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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1624-1628
Copyright © 2003 by The Endocrine Society

Oxidative Stress and Insulin Requirements in Patients with Recent-Onset Type 1 Diabetes

Robert D. Hoeldtke, Kimberly D. Bryner, Daniel R. McNeill, Sarah S. Warehime, Knox Van Dyke and Gerald Hobbs

Departments of Medicine (R.D.H., K.D.B., D.R.M., S.S.W.), Biochemistry and Molecular Pharmacology (K.V.D.), and Community Medicine and Statistics (G.H.), West Virginia University, Morgantown, West Virginia 26506-9159

Address all correspondence and requests for reprints to: Robert D. Hoeldtke, M.D., Ph.D., Department of Medicine, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, P.O. Box 9159, Morgantown, West Virginia 26506-9159. E-mail: rhoeldtke{at}hsc.wvu.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The purpose of this study was to analyze biochemical measures of oxidative stress and assess their relationship to insulin requirements early in type 1 diabetes. Thirty-seven patients enrolled in a 3-yr longitudinal study of the effects of oxidative stress on the early natural history of this disorder. We measured plasma nitrite and nitrate (collectively NOx), nitrotyrosine, and 8-iso-prostaglandin F2{alpha} (8-iso-PGF2{alpha}). Plasma NOx was 34.0 ± 4.9 µmol/liter in the control subjects and 52.4 ± 5.1, 50.0 ± 5.1, and 49.0 ± 5.2 µmol/liter in the diabetic patients at the first, second, and third evaluations, respectively (P < 0.01). Nitrotyrosine was 13.3 ± 2.0 µmol/liter in controls and 26.8 ± 4.4, 26.1 ± 4.3, and 32.7 ± 4.3 µmol/liter in the diabetic patients (P < 0.01). 8-Iso-PGF2{alpha} was higher in the poorly controlled than in the well controlled patients. NOx correlated with insulin dose at the first (P < 0.05), second (P < 0.025), and third (P < 0.05) evaluations. 8-Iso-PGF2{alpha} correlated with insulin dose at the first (P < 0.01) and third (P < 0.0025) evaluations.

Systemic measures of oxidative stress correlate with insulin requirements in early type 1 diabetes. These results suggest that oxidative stress is taking place in the pancreas and damaging the ß-cell.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CHRONIC HYPERGLYCEMIA HAS an adverse effect on ß-cell function, which eventually leads to worse hyperglycemia (1). This vicious cycle has led to the adage hyperglycemia begets hyperglycemia; the phenomenon has been designated glucose toxicity. The latter affects both type 1 and type 2 diabetes and was documented in the Diabetes Control and Complications Trial (DCCT) (2) and the United Kingdom Prospective Diabetes Study (3). The problem is extremely common, particularly in type 2 patients, in whom deterioration in control over time develops in the majority of patients (3). The problem is also clinically important in type 1 diabetes, because the preservation of residual ß-cell function during the first 5 yr of diabetes leads to improvement in glycemic control and has a long-lasting benefit with respect to the prevention of complications (2). Although the mechanism of glucose toxicity is unknown, recent in vitro (4, 5, 6) and whole animal studies have implicated reactive oxygen species (oxidative stress) (7, 8, 9) that promote the formation of cytotoxic lipid peroxides (10) and damage the ß-cell by a variety of mechanisms (7, 8, 9, 10). To determine whether these factors might play a role in human diabetes, we assessed oxidative stress and nitric oxide production in samples saved from a cohort of patients with recent-onset type 1 diabetes who participated in a longitudinal study of the early natural history of this disorder (11). We measured plasma nitrite and nitrate (collectively NOx) as an index of nitric oxide production and 8-iso-prostaglandin F2{alpha} (8-iso-PGF2{alpha}), an isoprostane that provides a measure of oxidative stress and lipid peroxidation. We also measured nitrotyrosine (NTY), which is an index of peroxynitrite, a cytotoxic compound formed from the superoxide anion and nitric oxide (8). Finally, we measured antibodies to glutamic acid decarboxylase (GAD65Ab) and islet cell (IA-2) autoantibodies, because experimental studies have indicated that nitric oxide mediates autoimmune destruction of ß-cells (12).

This study was designed to assess peripheral nerve function (11), not insulin secretion; therefore, unfortunately, blood samples from fasting patients were not saved for C peptide analysis. The insulin doses of the patients were recorded, however, and these are known to vary inversely with ß-cell function in early diabetes (13). Our results indicate that oxidative stress can be detected in poorly controlled patients early in diabetes, and some of the measures of oxidative stress correlated with the insulin requirements of the patients. Taken together these results suggest that oxidative stress has an adverse effect on ß-cell function, and this may explain glucose toxicity.


