1. Introduction

Type 1 Diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta (β) cells, resulting in severe insulin deficiency ^{[1, 2]}. It is the predominant form of diabetes during childhood and adolescence but can be present in adulthood, with typical symptoms of polyuria, polydipsia, and weight loss. ^[3]

T1D is usually considered as a multifactorial disease in which environmental risk factors trigger an immune-mediated destruction of the pancreatic beta cells in genetically susceptible persons. ^[4] T1D is a metabolic disorder characterized by chronic hyperglycemia and other disturbances of carbohydrate, lipid and protein metabolism. ^[5] It is also associated to other disorders such as mild kidney disease, endothelial dysfunction and oxidative stress ^{[5, 6]}.

Oxidative stress is defined as an imbalance between prooxidants and antioxidants and is often associated with free radical overproduction and/or defective physiological defence mechanisms. ^[7] T1D is associated with increased oxidative stress and free radical production. ^{[8, 9]} Increased production of reactive oxygen species as well as reduced antioxidant defense mechanisms have been suggested to play a role in the development of diabetic complications such as atherosclerosis, a major cause of morbidity and mortality in these patients. ^[7] Several mechanisms are implicated in the increased oxidative stress in diabetes mellitus: hyperglycemia, oxygen free radical generation due to nonenzymatic protein glycosylation, glucose autooxidation and glycation products, changes in antioxidant defense systems, lipid alterations and oxidizability of lipoproteins. ^[6]

T1D is a chronic illness that requires a holistic approach in terms of care to prevent both acute and long-term complications. Nutritional management for diabetic patients has been evolving for several years as the pathophysiological basis of the complications incurred from diabetes become more explicit.

Medical nutrition therapy (MNT) is actually included in diabetes treatment. It is important in preventing diabetes, managing existing diabetes, and preventing or slowing the rate of development of diabetes complications. MNT is an important component of self-management education. MNT included advices to patients and their families about healthful eating practices to achieve glycemic control and to avoid complications such obesity, dyslipidemia, cardiovascular disease and hypertension. ^{[10, 11, 12, 13]} MNT for diabetics includes dietary interventions and physical activity. Making healthy food choices every day has both immediate and long-term effects. With education, practice, and assistance from a dietitian and/or a diabetes educator, it is possible for diabetic patients to eat well and control diabetes.

There is no optimal diet for diabetic patients and recommendations include low carbohydrate diet, consumption of low–glycemic index foods, reduction in dietary cholesterol and saturated fats, increase fruits, vegetables, and whole grains intake ^{[13, 14]}. In addition to the macronutrients, micronutrients are an important component of a balanced diet. Diabetic patients are usually micronutrient deficient because of poor dietary choices. ^[15]

The so-called Mediterranean diet may be an option, with beneficial effects in diabetes. ^{[16, 17]} However, despite these recommendations, it is known that many T1D patients do not consume a healthful diet ^{[11, 15, 18]}.

It is therefore of great interest to educate people with T1D in having a good balanced and healthy diet to obtain optimal glycemic control and to prevent the development of diabetes complications.

The aim of this study was to determine how nutritional education of type 1 diabetic patients can have beneficial effects on glucose and lipid levels and on oxidative stress after 3-years of follow-up.

2. Methods

40 men with T1D aged between 20 and 40 years were included in this study and followed up during 3 years. These patients were recruited at the Public Health establishment and at the endocrinology department of Tlemcen University Hospital Center (West Algeria) where they were routinely examined by their treating physician and all had insulin treatment. For the purpose of comparison, 50 nondiabetic men, with similar age range, were recruited as controls. The participation in this study was voluntary and all participants were informed about the goals of the work in progress and gave their written consent. The study was performed according to the Declaration of Helsinki. The study was approved by the Tlemcen Hospital Committee for Research on Human Subjects. The characteristics of the study population are given in Table 1.

All the patients completed the 3-year follow-up. Each patient was reviewed at 1 month, and six monthly thereafter until the last visit (3 years). At each visit, physical examination was carried out. Anthropometric measurements (height, weight, BMI) were conducted for all participants.

For the pourpose of this study, at baseline, dietary advices were provided to all participants and included a balanced diet, a high intake of fruits especially citrus fruits such as oranges and grapefruit, vegetables that have few carbohydrates but are rich in vitamins, minerals, fiber, and phytochemicals, and whole grains, a high intake of olive oil and fish but a low intake of saturated lipids, dairy products, meat, and sugar sweetened products. ^[17] Recommendations on eating smaller meals and progressively snacking throughout the day can make blood sugar easier to monitor and prevent levels from peaking. The coordination between nutrition and insulin treatment in diabetic patients was made by their physicians. Regular and moderate physical activity advices were also provided.

A diatery questionnary was given to participants at the beginning of the study and throughout the follow up. The 24 hours (h) multiple pass recall (MPR) was performed as described by Touvier et al., ^[19] basically consisting of a list of foods and drinks consumed, a detailed description and a review with the interviewer probing for information on food details. Estimation of consumption is obtained by appropriate questions regarding food identification, preparation and ingredients, portion sizes and the use of household implements. In this study, the 24 h MPR was administered on three separate occasions to include one weekend day and two weekdays. Values for energy intake and nutrients were derived from intake records using the nutritional analysis program with database of food composition (REGAL Windows, France).

At baseline and at 3-year follow up, fasting venous blood samples were collected by venipuncture into heparinized tubes and were centrifuged. Plasma was separated for biochemical parameters, Vitamin C and free radical determinations. The remaining erythrocytes were washed in isotonic saline and hemolyzed by the addition of cold distilled water and the cell debris was removed by cetrifugation (2000g for 15 minutes). The hemolysates were assayed for antioxidant / oxidant markers.

Plasma glucose, cholesterol and triglycerides were measured using enzymatic colorimetric methods using appropriate kits (BioAssay Systems, Hayward, CA, USA). LDL-cholesterol was assayed by precipitation and quantitative colorimetric methods using specific kits (Crystal Chem, Downers Grove, IL, USA). The determination of glycated hemoglobin (HbA_1c) was carried out using Human Hemoglobin A1c kit (Crystal Chem, USA).

Plasma nitric oxide (NO) was determined by the colorimetric method of Griess as described by Guevara et al. ^[20] The determination of plasma superoxide anion O2^.- was based on nitro blue tetra- zolium (NBT) reduction in mono formazan by O2^.-. ^[21] Erythrocyte malondialdehyde (MDA), a marker of lipid peroxydation, was estimated by the method using thiobarbituric acid (TBA) (Sigma Aldrich kit; St. Louis, MO, USA). Erythrocyte carbonyl proteins, resulting from a covalent modification induced by radical derivatives or reactive oxygen species, were highlighted by a reaction with dinitrophenylhydrazine (DNPH) to form a dinitrophenylhydrazone adducts (Sigma Aldrich Kit).

Plasma vitamin C levels were estimated using Folin phenol reagent in an acidic range of pH, after deproteinization with trichloroacetic acid. ^[22] Erythrocyte catalase (CAT EC 1.11.1.6) activity was measured by spectrophotometric analysis of the rate of hydrogen peroxide decomposition at 240 nm (Sigma Aldrich kit). Erythrocyte reduced glutathione (GSH) levels were assayed by a colorimetric method based on the reduction of 5,5-dithiobis- (2-nitrobenzoic) acid by GSH to generate 2-nitro-5-thiobenzoic acid, according a Sigma Aldrich kit. Erythrocyte superoxide dismutase (SOD) activity was measured by utilizing Dojindo's highly water-soluble tetrazolium salt (Sigma Aldrich kit).

The results are expressed as the mean ± standard deviation (SD). Statistical analysis between diabetics and controls was carried out using STATISTICA 4.1 program (StatSoft, Tulsa, OK). The significance of the differences between two groups (diabetic versus control at baseline or at 3-years follow up; or baseline versus 3-years follow up in each group) was determined by Student’s t-test after analysis of variance.

3. Results

Table 1 showed no significant difference of BMI between controls and diabetic patients during the study. Nutritional recommendations had no effects on BMI in etheir control or diabetic group. Physical activity habits were moderate in all participants and did not change after 3 years. At baseline, plasma glucose, TC, TG, LDL-C and HbA1C levels were significantly increased in diabetic patients compared to control values (Table 1).

Table 1. Characteristics of the study population

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Significant differences were found for plasma glucose, TC, TG, LDL-C and HbA1C between diabetic patients at baseline and after 3 years, showing a reduction after nutritional advices. It is important to note that lipid levels were normalized in diabetic patients to control values after 3-years follow up. However, glycemia and HbA1C levels remained high in diabetic patients compared to controls.

At baseline, plasma NO and O2.- levels were significantly raised in all diabetic patients in comparison to controls (Table 2). Similarly, erythrocyte MDA and carbonyl protein levels were significantly increased in diabetic patients compared to controls. On the other hand, values of these oxidant markers decreased in a meaningful way after the 3-years follow up in all diabetic patients compared to initial values. However, they remained significantly higher than control values.

