Diabetes is a group of metabolic diseases characterized by hyperglycemia. Clinical expression of diabetes is dependent on both genetic and acquired factors (1).

The metabolic effects of oxidants, which are believed to contribute to many diseases, may influence the development of some forms of diabetes. The oxidant hydrogen peroxide (H2O2) is a by-product of normal cellular respiration and is also formed from superoxide anion by the action of superoxide dismutase. H2O2 has been reported to damage pancreatic β-cells (2,3,4) and inhibit insulin signaling (5).

The enzyme catalase (E.C. has a predominant role in controlling the concentration of H2O2 (6,7), and consequently, catalase protects pancreatic β-cells from damage by H2O2 (3,8). Low catalase activities, which have been reported in patients with schizophrenia and atherosclerosis (9), are consistent with the hypothesis that long-term oxidative stress may contribute to the development of a variety of late-onset disorders, such as type 2 diabetes (10,11). Two categories of genetic deficiencies of erythrocyte catalase, which were reviewed in 1995 (12), are acatalasemia (<10% of normal activity) and hypocatalasemia (∼50% of normal activity). In Hungary, 1 acatalasemic and 12 hypocatalasemic families have been described (10,13,14). These families include 2 acatalasemic, 61 hypocatalasemic, and 66 normocatalasemic individuals. Diabetes was diagnosed in eight members of these families. Both acatalasemic individuals were women with type 2 diabetes; five of the hypocatalasemic women had type 2 diabetes, and the only man with diabetes among the eight was hypocatalasemic. Therefore, for this cohort with inherited catalase deficiency, the incidence of diabetes was 12.7%. None of the 66 normocatalasemic members of the families had diabetes. Thus, it was suggested that deficiency of catalase and oxidant damage may contribute to the development of diabetes (10,11).

In this study, we report 1) the frequency of catalase deficiency observed among Hungarian subjects who do not have other family members with low catalase activity, 2) the blood catalase activity of randomly selected diabetic subjects, 3) data from laboratory indicators of glycemic control as well as insulin and C-peptide concentrations in nondiabetic hypocatalasemic and normocatalasemic members of five of the Hungarian families with catalase deficiency, and 4) insulin and C-peptide concentrations in diabetic patients with acatalasemia and hypocatalasemia.

Samples from 21,750 hospital patients, 1,630 clinic patients, and 3,300 healthy control subjects between the ages of 14 and 93 years were screened for catalase activity during a 3-year study program in the Sümeg region of Western Hungary. The criteria for diagnosis of diabetes were fasting plasma glucose >7 mmol/l, oral glucose tolerance test maximum glucose concentrations >11.1 mmol/l, and HbA1c >6.1%. Glucose was determined by a glucose oxidase-peroxidase method (Glucose test; Reanal, Budapest). The reference range for fasting glucose was 3.5–6.0 mmol/l.

Blood catalase activity was measured with a spectrophotometric assay (9,13). The mean ± 1 SD of the reference range for blood catalase activity was 113.3 ± 16.5 MU/l (14). Decreased blood catalase activity was defined as <80.3 MU/l, i.e., below the mean − 2 SD. Serum fructosamine was measured with the Roche Fructosamine Test (Roche Diagnostics, Basel). The reference range was ≤283 μmol/l. HbA1c was determined with a high-performance liquid chromatography method (Diamat; BioRad, Richmond, CA). The reference range was 4.2–6.1%. Serum insulin concentrations were determined using the radioimmunoassay method from Izotóp Intézet (Budapest). The reference range for fasting serum insulin was 5–35 mU/l (1 mU/l = 5.99 pmol/l). Serum C-peptide was determined using the C-PEP-CTZ radioimmunoassay kit from CIS Bio International (Cedex, France). The reference range was 280–1,320 pmol/l. Student’s t test was used to evaluate the statistical significance of the differences between mean values.

The screening of a large population (26,680 subjects) of individuals from Hungarian hospitals and clinics as well as control subjects resulted in 174 nonanemic subjects with blood catalase activities below the reference range. Among these individuals, 13.8% had diabetes. This frequency is higher than that observed in hospitals (7.8%) or in the general population (1.7%) in Hungary (10).

Blood catalase activities among 137 randomly selected diabetic patients had a mean activity of 94.4 ± 19.2 MU/l. This mean value was significantly lower (P < 0.001) than the mean for the reference range. These diabetic patients were not members of families with established familial catalase deficiency. There was no significant difference (P > 0.7) between the mean catalase activities of the 45 patients with type 1 diabetes and the 92 patients with type 2 diabetes in this group.

Samples from five women with type 2 diabetes and inherited catalase deficiency (one acatalasemic subject with 7.6 MU/l and four hypocatalasemic subjects with 66.3, 24.4, 30.9, and 66.1 MU/l, respectively) were analyzed for insulin and C-peptide concentrations. In three patients (one acatalasemic and two hypocatalasemic subjects), insulin levels (1.1, 4.1, and 4.4 mU/l, respectively) were below the reference range (5–35 mU/l); the insulin level in the fourth hypocatalasemic patient was in the reference range (26.3 mU/l), and the insulin level in the fifth patient was above the reference range (40.0 mU/l).

In these patients, the C-peptide values (40.3, 189.1, 15.9, and 8.6 pmol/l, respectively) were below the reference range (280–1,320 pmol/l), and in one hypocatalasemic patient, the C-peptide value (1,185 pmol/l) was near the upper end of the reference range. The C-peptide versus insulin ratios in these patients were 0.36, 1.04, 0.52, 1.12, and 4.3 pmol/l, respectively, all of which were lower than the generally accepted ratio of >5:1 (15).