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

A total of 37 patients (10 men and 27 women) with type 1 diabetes enrolled 2–22 months after diagnosis in a 3-yr longitudinal study (Table 1Go). Patients with symptoms of neuropathy, other systemic illnesses, or excessive alcohol consumption (an average of more than two drinks per day) were excluded from the study. All patients were taught to monitor their glucose levels at home and adjust their insulin doses as necessary to maintain optimal glycemic control. Hemoglobin A1 (HgbA1) was measured one to four times a year for 3 yr. A total of 36 patients underwent three annual evaluations, and 1 patient withdrew after the second year.


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  		Table 1. Characteristics of patients

 
Patients were administered a specific weight-maintaining diet containing 130 mEq sodium daily for 3 d before their annual evaluation. It did not include foods with high nitrite content (celery, lettuce, or spinach). Patients were admitted to the hospital on the third day of the diet; peripheral nerve testing was performed, blood was collected (11), and aliquots were saved for the analysis of nitric oxide metabolites and 8-iso-PGF2{alpha}. We also measured antibodies to glutamic acid decarboxylase (GAD65Ab) and islet cell antibodies (IA-2Ab). Forty-one age- and gender-matched control subjects were administered the same diet, admitted to the hospital, and subjected to the same experimental protocol. The protocol was approved by the institutional review board of West Virginia University, and informed consent was obtained from all participants.

Biochemical measurements

HgbA1 was measured by agar gel electrophoresis (14). The reference range for the nondiabetic population was 4.7–7.3%. Serum NO3 was converted to NO2 by nitrate reductase, which was quantitated by the Griess reaction colormetrically (15). Plasma proteins were precipitated with acetone and then digested with pronase. 3-NTY was measured with HPLC and detected electrochemically (CoulArray, ESA, Chelmsford, MA) (16). 8-Iso-PGF2{alpha} was measured by an ELISA method (17) using a kit from Cayman Laboratories (Ann Arbor, MI). GAD65Ab and IA-2Ab autoantibodies were measured by Ake Lernmark (University of Washington, Seattle, WA) (18).

Statistical analysis

Associations between biochemical parameters and insulin dose were assessed using regression analysis (19).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
No vascular complications or symptoms of neuropathy developed in the diabetic patients during the course of this study. One patient developed hypertension, and one patient withdrew from the study after the second evaluation. Twenty of the 37 patients maintained glycemic control within American Diabetes Association guidelines (HgbA1, <1% above the upper limit of normal for the nondiabetic population). Patients were stratified each year according to whether their glycemic control was good or poor by determining whether their average HgbA1 was respectively below or above the median of the average HgbA1 determinations for all patients at that evaluation. Patients in good glycemic control had the same age and gender distribution as those in poor control.

NOx concentrations were higher in the diabetic patients at the first (52.4 ± 5.1 µmol/liter), second (50.0 ± 5.1 µmol/liter), and third (49.0 ± 5.2 µmol/liter) evaluations than in the control subjects (P < 0.01) whose NOx was only 34.0 ± 4.9 µmol/liter (Table 2Go). NOx was elevated in the diabetic patients with high HgbA1 compared with controls (P < 0.05 at each evaluation), but was nearly normal in the well controlled diabetic patients (Table 3Go). NOx was higher in the diabetic women than in the control women (P < 0.01) and the diabetic men (P < 0.025). NOx was no different in the diabetic vs. nondiabetic men.


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  		Table 2. Nitrosative stress in early diabetes

 

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  		Table 3. Effects of glycemic control on nitrosative stress and 8-iso-PGF2{alpha}

 
NTY was 13.3 ± µmol/liter in the control subjects and was approximately double in the diabetic patients (Table 2Go). The increased NTY was observed in the male as well as the female patients with diabetes. Those in poor control had a larger increase in NTY. We detected no chlorotyrosine, an indicator of myeloperoxidase activity (an alternative source of NTY), in patients or controls.

8-Iso-PGF2{alpha} was not increased in the diabetic patients compared with controls. Nevertheless, 8-iso-PGF2{alpha} was higher in the poorly controlled vs. the well controlled diabetic patients (Table 3Go). The diabetes-related gender difference described for NOx was also seen for 8-iso-PGF2{alpha}. There was a strong correlation between 8-iso-PGF2{alpha} and NOx in the diabetic patients at the first (P < 0.05), second (P < 0.001), and third (P < 0.001) evaluations. To establish that these correlations were not merely a reflection of the gender differences for these parameters, we calculated gender specific z-scores for NOx and 8-iso-PGF2{alpha} and documented that these were correlated (Fig. 1Go).