Table 2. Oxidant markers in the study population

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Initially, plasma vitamin C and erythrocyte GSH concentrations were reduced in diabetic patients compared to their controls (Figure 1). After nutritional advices, a rise in vitamin C and GSH levels was observed in the diabetic group, reaching the control values after 3 years.

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Figure 1. Plasma vitamin C and erythrocyte GSH concentrations in the study population

At baseline, erythrocyte antioxidant enzyme activities (Catalase and SOD) were found to be significantly decreased in diabetic patients versus controls (Figure 2). After the 3-year follow up, these enzymes activities increased in the diabetic group compared to the initial values, but remained lower than the control antioxidant enzyme activities.

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Figure 2. Antioxidant enzyme activities in the study population

As shows in Table 3, there was no significant difference in daily energy intake of diabetic patients and controls at each time. However, the qualitative composition of nutritional intake was altered in diabetic patients at baseline. Protein intake was decreased while total carbohydrate, simple carbohydrate, total lipid and saturated fatty acid intakes, expressed as percentages of total energy intake, were significantly increased in diabetic patients compared to controls at baseline. Indeed, complex carbohydrate and polyunsaturated fatty acid proportions were reduced in the diabetic group compared to the control group at baseline. After nutritional management, a correction of daily nutrient consumption was observed in diabetic patients who showed protein, lipid and carbohydrate intakes similar to those observed in controls after 3-years follow-up (Table 3).

Table 3. Daily consumption of nutrients

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Additionally, significant reduction in fiber and vitamin C intakes and significant increase in cholesterol and sodium intakes were found in diabetic patients compared to control subjects at baseline. All these nutrient intakes were corrected in diabetic patients and joined control values after 3 years of the study.

4. Discussion

In our study, T1D patients were treated with insulin but presented altered metabolic control mainly due to inadequate dietary habits. Nutritional recommendations were given to these patients who showed a good compliance to the program. The main findings of this study were that nutritional advices induced a decrease in metabolic abnormalities linked to diabetes after 3 years of follow-up.

At baseline, our results provide evidence that glucose, lipid metabolism and oxidant/antioxidant status are altered in T1D. In this study, all diabetic patients had increased plasma glucose concentrations compared with control values, reflecting probably an insulin deficiency state. High fasting glucose levels were associated to high HbA1c amounts reflecting bad diabetic control despite insulin treatment in these patients, in agreement with previous studies. ^{[23, 24, 25]} HbA1c is a biomarker of long term glucose control that reflects blood glucose concentrations over the previous 6 to 8 weeks. ^[11] In agreement with previous studies, ^{[5, 6, 8]} diabetic patients showed altered lipid concentrations and qualitative changes of lipoprotein fractions such as high plasma cholesterol, triglyceride and LDL-C levels compared to controls. The association between diabetes and hyperlipidaemia is well established, contributing to the risk of coronary artery disease ^{[26, 27]}. In addition, increased levels of TG, TC and LDL-C are influenced by the increase of blood HbA1c and glucose concentrations.

Our baseline data provide convincing evidence for altered plasma and erythrocyte antioxidant/oxidant status in T1D patients. Oxidative stress in diabetic patients is induced by a decrease in the antioxidant defense system and by an elevation in free radical production. In fact, all diabetic patients present high levels of oxidant markers (NO, O2^.-, MDA and CP) and low concentrations of antioxidants (vitaminC, catalase, SOD, GSH). The same results were observed in other studies ^{[6, 8, 9, 28, 29]}. The role of hyperglycemia to induce synthesis of reactive oxygen species by glucose oxidation leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction (ED) and other metabolic disturbances. ^[30] The interaction between C-peptide, nitric oxide and endothelial dysfunction has been identified in T1D ^{[30, 31]}. In our study, low levels of vitamin C could reflect its high utilisation rate, suggesting that this vitamin may be used to reduce oxidative stress in diabetic patients, as previously reported ^[32].

Indeed, as observed in our study, the poor glycemic control in diabetic patients is associated with the diminution of protective antioxidant enzyme activities which could increase cell vulnerability to oxygen radical attack, and thus increase diabetic complications.

In our study, the nutritional recommendations allowed an improvement in metabolic parameters and alleviated oxidative stress in diabetic patients after 3-years follow-up.

Our results on baseline dietary habits in T1D patients revealed higher intakes of simple carbohydrates, fat, saturated fat and cholesterol and lower intakes of proteins, unsaturated fat and fiber than control values. The same findings were reported previously among adults with T1D. ^{[12, 33]} Indeed, diabetic patients had increased intake of sodium and decreased intake of vitamin C. It has been recently confirmed that the consumption of high amounts of refined carbohydrates in food and beverage increases the risk of dyslipidaemia. ^{[34, 35]} An epidemiological analysis found an association between diabetes prevalence and sugar availability. ^[36] Moreover, chronic consumption of a Western diet, characterized by foods rich in sugar and abundant in total and saturated fat, has been suggested to play a role in the development of diabetes. ^[37] Dietary fats affected glycemic control in T1D patients. ^[38] Large carbohydrate meals may contribute to poorer outcomes, through impact on late postprandial glycemia and Hb A1C. ^[39] Previous studies have shown that people with T1D had a high saturated fat intake and a low fiber, fruits and vegetables intakes, which could increase the risk of the development of atherosclerosis. ^[40] A high sodium intake has been associated with an increased risk of mortality in diabetic patients. ^[41]

In our study, after 3-years of nutritional advices, daily macronutrient and micronutrient consumption in diabetic patients was improved and was similar to that found in controls. Compared to baseline nutrition, diabetic patients increased their protein, fiber, polyunsaturated fatty acids and vitamin C intakes and reduced their simple carbohydrate, saturated fatty acid, cholesterol and sodium intakes. Globally, metabolic abnormalities of type 1 diabestes observed at baseline were improved after nutritional advices.

There are several studies suggesting that diet can play an important role in treating the complications of diabetes. ^{[42, 43]} It is well documented that medical nutrition therapy favors the reduction of glucose and glycated hemoglobin levels. ^[42] Previous studies from Sweden in which individuals were instructed to consume low carbohydrates diets for up to four years found a significant decrease in HbA1c, dramatic reduction in hypoglycemic episodes, and improvement in lipid profiles in those with good adherence ^{[44, 45]}. Other studies have found that legume intake had a positive effect on HbA1c in women. Legumes are composed of various nutrients, including complex carbohydrates, vegetable protein, dietary fiber, oligosaccharides, and minerals. Legumes rich in complex carbohydrates and fibers are considered foods with low glycemic index, which are thought to be beneficial to patients with diabetes ^[11].

Other studies have linked dietary intervention with better glycemic control and lower levels of triglycerides and LDL cholesterol. ^[46] A previous study indicated that there is potential of reducing HbA1c levels and CVD risk by increasing dietary fiber. ^[47] Due to the recognized beneficial effects of dietary fiber intake in people with diabetes, higher intakes are recommended for adults with diabetes ^{[48, 49]}.

Management of hyperlipidemia requires a reduction in saturated fat intake and an increase in dietary sources of both soluble fiber and anti-oxidants. ^[50] Polyunsaturated fats (PUFAs) should be included in the diet. These fatty acids improve lipid profile, modify platelet aggregation and decrease cardiovascular mortality in people with diabetes ^[51].

Both the quantity and quality (high biological value) of protein intake must be optimized to meet requirements for essential amino acids, necessitating adequate clinical and laboratory monitoring of nutritional status in the individual with diabetes and cardiovascular diseases. ^[52]

Indeed, optimum vitamin, mineral and antioxidant intake should be maintained for general health and cardiovascular protection. In our study, after 3 years of nutritional advices, we note that antioxidant markers (Vitamin C, GSH, SOD and Catalase) are increased with decreasing oxidant markers (NO, O2, MDA and CP) in these diabetic patients compared to baseline values. These changes in redox status are probably due to decreased ROS production following glucose and lipid improvement, and also eating habit changes. Our results of the daily intake of vitamin C showed a significant increase compared to baseline values. However, redox status remained altered in diabetic patients who were still exposed to oxidative stress. Other recommendations such as moderate exercise training or antioxidant supplementation are then necessary to improve redox homeostasis.

5. Conclusion

Nutritional recommendations to patients with diabetes type 1 induced an improvement in glycemic control and lipid profile and subsequently a reduction in ROS generation which could help to prevent diabetic long-term complications. However, these diabetic patients were still subjected to oxidative stress after 3-years follow-up. Future interventions that target physical activity and dietary treatment assessed on an individual basis may be effective strategies to decrease all metabolic alterations in type 1 diabetes.

Acknowledgments

This work was supported by the Algerian Research Project from the Algerian Health investigation office (ATRSS) on diabetes in Algeria.

Disclosure

None declared.

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