ± 0.6 and 3.53 ± 0.3 vs. 2.76 ± 0.2 gm · kg lean body wt-1 · min-1, respectively, P < 0.01; Table 3). GP was directly correlated with serum cortisol concentration for DM (r = 0.549, P < 0.05) and cancer patients (r = 0.541, P < 0.05).

                              
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Table 3.   Fasting glucose concentration and total glucose production

Leucine metabolism. DM and CA patients had a significant increase in leucine appearance, leucine oxidation, and percent leucine appearance that was oxidized (Table 4). Fasting leucine concentration was increased in the DM group (127 ± 7 vs. 91 ± 6 and 91 ± 5 µmol · kg lean body wt-1 · min-1; DM, CA, and NV, respectively, P < 0.01). Plasma glucagon concentration was directly correlated with leucine appearance for the CA group (r = 0.502, P < 0.05) and for the NV group (r = 0.533, P < 0.05).

                              
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Table 4.   Fasting leucine kinetics


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Biological markers of the injury response. CRP, IL-6, and TNF-alpha may be elevated in type 2 diabetic patients (11, 23-25). Cancer patients given TNF-alpha increase ACTH and serum cortisol two- to fourfold (19). In our DM and CA groups, cortisol concentrations were increased, which was suggestive of an injury response. However, CRP, IL-6, and TNF-alpha concentrations were not significantly increased in our DM patients. The etiology for the increased cortisol and reduced free T3 concentrations observed in patients with type 2 diabetes mellitus is unknown. Our DM patients did not have a recent injury, nor did they have a history of hypoglycemic episodes.

The increased injury response in CA patients may have been due to an elevation in several cytokines secondary to a foreign-body response elicited by the tumor. An increase in inflammatory cytokines (TNF-alpha , IL-1, IL-6, etc.) may result in a systemwide injury response, which can augment cortisol production via a stimulation of the hypothalamic-pituitary axis. In our study, the IL-6 concentration was elevated in the CA patients. The stereotypical response to injury includes a reduction in glucose utilization and elevations in amino acid mobilization and glucose production (15). These three processes commonly occur in cancer patients (4, 7, 17, 32-34, 36). Elevated rates of leucine appearance, leucine oxidation, and fasting glucose production were observed in our normal-weight DM patients and CA volunteers.

Reduced glucose utilization is the hallmark lesion that occurs with type 2 diabetes mellitus. However, patients with pancreatic (4), colon (7), head and neck (34), gastrointestinal (36), and lymphoma (17) types of cancer also have reduced glucose utilization demonstrated by the euglycemic-hyperinsulinemic glucose clamp technique. If the tumor is removed, glucose utilization increases to within the normal range (36). In colon cancer patients, reduced glucose utilization returns to normal 14 days after colon cancer surgery (7). The normalization of glucose utilization suggests that surgery removes the source of the inflammatory response. Although none of the markers of systemic injury (cytokines, acute-phase reactants, cortisol) was repeated in these cancer patients postoperatively (7, 36), a reduction in the cytokine, acute-phase reactant, and serum cortisol concentrations may have contributed to the improved glucose utilization observed after tumor removal.

Serum cortisol and glucose production. Although serum cortisol was only mildly increased in the DM and CA groups, it was directly correlated with the rate of glucose production in both groups. The correlation had an r value of 0.5, suggesting that serum cortisol may influence glucose production. This may be via its ability to stimulate gluconeogenesis (12). Serum cortisol is directly correlated with the gluconeogenesis in both healthy volunteers (12, 34) and patients with cancer (34). However, caution should be used with these correlations, because cortisol secretion is released in a pulsatile manner.

In a review of the literature, there are nine publications that have measured serum cortisol concentration in patients with type 2 diabetes mellitus compared with normal volunteers (1, 3, 9, 14, 15, 22, 26, 28, 29). Seven of the nine publications report a significant increase in serum cortisol concentration in type 2 diabetic volunteers compared with normal controls (3, 9, 14, 22, 24, 26, 29). The largest study (n = 90) reported a 60% increase in serum cortisol concentration (14), which was greater than the 28% increase observed in our study. Only one of those studies evaluated the pituitary-adrenal axis in patients with type 2 diabetes mellitus. Pituitary ACTH release and adrenal cortisol secretion were increased in patients with type 2 diabetes mellitus (26). Urine free cortisol was not determined in these studies. However, in two other studies, urine free cortisol was increased in type 2 diabetic patients compared with weight-matched volunteers (27, 30). An elevation in urine free cortisol is consistent with a mild form of systemic injury. A mild elevation in serum cortisol may contribute to metabolic abnormalities such as those seen in patients with insulin resistance (12). The increased cortisol concentration in our DM patients was unrelated to serum cytokine concentrations (TNF-alpha and IL-6).

Thyroid hormone and glucose utilization. T3 increases glucose oxidation, glucose production, and glucose utilization (18). T3 has been directly correlated with glucose utilization in normals (18) and in cancer patients (32). In our study, both DM and CA patients had reduced free T3 concentrations. A reduced T3 concentration observed in systemic injury conserves energy and may contribute to a reduction in glucose utilization and glucose production.