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  		Figure 1. NOx vs. 8-iso-PGF2{alpha}. These data were gathered at the third evaluation. The correlation between NOx and 8-iso-PGF2{alpha} was 0.55 (P < 0.001). The NOx and 8-iso-PGF2{alpha} indexes, (gender-specific z-scores) were also correlated (r = 0.53; P < 0.001).

 
NOx correlated with insulin dose at the first (P < 0.05), second (P < 0.025), and third (P < 0.05) evaluations. 8-Iso-PGF2{alpha} correlated with insulin dose at the first (P < 0.01) and third (P < 0.0025) evaluations (Fig. 2Go). Gender-specific z-scores for NOx correlated with insulin dose in yr 2 (P < 0.025) and yr 3 (P < 0.05). Gender-specific z-scores for 8-iso-PGF2{alpha} correlated with insulin dose at the first (P < 0.025) and third (P < 0.005) evaluations (Fig. 2Go). The mean NOx for the three evaluations correlated with the mean insulin dose (P < 0.05), and the mean 8-iso-PGF2{alpha} for each patient correlated with their mean insulin dose (P < 0.025). NTY, however, did not correlate with insulin dose. There was no correlation between any of these biochemical parameters and GAD65Ab or IA-2Ab.



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  		Figure 2. 8-Iso-PGF2{alpha} vs. insulin requirement. These data were gathered at the third evaluation. 8-Iso-PGF-F2{alpha} correlated with insulin dose (r = 0.48; P < 0.0025). The 8-iso-PGF2{alpha} index also correlated with the insulin dose (r = 0.44; P < 0.005).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Oxygen continuously enters all tissues to provide energy and sustain life. Although the major end products of oxygen metabolism, carbon dioxide and water, are nontoxic, some of the byproducts of oxygen metabolism, such as the superoxide anion and the hydroxyl ion, have unpaired electrons and are therefore unstable and prone to react with and damage tissues. Oxidative stress refers to the circumstance in which these reactive oxygen species are formed excessively or when there are inadequate endogenous defenses. Oxidative stress has been shown to induce complications in animal models of diabetes, but the importance of this in man has been difficult to demonstrate, and there is currently little evidence that oxidative stress is detrimental in human diabetes. Recent data from this cohort, however, have shown that oxidative stress has a negative impact on peripheral nerve function (20). Moreover, previous in vitro (4, 5, 6) and whole animal (7, 8, 9) studies have suggested that hyperglycemia has detrimental effects on the ß-cell that are similar to its effects on endothelial cells and nerves. This led us to postulate that the biochemical mechanisms that were adversely affecting peripheral nerve function in early diabetes were also damaging the ß-cell. The associations between biochemical measures of oxidative stress and insulin requirements are consistent with this hypothesis and suggest that glucose toxicity is linked to oxidative stress in type 1 diabetes.

The validity of this conclusion is based on the assumption that insulin requirements provide a mirror image of ß-cell function throughout the course of this study. Inverse correlations between ß-cell function and insulin requirements were reported by Marner et al. (21) for the first 3 yr of type 1 diabetes, and this was confirmed in the DCCT (2, 22). Moreover, analysis of DCCT data indicates that this association persists during the fourth year of diabetes and is thus perfectly maintained throughout the duration of the present study (Fig. 3Go) (22).



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  		Figure 3. Stimulated C peptide vs. insulin requirements in the DCCT. The dotted line represents the baseline data on DCCT participants who entered the trial within 2 yr of diagnosis (comparable to our patients at the first evaluation). The solid line represents patients who entered the DCCT during the third year of their illness (comparable to our patients at the second evaluation). The dashed line represents patients who entered the trial during their fourth year (comparable to our patients at the third evaluation). The associations between these parameters were significant (P < 0.001) each year.