The indicators of hypoglycemia and β-cell secretion in nondiabetic catalase-deficient (n = 7) and age-matched (45.1 ± 10.5 vs. 44.7 ± 17.9 years) normocatalasemic relatives (n = 12) were for catalase (mean ± SD) 62.4 ± 23.5 vs. 114.3 ± 17.0 MU/l (P < 0.001), glucose 5.25 ± 0.72 vs. 4.94 ± 0.40 mmol/l (P = 0.241), HbA1c 5.38 ± 0.49 vs. 4.98 ± 0.41% (P = 0.078), fructosamine 235.6 ± 43.8l vs. 224.8 ± 26.2 μmol/l (P = 0.508), insulin 8.0 ± 3.4 vs. 18.8 ± 7.9 mU/l (P < 0.001), and C-peptide 173.7 ± 85.4 vs. 336.8 ± 189.8 pmol/l (P = 0.046).

The elevated concentrations of H2O2 that must exist in individuals with catalase deficiency may damage pancreatic cells, influence insulin release and signaling, and alter glucose metabolic processes, as discussed elsewhere (2,3,4,5,8,9,16,17). The increased frequency of diabetes associated with catalase deficiency and the observed low catalase activity among diabetic patients are consistent with the hypothesis that long-term oxidative stress due to lower-than-normal catalase activity may be a risk factor for diabetes.

In model systems that have a normal expression of catalase, the activity of this antioxidant enzyme has been observed to increase in response to oxidative stress (3,18) and protect pancreatic β-cells. Our data are consistent with the hypothesis that individuals with inherited catalase deficiency lack this ability to protect their β-cells and are consequently at risk of developing diabetes. It is clear from the small fraction of catalase-deficient subjects who have diabetes that this enzyme deficiency alone cannot be used to predict whether an individual will develop diabetes. It is also clear that catalase deficiency may be a risk factor for diabetes, at least in the Hungarian population that we analyzed.

The kind of diabetes involved with catalase deficiency may not be classic type 2 diabetes in which individuals progress from impaired glucose tolerance with modest hyperglycemia and hyperinsulinemia to overt diabetes. The low insulin and C-peptide values in most of the nondiabetic hypocatalasemic subjects and in the diabetic subjects with catalase deficiency indicate that most diabetic and diabetes-susceptible individuals with catalase deficiency may not have hyperinsulinemia of classic type 2 diabetes.

In conclusion, a mechanism may be that an elevated concentration of hydrogen peroxide, due to decreased catalase activity, could contribute to oxidative destruction of pancreatic β cells, to decreased insulin secretion and insulin effectiveness, and to the onset of diabetes.

This study was supported by Grant OTKA TO 30154 from the Hungarian Scientific Research Fund.

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Diabetes Care
Murata M, Imada M, Inoue S, Kawanishi S: Metal mediated DNA damage by diabetogenic alloxan in the presence of NADH.
Free Radic Biol Med
Tiedge M, Lortz S, Munday R, Lenzen S: Complementary action of anti-oxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against toxicity of reactive oxygen species.
Jorns A, Tiedge M, Lenzen S, Munday R: Effect of superoxide dismutase, catalase, chelating agents, and free radical scavengers on the toxicity of alloxan to isolated pancreatic islets in vitro.
Free Rad Biol Med
Hausen LL, Ikeda Y, Olsen GS, Busch AK, Mosthaf L: Insulin signaling is inhibited by micromolar concentrations of H2O2: evidence for a role of H2O2 in tumor necrosis factor alpha-mediated insulin resistance.
J Biol Chem
Gaetani GF, Ferraris AM, Rolfo M, Mangerini R, Arena S, Kirkman HN: Predominant role of catalase in the disposal of hydrogen peroxide within human erythrocytes.
Mueller S, Riedel HD, Stremmel W: Direct evidence for catalase as the predominant H2O2 removing enzyme in human erythrocytes.
Tiedge M, Lortz S, Drinkgern J, Lenzen S: Relation between antioxidant enzymes gene expression and antioxidative defense status of insulin producing cells.
Góth L, Vitai M: Hypocatalasemia in hospital patients.
Clin Chem
Góth L, Eaton J: Hereditary catalase deficiencies and increased risk of diabetes.
Góth L: Lipid and carbohydrate metabolism in acatalasemia.
Clin Chem
Eaton JW, Ma M: Acatalasemia. In The Metabolic Bases of Inherited Disease. 7th ed. Scriver C, Beudet A, Sly W, Valle DL, Eds. New York, McGraw-Hill, 1995, p. 2371–2383
Góth L: Two cases of acatalasemia in Hungary.
Clin Chim Acta
Vitai M, Góth L: Reference ranges of normal blood catalase activity and levels in familial hypocatalasemia in Hungary.
Clin Chim Acta
Tietz NW: Clinical Guide to Laboratory Tests. 3rd ed. Philadelphia, W.B. Saunders, 1995, p. 177
Wollheim CB: Beta cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes.
Heales SJR: Catalase deficiency, diabetes, and mitochondrial function.
Xu B, Moritz JT, Epstein PN: Overexpression of catalase provides partial protection to transgenic mouse beta cells.
Free Radic Biol Med

Address correspondence to László Góth, Department of Clinical Biochemistry and Molecular Pathology, University of Debrecen, Debrecen PO Box 40, Hungary H-4012. E-mail: goth@jaguar.dote.hu.