The etiology of the reduced free T3 concentration seen in diabetic and cancer volunteers is unknown. A reduced free T3 concentration has been reported in diabetes (6, 20, 21). A reduced free T3 concentration observed in diabetes might be a mechanism that can conserve skeletal muscle mass in the face of poor diabetic control. However, T3 concentrations fail to normalize with improved diabetic control (21). A low carbohydrate intake is known to reduce free T3 (13), but there was no evidence of a reduced intake in our patients.

A reduced free T3 can also occur when there is an injury response, when T4 is deiodinated in the liver to reverse T3. Unfortunately, we did not measure reverse T3 in our study to confirm that the reduced free T3 was due to a mild injury response. When the systemic injury is large, the free T4 is also reduced. The reduction in free T4 is less common when the injury is mild. Free T4 was normal in our DM and CA groups. Finally, neither of these groups had clinical signs of hypothyroidism, and their thyroid-stimulating hormone concentration was in the normal range despite their free T3 concentration being reduced.

Leucine metabolism in injury and diabetes mellitus. Insulin deficiency is associated with an elevation in leucine appearance and oxidation, as seen in patients with type 1 diabetes (5, 10). Leucine appearance has been reported to be normal in type 2 diabetic patients under moderate glucose control (Hb A1c 8.5 and 8.7%, Refs. 16 and 35). However, leucine oxidation was increased in one of these studies (35). Under poor metabolic control (Hb A1c 11.8%), leucine oxidation was borderline elevated in six patients with type 2 diabetes (31). An increase in insulin therapy failed to reduce leucine metabolism in patients with type 2 diabetes mellitus (31). Our patients also had a poor glucose control (Hb A1c 10.1%), which may have contributed to the observed increase in leucine oxidation and appearance.

Besides poor diabetic control, the elevated rate of leucine appearance may have been due to an elevation in serum cortisol (2) or glucagon concentration (5, 26). Glucagon administration is known to increase leucine oxidation and appearance (5). However, glucagon concentration was correlated with leucine appearance only in CA patients (r = 0.533, P < 0.05) and in NV (r = 0.502, P < 0.05). The lack of a correlation in DM patients suggests that other factors may be contributing to the observed increase in leucine metabolism. Although cortisol was increased in the CA and DM groups, there was no correlation between cortisol and leucine metabolism. The small number of DM patients studied (n = 16) may not have excluded a sampling size (beta ) error. Overall, leucine appearance and oxidation were increased in both DM and CA. The etiology in the CA patients may be due to their injury response, as demonstrated by an increase in CRP and IL-6. However, if systemic injury response is to be considered responsible for the increased leucine metabolism observed in the DM patients, then the mechanism appears to be different from that seen in the CA patients. In an earlier study, TNF-alpha was correlated with leucine appearance in cancer patients (r = 0.719, P < 0.05) and normal volunteers (r = 0.581, P = 0.06) (32). However, measurements of TNF-alpha failed to correlate with leucine appearance in the present study. Likely, a different mechanism is responsible for the increase in leucine appearance and oxidation seen in DM compared with CA patients.

In summary, DM and CA patients had increased serum cortisol concentration and a reduced free T3 concentration. Both groups had an increased glucose production, leucine oxidation, and plasma leucine appearance. One major difference between the two groups was the magnitude of glucose production and fasting glucose concentration noted in the DM patients. The similar change in leucine metabolism suggested that a similar process exists. However, a clear-cut injury response was substantiated only in the CA group, as inflammatory cytokines and CRP concentrations were not significantly increased in the DM patients. The injury response in the CA patients may have contributed to their increased amino acid and glucose metabolism. Although cortisol concentrations are increased in type 2 diabetes mellitus, an injury response is an unlikely explanation for the observed abnormalities in amino acid and glucose metabolism.


    ACKNOWLEDGEMENTS

We thank Dr. Armida Parala for editing the manuscript, Merlyn Dubria and Connie Soriano for their valuable work with the inpatient studies, Dr. Mary Grosvenor for nutritional evaluations and dietary analysis, Vincent Atienza, Stephanie Griffiths, Mario Paredes, Maria Lajoie, Lynda Sutter, Ron Nadjafi, and Ed Chang for technical assistance, and all the nurses of the Clinical Research Center for their help and cooperation.


    FOOTNOTES

This study was supported in part by Clinical Investigator Award KO8-DK-02083, National Institutes of Health General Clinical Research Center Program M01 RR-00425, and Pfizer Pharmaceuticals.

Address for reprint requests and other correspondence: J. A. Tayek, Harbor-UCLA Medical Center, UCLA School of Medicine, 1000 West Carson St., Box 428, Torrance, CA 90509 (E-mail: tayek{at}humc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published February 5, 2002;10.1152/ajpendo.00132.2001

Received 19 March 2001; accepted in final form 2 February 2002.


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DISCUSSION
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