 
A number of mechanisms have been proposed for the adverse effects of oxidative stress on the ß-cell. Reactive oxygen species interfere with the transcription of insulin promoter genes and cause protein glycation and cross-linking, pancreatic fibrosis, and lipid peroxidation (4, 5, 6, 7, 23). We also measured nitric oxide production, because reactive oxygen intermediates stimulate nuclear factor-{kappa}B, which, in turn, enhances the transcription of inducible nitric oxide synthase (iNOS), a major source of nitric oxide production, in patients with diabetes (8). iNOS is increased in smooth muscle throughout the vasculature in experimental diabetes (24), and recent clinical studies have indicated that nitric oxide biosynthesis (25) and plasma NOx are increased (26) in type 1 diabetes. iNOS is also present in the ß-cell, where its chemical properties and physiological regulation are similar to those in macrophages and smooth muscle (8). Thus, it is reasonable to assume that the systemic nitrosative stress we have documented in plasma samples is also taking place in the pancreas even within the ß-cell itself. iNOS activity in ß-cells has been linked in animals to their susceptibility to injury. INOS-deficient mice, for example, are resistant to the diabetogenic effects of streptozotocin (27). By contrast, animals that overexpress iNOS develop insulin-dependent diabetes (28). Nitric oxide has many adverse effects on the ß-cell, where it inhibits insulin secretion, disrupts electron transport, promotes apoptosis, and causes lipid peroxidation (8, 28, 29). Our data indicate that these considerations are may be clinically relevant. The correlations between NOx and 8-iso-PGF2{alpha} suggest that these parameters are responding to a common stimulus or are otherwise physiologically linked. Accordingly, it has previously been shown that iNOS-deficient mice have dramatically decreased NOx and 8-iso-PGF2{alpha} (21). We therefore postulate that oxidative stress-induced iNOS activation is the source of NO overproduction in diabetes, and the latter has a quantitatively significant impact on NOx in hyperglycemic patients. The correlations between these parameters and insulin requirements suggest that activation of iNOS may be one of the mechanisms by which hyperglycemia and oxidative stress damage the ß-cell (Fig. 4Go).



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  		Figure 4. Theoretical schema linking oxidative stress and glucose toxicity. [.O2]–, Superoxide anion; [.NO], nitric oxide; [OONO]–, peroxynitrite.

 
There are other possible interpretations of our data. Yki-Jarvinen (1) observed that hyperglycemia led to insulin resistance in type 2 diabetes and proposed this as one of several mechanisms for glucose toxicity. Insulin sensitivity was not tested in our study, but we think that insulin resistance is an unlikely explanation for our results, because ß-cell failure is the predominant metabolic disturbance and determinant of insulin requirements in early type 1 diabetes (13). Could our results merely reflect the fact that ß-cell dysfunction leads to hyperglycemia, and the latter causes oxidative stress? Our results are clearly consistent with this conclusion, but we offer a broader interpretation of the data that is based on abundant animal studies showing that oxidative stress damages the ß-cell (4, 5, 6, 7, 8, 9, 10, 23). This creates a vicious cycle by which oxidative stress is both the cause and the result of ß-cell dysfunction. This hypothesis has been shown to be true in animals. Administration of vitamin E to GK rats, a model of type 2 diabetes, improves both insulin secretion and glycemic control (30). The combination of vitamin E and N-acetyl-L-cysteine (another antioxidant) attenuates the apoptosis of ß-cells, increases insulin content and insulin mRNA in the pancreas, and improves insulin secretion in a murine model of type 2 diabetes (31). Several small clinical studies have indicated that similar effects may be possible in man. The natural antioxidants {alpha}-lipoic acid (32) and vitamin E (17, 32) suppress 8-iso-PGF2{alpha} and other measures of lipid peroxidation. Antioxidant therapy did not lead to noticeable changes in insulin requirements, however, in any of these studies.

In summary, we have documented that oxidative stress takes place early in type 1 diabetes, particularly in poorly controlled patients. Some of the systemic measures of oxidative stress correlated with the insulin requirements of the patients. This suggests that these metabolic events were taking place in the pancreas and causing ß-cell damage. These results are consistent with experimental studies indicating that oxidative stress is the cause of glucose toxicity.


   Acknowledgments
 
Gratitude is expressed to Chris Baylis, Ph.D., for measuring NOx. We thank Ake Lernmark, Ph.D., for analyzing the GAD65Ab and IA-2 autoantibodies.


   Footnotes
 
This work was supported by NIH Grant DK-32239 (to R.D.H.) and the Compton Nutrition Foundation.

Abbreviations: DCCT, Diabetes Control and Complications Trial; HgbA1, hemoglobin A1; iNOS, inducible nitric oxide synthase; NOx, nitrite and nitrate; NTY, nitrotyrosine; 8-iso-PGF2{alpha}, 8-iso-prostaglandin F2{alpha}.

Received October 4, 2002.

Accepted January 15, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals