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Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus
Complementary Therapies in Clinical Practice 19 (2013) 15e19
Contents lists available at SciVerse ScienceDirect
Complementary Therapies in Clinical Practice journal homepage: www.elsevier.com/locate/ctcp
Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus Mamdouh Abdulrhman b, *, Mohamed El Hefnawy a, Rasha Ali b, Iman Abdel Hamid b, Ahmad Abou El-Goud b, Doaa Refai b a b
National Institute of Diabetes, Cairo, Egypt Pediatric Department, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
a b s t r a c t Keywords: Honey Diabetes Glycemic index C-peptide
This study was a case control cross sectional study that was conducted on 50 patients with type 1 diabetes mellitus and 30 controls without diabetes. The mean age of patients was 10.02 years. Oral sugar tolerance tests using glucose, sucrose and honey and measurement of fasting and postprandial serum Cpeptide levels were done for all subjects in three separate sittings. The glycemic index (GI) and the peak incremental index (PII) were then calculated for each subject. Honey, compared to sucrose, had lower GI and PII in both patients and controls (P < 0.01). In both patients and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01). Conclusion: Because of its possible stimulatory effect on diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Experimental and epidemiological studies have shown that reduction of postprandial plasma glucose delays the development of cardiovascular complications.1 During the last 15e20 years it has also been observed that patients with type 1 diabetes mellitus (DM) who had a detectable, even low, level of C-peptide are less prone to develop microvascular complications of the eyes, kidneys, and peripheral nerves.2 Honey is a natural substance produced by honey bees. It is composed of sugar and non-sugar parts. Glucose and fructose, the main sugars in honey, constitutes about 70% of the honey solids. The non-sugar part of honey consists of water and other elements.3 The water content of honey ranges between 15 and 20% (average 17.2%). Honey also contains acids, proteins and minerals. The protein and amino acid content of honey varies from 0.05 to 0.3%. The honey proteins are mainly enzymes. Varying amounts of mineral substances ranging from 0.02 to 1.03 g/100 g are also present in honey. Honey possesses antiinflammatory,4 antioxidant5 and antimicrobial properties.6 The antioxidant properties of honey are mainly attributed to
its content of polyphenols. Further more, honey produced an attenuated postprandial glycemic response when compared with sucrose in both patients with type 2 DM and normal subjects.7 According to the international table of glycemic index and glycemic load values8 the mean (SD) GI of 11 types of honey was 0.55 (0.05). Diets with GI of 0.55 or less are considered low GI diets.9 Our previous study10 may be the only study which evaluated the effects of honey ingestion on C-peptide level in patients with type 1 DM. This study involved only 20 patients with type 1 DM and 10 controls without diabetes and the results showed that honey, as compared with either glucose or sucrose had a significantly lower glycemic index (GI) and peak incremental index (PII); and regarding its effect on C-peptide, honey produced a significantly higher Cpeptide level in controls, but the rise of C-peptide was not significant in patients with type 1 DM. However this study10 was limited by its small number of cases. Therefore in the present study the effects of these sugars were evaluated in more 30 patients with type 1 DM and 20 controls without diabetes. Finally the results obtained from the 50 patients and 30 controls of both studies were analyzed. 2. Patients and methods
* Corresponding author. Tel.: þ20 1006208547. E-mail addresses: [email protected] (M. Abdulrhman), drhefnawy@ yahoo.com (M. El Hefnawy), [email protected] (R. Ali), dr_imana30@ yahoo.com (I. Abdel Hamid), [email protected] (A. Abou El-Goud), [email protected] (D. Refai). 1744-3881/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctcp.2012.08.002
Fifty patients with type 1 DM, aged 1e18 (mean 10.02 years) and 30 healthy children and adolescents without diabetes, aged 1e18 (mean 9.7 years) were studied. All patients with type 1 DM had a mean (SD) glycosylated hemoglobin of 9.7% (1.91)
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M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19
[range ¼ 6.8e15.5%]. The mean (SD) duration of diabetes was 3.15 (2.51) year [range ¼ 1monthe10 years]. The sex ratio in patients and controls was 26:24 and 16:14, respectively. The patients were recruited from the regular attendants of the children clinic of the National Institute of Diabetes in Cairo, Egypt. 2.1. Inclusion criteria All patients with type 1 DM were candidates for this study. The patient was considered suffering from type 1 DM if the fasting Cpeptide level was below 0.4 ng/dl.11
Glycemic index of the food ¼
3. Measurement of fasting and postprandial serum C-peptide level: Venous blood samples were withdrawn from each subject at 0 (fasting) and 2 h postprandial after ingestion of each individual sugar. The samples were then centrifuged and serum was stored in aliquots at 20 C. At the end of the study, samples were calibrated for C-peptide using the biosource c-pep-easia.d 4. Calculation of glycemic and peak incremental indices as was described by Jenkins,13 (1987)
Area under glycemic curve of test food Area under glycemic curve of glucose
2.2. Exclusion criteria Area under curve (AUC) refers to the area included between the baseline and incremental blood glucose points when connected by straight lines. The area under each incremental glucose curve is calculated using the trapezoid rule (note: only areas above the baseline are used). Peak incremental index (PII) is defined as the ratio of the maximal increment of plasma glucose produced by sugar to that produced by glucose7
1. Coexisting renal or hepatic impairment 2. Coexisting diseases e.g., malignancy, other endocrine disorders 3. Patients on steroid therapy. The study was approved by the local ethical committee, and an informed consent was obtained from at least one parent of each subject before the study. All patients were receiving three insulin injections per day, each consisting of a mixture of a medium-acting insulin (isophane NPH) and a short-acting soluble insulin (human Actrapid).
Peak incremental index ¼
Maximal increment produced by the sugar tested Maximal increment produced by glucose
We followed the same methodology as in our previous study.10 All subjects were subjected to the following: 1. Anthropometric measures including weight in kg and height in cm. The BMI [weight (kg)/height (metre)2] was then calculated. 2. Oral sugar tolerance tests using glucose, sucrose and honey in three separate sittings: After an overnight fast (8 h) and omission of the morning insulin dose, a calculated amount of each sugar (amount ¼ weight of subject in kg 1.75 with a maximum of 75 g)12 was diluted in 200 mL water and then ingested over 5 min in a random order, on separate mornings 1 week apart. The honey used in this study was a raw Egyptian clover honey supplied by a beekeeper without heating or irradiation. The honey dose for each patient was calculated based on the fact that each 100 g of the honey used in this study contained 77.3 g sugars. So if, for example, a patient weighs 20 kg, he/she should receive 20 1.75 ¼ 35 g sugar which will be present in (35 100) O 77.3 ¼ 45.3 g honey. Venous blood was sampled just before ingestion and then every 30 min postprandial for 2 h thereafter. Samples were left to clot, centrifuged and glucose assay was performed chemically on the Synchron CX5 autoanalyser (Beckman instruments Inc.).c
c
Beckman, 200 S. Kraemer Blvd, Brea, CA 92621, USA.
Maximal increment is the difference between the peak point and the fasting point. 3. Statistical analysis The collected data were revised, coded, tabulated and introduced to a PC using Statistical package for Social Science (SPSS 15.0.1 for windows; SPSS Inc, Chicago, IL, 2001). All numeric variables were expressed as mean standard deviation (SD). Student ttest was used to assess the statistical significance of the difference between two study group means. Paired t-test was used to assess the statistical significance of the difference between two means measured twice for the same study group. Chi-square (c2) test was used to compare frequency of qualitative variables amongst the different groups. For statistical power calculation STATAÒ version 11 program was used. 4. Results No significant difference was found between patients with type 1 DM and controls without diabetes as regards the age, sex and anthropometric measures. The fasting serum glucose level did not differ significantly between subjects in both groups (Table 1 and 2).
d
Biosource Europe S. AdRue de l’industrie 8, 1400 Nivelles, Belgium.
M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19 Table 1 Mean serum glucose (SD) (mg/dl) in subjects without diabetes (control) following equivalent amount of glucose, sucrose or honey. Time (min)
Glucose
0 30 60 90 120
80.47 94.43 111.43 116.40 97.27
a b c d e f g h
Sucrose 12.78 15.82 17.22 17.47 14.45h
78.50 100.97 118.40 124.90 109.13
80.60 90.50 100.23 100.47 87.50
Honey
10.84 11.10a 13.71b,c 14.07d,e 9.50f,g
P ¼ 0.0120 compared to sucrose (95% CI of this difference: From 18.55 to 2.39). P ¼ 0.0072 compared to glucose (95% CI of this difference: From 19.24 to 3.16). P < 0.0001 compared to sucrose (95% CI of this difference: From 25.98 to 10.36). P ¼ 0.0003 compared to glucose (95% CI of this difference: From 24.13 to 7.73). P < 0.0001 compared to sucrose (95% CI of this difference: From 33.15 to 15.71). P ¼ 0.003 compared to glucose (95% CI of this difference: From 16.09 to 3.45). P < 0.0001 compared to sucrose (95% CI of this difference: From 29.53 to 13.73). P ¼ 0.0095 compared to sucrose (95% CI of this difference: From 20.71 to 3.01).
The mean (SD) fasting C-peptide of patients and controls were 0.19 (0.10) and 1.41 (0.61), respectively (P < 0.01). The GI and PII of either sucrose or honey did not differ significantly between patients and controls (P > 0.05). Both the GI and PII of honey were significantly lower when compared with sucrose in patients and controls (P < 0.01) (Table 3). In both patients with diabetes and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01; with a statistical power of 98%) (Table 4 and Fig. 1). 5. Discussion The glycemic index of foods was developed to compare the postprandial responses to constant amounts of different carbohydrate-containing foods. A meta-analysis of loweglycemic index diet trials in subjects with diabetes14 showed that such diets produced a 0.4% decrement in HbA1C when compared with higheglycemic index diets. Moreover, the low glycemic index diet reduced episodes of hypoglycemia in patients with either type 1 or type 2 diabetes.15 Oxidative stress and its contribution to low-density lipoprotein oxidation have been implicated in the pathogenesis of vascular complications in diabetes. The results of the study done by Ceriello et al.16 suggested that postprandial hyperglycemia may contribute to oxidative stress in patients with diabetes, providing a mechanistic link between hyperglycemia and vascular disease. C-peptide or connecting peptide is a 31-amino acid segment that links the A and B chains of proinsulin and serves to promote the efficient folding, assembly and processing of the insulin
Table 2 Mean serum glucose (SD) (mg/dl) in patients with diabetes following equivalent amount of glucose, sucrose or honey. Time (min)
Glucose
0 30 60 90 120
155.18 220.28 294.62 294.38 273.84
Sucrose 78.84 74.33 78.72 78.22 85.92h
147.66 236.90 293.90 320.78 318.70
Table 3 Glycemic index (GI) mean (SD) and peak incremental index (PII) of honey and sucrose (glycemic index of glucose ¼ 1; peak incremental index of glucose ¼ 1).
Honey 13.06 19.11 16.40 19.27 19.43
Honey 68.87 65.38 58.98 56.94 76.75
156.82 197.36 246.38 232.48 203.66
17
76.56 79.34a 66.31b,c 66.96d,e 59.75f,g
GI
Sucrose PII
GI
PII
Subjects without 0.614 0.194a 0.60 0.160a 1.39 0.331 1.28 0.297 diabetes Patients with 0.59 0.332b 0.613 0.263b 1.28 0.473 1.26 0.423 diabetes a P < 0.0001 compared to sucrose (GI: 95% to 0.64) (PII: 95% CI of difference: From 0.80 b P < 0.0001 compared to sucrose (GI: 95% to 0.53) (PII: 95% CI of difference: From 0.79
CI to CI to
of this difference: From 0.92 0.56). of this difference: From 0.85 0.51).
molecule in the beta cell endoplasmic reticulum in the course of insulin biosynthesis.17 Equimolar amounts of insulin and C-peptide are subsequently stored in secretory granules of the beta cells and eventually released into the portal and systemic circulations. Since its discovery in 1967, there has been a general view that the C-peptide was devoid of physiological effects other than its role in insulin biosynthesis. C-peptide is co-secreted with insulin by the pancreatic cells as a by-product of the enzymatic cleavage of proinsulin to insulin and thus plasma concentrations of C-peptide effectively reflect the endogenous insulin secretion.2 Thus Cpeptide is considered to be a good marker of insulin secretion. The study of Panero et al.,18 which involved a large cohort of patients with type 1 diabetes, showed that a remaining fasting Cpeptide level above 0.06 nM/L (0.02 ng/mL) conferred a statistically significant protective effect against the development of microvascular complications independently of glycemic control, duration of diabetes, age, and sex. Studies evaluating the effect of honey ingestion on insulin and C-peptide levels in type 2 DM showed controversial results.19,20 To our knowledge, our previous study10 was the first and only study which evaluated the effect of honey on C-peptide level in type 1 DM. In this study honey caused significant postprandial rise of plasma C-peptide levels when compared to glucose and sucrose in subjects without diabetes, but the rise was not significant in patients with diabetes. However the limitation of this study was that it involved small number of subjects. Based on the results of the present study it may be hypothesized that: “honey might have the ability to stimulate not only the healthy but as well the diseased beta cells of pancreas”. In both patients with diabetes and controls without diabetes, although the glycemic and peak incremental indices of honey were significantly lower, as compared with either glucose or sucrose, the rise of Cpeptide levels after honey ingestion in both patients with diabetes and controls was highly statistically significant, as compared with either glucose or sucrose. Whether the sugar or the non-sugar components of honey or both are responsible for stimulation of the diseased beta cells, needs further studies. We hypothesize that the non-sugar part of honey might be the main factor responsible
Table 4 Mean C-peptide (SD) (ng/mL) following equivalent amount of glucose, sucrose or honey in subjects without diabetes and in patients with diabetes.
a
P ¼ 0.0077 compared to sucrose (95% CI of this difference: From 68.39 to 10.69). P ¼ 0.0013 compared to glucose (95% CI of this difference: From 77.13 to 19.35). P ¼ 0.0003 compared to sucrose (95% CI of this difference: From 72.43 to 22.61). d P < 0.0001 compared to glucose (95% CI of this difference: From 90.80 to 33.00). e P < 0.0001 compared to sucrose (95% CI of this difference: From 112.97 to 63.63). f P < 0.0001 compared to glucose (95% CI of this difference: From 99.55 to e 40.81). g P < 0.0001 compared to sucrose (95% CI of this difference: From 142.34 to e 87.74). h P ¼ 0.007 compared to sucrose (95% CI of this difference: From 77.19 to 12.53). b
Group
C- peptide (ng/mL)
c
Subjects without diabetes Patients with diabetes a b c d
P P P P
< < ¼ <
0.0001 0.0001 0.0003 0.0001
compared compared compared compared
to to to to
After glucose
After sucrose
After honey
4.15 0.53 0.33 0.18
4.21 0.67 0.36 0.20
5.99 0.83a,b 0.60 0.41c,d
sucrose (95% glucose (95% sucrose (95% glucose (95%
CI CI CI CI
of this of this of this of this
difference: difference: difference: difference:
From 1.39 to From 1.48 to From 0.11 to From 0.14 to
2.17). 2.20). 0.37). 0.40).
18
M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19
Fig. 1. Per cent increase of C-peptide following equivalent amount of glucose, sucrose or honey in subjects without diabetes (controls) and in patients with diabetes (p < 0.01).
for stimulation of beta cells. This is because despite its lower glycemic and peak incremental indices when compared to either glucose or sucrose, honey caused significant postprandial increase in the C-peptide level. We considered this finding important in patients with type 1 DM because patients who retain a low but detectable level of Cpeptide are less prone to develop microvascular complications of the eyes, kidneys, and peripheral nerves.18,21 The question: Would long term use of honey have a potential beneficial effect that might allow preservation of at least a modest beta cell function over time? To answer this question further studies are recommended. To our knowledge, no studies were done to evaluate the effects of long term use of honey in type 1 DM. However, in patients with type 2 DM, Bahrami et al.22 investigated the effect of 8-week honey consumption on body weight and blood lipids, and they found that body weight, total cholesterol, low-density lipoprotein-cholesterol and triglyceride decreased (P ¼ 0.000), and high-density lipoprotein-cholesterol increased significantly (P < 0.01) in honey group; but the levels of HbA1C increased significantly in this group (P < 0.01). In their study the levels of C-peptide were not measured. Further more, Oizumi et al.23 reported the beneficial effects of a palatinose based formula (PBF) on metabolic syndrome related parameters in subjects with impaired glucose tolerance. Palatinose is a disaccharide present in honey, which has the characteristics of delayed digestion and absorption. They reported that a 12-week PBF consumption suppressed postprandial hyperglycemia indicated as 2h-postprandial glucose levels, improved the lipid profile such as serum free fatty acid (FFA) levels, and at least in a viscerally obese population, reduced visceral fat accumulation indicated as visceral fat area. Recently, Zmys1owska et al.24 found a negative correlation between FFA and C-peptide measurements in patients with type 1 DM. Whether or not ingestion of honey for an extended period of time in patients with type 1 diabetes would have similar effects needs further studies. Type 1 DM is a complex autoimmune disease that is untimely caused by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Buschard et al.25 focused in their review on the possible environmental factors leading to type 1 DM in genetically susceptible individuals. Amongst these factors are viral induced autoimmune inflammatory insulitis with subsequent beta cell destruction, and increased intestinal permeability due to inflammation that might be also induced by viruses. Also Pietropaolo et al.26 stated that chronic inflammation of pancreatic islets is a central aspect of type 1 DM pathogenesis. Further more Bonnefont-Rousselot et al.27 discussed the role of oxidative stress in the origin of type 1 DM. Through its antiinflammatory,4 anti-
oxidant5 and antiviral28 properties, honey might help healing the diseased beta cells. Further more Olofsson et al.29 suggested that honey be considered a fermented food product because of the lactic acid bacteria of the genera Lactobacillus and Bifidobacterium involved in honey production. Therefore through its possible probiotic effect, honey may help reducing intestinal inflammation and permeability, and changing the composition of bacterial flora, a factor involved in the pathogenesis of type 1 DM.25 To summarize; it may be hypothesized that honey might have the ability to stimulate beta cells through the following possible mechanisms; (a) direct stimulatory effect, as more evident in subjects without diabetes where the beta cells are supposed to be healthy, and (b) indirect stimulatory effect through its antiinflammatory, antioxidant, antiviral and probiotic effects, as more evident in patients with type 1 diabetes where the cells are supposed to be unhealthy. Beta-Cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Human and animal studies of beta-cell destruction and regeneration in type 1 DM were reviewed by Akirav et al.30 and their conclusion was that: “residual beta cells play a significant role for the design of therapeutic trials: they not only may respond to combination therapies that include stimulants of metabolic function but are also the potential source of new beta cells.” Therefore it may be recommended to consider honey amongst the future therapeutic trials in type 1 DM aiming to target beta cells. The positive effect of a single test meal of honey in type 1 DM is not enough to recommend honey as a preferred sugar substitute or dietary supplement in these patients. Before recommending that, further studies with long term follow up are needed. 6. Conclusion In type 1 DM, honey, compared to sucrose, had lower glycemic and peak incremental indices. However, before recommending honey as a preferred sugar substitute or dietary supplement in patients with type 1 DM, further studies are needed to evaluate the effects of long term ingestion of honey in these patients. On the other hand, because of its possible ability to stimulate the diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas. Conflict of interest Nothing to be declared. No any financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work. Author disclosure statement No competing financial interests exist. Acknowledgments We thank very much all children and their parents who agreed to participate in this study. We thank Dr. Emara I, assistant professor of biochemistry at National Institute of Diabetes in Cairo, who did the laboratory tests. We also thank Dr. Ahmed W, lecturer of community medicine department, of Ain Shams University, Cairo, Egypt, who did the statistical analysis. References 1. Chiasson J, Josse R, Gomis R, Hanefeld M, Karasik A, Laakso M, STOPNIDDM. Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM trial. Lancet 2002;259:2072e7. 2. Sj€oberg S, Gunnarsson R, Gj€otterberg M, Lefvert AK, Persson A, Ostman J. Residual insulin production, glycemic control and prevalence of microvascular
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lesions and polyneuropathy in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987;30:208e13. White J. Composition of honey. In: Crane E, editor. Honey. A comprehensive survey. London: Heinemann ed.; 1975. p. 157e206. Al Waili N, Boni N. Natural honey lowers plasma prostaglandin concentrations in normal individuals. J Med Food 2003;6(2):129e33. Gheldof N, Engeseth N. Antioxidant capacity of honeys from various floral sources based on the determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in human serum samples. J Agric Food Chem 2002;50(10):3050e5. Molan P. The antibacterial activity of honey. 1. The nature of the antibacterial activity. Bee World 1992;73(1):5e28. 2. Variation in the potency of the antibacterial activity. Bee World 1992; 73(2): 59e76. Samanta A, Burden A, Jones G. Plasma glucose responses to glucose, sucrose, and honey in patients with diabetes mellitus: an analysis of glycemic and peak incremental indices. Diabet Med 1985;2:371e3. Foster-Powell K, Holt SH, Brand-Miller JC. International table of glycemic index and glycemic load values: 2002. Am J Clin Nutr 2002;76(1):5e56. Glycemic index. TemaNord2005:589. Copenhagen: Nordic Council of Ministers, http://www.norden.org/en/publications/publications/2005-589; 2005. Abdulrhman M, El-Hefnawy M, Hussein R, El-Goud AA. The glycemic and peak incremental indices of honey, sucrose and glucose in patients with type 1 diabetes mellitus: effects on C-peptide level-a pilot study. Acta Diabetol 2011;48(2):89e94. Connors T. Interpreting your C-peptide values; diabetes health, http://www. diabeteshealth.com.htmL; 1 Sept 2000. Updated 2000/09, [accessed Jan 2008]. Barker JM, McFann K, Harrison LC, Fourlanos S, Krischer J, Cuthbertson D, et al. Pre-type 1 diabetes dysmetabolism: maximal sensitivity achieved with both oral and intravenous glucose tolerance testing. J Pediatr 2007;150(1):31e36.e6. Jenkins DJ. The glycemic index and the dietary treatment of hypertriglyceridemia and diabetes. J Am Coll Nutr 1987;61:11e7. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care 2003;26:2261e7. Erbe JK. Low glycemic index diets for the management of diabetes. Am Fam Physician 2009 Nov 1;80(9):941. Ceriello A, Bortolotti N, Motz E, Pieri C, Marra M, Tonutti L, et al. Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism 1999;48(12):1503e8.
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17. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science 1967;157:697e700. 18. Panero F, Novelli G, Zucco C, Fornengo P, Perotto M, Segre O, et al. Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of patients with type 1 DM. Diabetes Care 2009;32(2): 301e5. 19. Bornet F, Haardt MJ, Costagliola D, Blayo A, Slama G. Sucrose or honey at breakfast have no additional acute hyperglycemic effect over an isoglucidic amount of bread in patients with type 2 DM. Diabetologia 1985;28(4):213e7. 20. Watford M. Small amounts of dietary fructose dramatically increase hepatic glucose uptake. Nutr Rev 2002;60(8):253e7. 21. Luppi P, Cifarelli V, Wahren J. C-peptide and long-term complications of diabetes. Pediatr Diabetes 2011;12(3 Pt 2):276e92. 22. Bahrami M, Ataie-Jafari A, Hosseini S, Foruzanfar MH, Rahmani M, Pajouhi M. Effects of natural honey consumption in patients with diabetes: an 8-week randomized clinical trial [abstract]. Int J Food Sci Nutr 2009;60(7):618e26. 23. Oizumi T, Daimon M, Jimbu Y, Kameda W, Arawaka N, Yamaguchi H, et al. A palatinose based formula improves glucose tolerance, serum free fatty acid levels and body fat composition. Tohoku J Exp Med 2007;212:91e9. 24. Zmys1owska A, Wyka K, Szadkowska A, Mianowska B, Pietrzak I, M1ynarski W. Free fatty acids level may effect a residual insulin secretion in type 1 diabetes. Pediatr Endocrinol Diabetes Metab 2011;17(1):26e9. 25. Buschard K. What causes type 1diabetes? lessons from animal models. APMIS 2011;119(Suppl. 132):1e19. 26. Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes 2007;56(5):1189e97. 27. Bonnefont-Rousselot D, Bastard JP, Jaudon MC, Delattre J. Consequences of the patients with type 1 DM status on the oxidant/antioxidant balance. Diabetes Metab 2000;26(3):163e76. 28. Zeina B, Othman O, Al-Assad S. Effect of honey versus thyme on Rubella virus survival in vitro. J Alternative Compl Med 1996;2(3):345e8. 29. Olofsson TC, Vásquez A. Detection and identification of a novel lactic acid bacterial flora within the honey stomach of the honeybee Apis mellifera. Curr Microbiol 2008;57(4):356e63. 30. Akirav E, Kushner JA, Herold KC. Beta-cell mass and type 1diabetes: going, going, gone? Diabetes 2008;57(11):2883e8.
Contents lists available at SciVerse ScienceDirect
Complementary Therapies in Clinical Practice journal homepage: www.elsevier.com/locate/ctcp
Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus Mamdouh Abdulrhman b, *, Mohamed El Hefnawy a, Rasha Ali b, Iman Abdel Hamid b, Ahmad Abou El-Goud b, Doaa Refai b a b
National Institute of Diabetes, Cairo, Egypt Pediatric Department, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
a b s t r a c t Keywords: Honey Diabetes Glycemic index C-peptide
This study was a case control cross sectional study that was conducted on 50 patients with type 1 diabetes mellitus and 30 controls without diabetes. The mean age of patients was 10.02 years. Oral sugar tolerance tests using glucose, sucrose and honey and measurement of fasting and postprandial serum Cpeptide levels were done for all subjects in three separate sittings. The glycemic index (GI) and the peak incremental index (PII) were then calculated for each subject. Honey, compared to sucrose, had lower GI and PII in both patients and controls (P < 0.01). In both patients and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01). Conclusion: Because of its possible stimulatory effect on diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Experimental and epidemiological studies have shown that reduction of postprandial plasma glucose delays the development of cardiovascular complications.1 During the last 15e20 years it has also been observed that patients with type 1 diabetes mellitus (DM) who had a detectable, even low, level of C-peptide are less prone to develop microvascular complications of the eyes, kidneys, and peripheral nerves.2 Honey is a natural substance produced by honey bees. It is composed of sugar and non-sugar parts. Glucose and fructose, the main sugars in honey, constitutes about 70% of the honey solids. The non-sugar part of honey consists of water and other elements.3 The water content of honey ranges between 15 and 20% (average 17.2%). Honey also contains acids, proteins and minerals. The protein and amino acid content of honey varies from 0.05 to 0.3%. The honey proteins are mainly enzymes. Varying amounts of mineral substances ranging from 0.02 to 1.03 g/100 g are also present in honey. Honey possesses antiinflammatory,4 antioxidant5 and antimicrobial properties.6 The antioxidant properties of honey are mainly attributed to
its content of polyphenols. Further more, honey produced an attenuated postprandial glycemic response when compared with sucrose in both patients with type 2 DM and normal subjects.7 According to the international table of glycemic index and glycemic load values8 the mean (SD) GI of 11 types of honey was 0.55 (0.05). Diets with GI of 0.55 or less are considered low GI diets.9 Our previous study10 may be the only study which evaluated the effects of honey ingestion on C-peptide level in patients with type 1 DM. This study involved only 20 patients with type 1 DM and 10 controls without diabetes and the results showed that honey, as compared with either glucose or sucrose had a significantly lower glycemic index (GI) and peak incremental index (PII); and regarding its effect on C-peptide, honey produced a significantly higher Cpeptide level in controls, but the rise of C-peptide was not significant in patients with type 1 DM. However this study10 was limited by its small number of cases. Therefore in the present study the effects of these sugars were evaluated in more 30 patients with type 1 DM and 20 controls without diabetes. Finally the results obtained from the 50 patients and 30 controls of both studies were analyzed. 2. Patients and methods
* Corresponding author. Tel.: þ20 1006208547. E-mail addresses: [email protected] (M. Abdulrhman), drhefnawy@ yahoo.com (M. El Hefnawy), [email protected] (R. Ali), dr_imana30@ yahoo.com (I. Abdel Hamid), [email protected] (A. Abou El-Goud), [email protected] (D. Refai). 1744-3881/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctcp.2012.08.002
Fifty patients with type 1 DM, aged 1e18 (mean 10.02 years) and 30 healthy children and adolescents without diabetes, aged 1e18 (mean 9.7 years) were studied. All patients with type 1 DM had a mean (SD) glycosylated hemoglobin of 9.7% (1.91)
16
M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19
[range ¼ 6.8e15.5%]. The mean (SD) duration of diabetes was 3.15 (2.51) year [range ¼ 1monthe10 years]. The sex ratio in patients and controls was 26:24 and 16:14, respectively. The patients were recruited from the regular attendants of the children clinic of the National Institute of Diabetes in Cairo, Egypt. 2.1. Inclusion criteria All patients with type 1 DM were candidates for this study. The patient was considered suffering from type 1 DM if the fasting Cpeptide level was below 0.4 ng/dl.11
Glycemic index of the food ¼
3. Measurement of fasting and postprandial serum C-peptide level: Venous blood samples were withdrawn from each subject at 0 (fasting) and 2 h postprandial after ingestion of each individual sugar. The samples were then centrifuged and serum was stored in aliquots at 20 C. At the end of the study, samples were calibrated for C-peptide using the biosource c-pep-easia.d 4. Calculation of glycemic and peak incremental indices as was described by Jenkins,13 (1987)
Area under glycemic curve of test food Area under glycemic curve of glucose
2.2. Exclusion criteria Area under curve (AUC) refers to the area included between the baseline and incremental blood glucose points when connected by straight lines. The area under each incremental glucose curve is calculated using the trapezoid rule (note: only areas above the baseline are used). Peak incremental index (PII) is defined as the ratio of the maximal increment of plasma glucose produced by sugar to that produced by glucose7
1. Coexisting renal or hepatic impairment 2. Coexisting diseases e.g., malignancy, other endocrine disorders 3. Patients on steroid therapy. The study was approved by the local ethical committee, and an informed consent was obtained from at least one parent of each subject before the study. All patients were receiving three insulin injections per day, each consisting of a mixture of a medium-acting insulin (isophane NPH) and a short-acting soluble insulin (human Actrapid).
Peak incremental index ¼
Maximal increment produced by the sugar tested Maximal increment produced by glucose
We followed the same methodology as in our previous study.10 All subjects were subjected to the following: 1. Anthropometric measures including weight in kg and height in cm. The BMI [weight (kg)/height (metre)2] was then calculated. 2. Oral sugar tolerance tests using glucose, sucrose and honey in three separate sittings: After an overnight fast (8 h) and omission of the morning insulin dose, a calculated amount of each sugar (amount ¼ weight of subject in kg 1.75 with a maximum of 75 g)12 was diluted in 200 mL water and then ingested over 5 min in a random order, on separate mornings 1 week apart. The honey used in this study was a raw Egyptian clover honey supplied by a beekeeper without heating or irradiation. The honey dose for each patient was calculated based on the fact that each 100 g of the honey used in this study contained 77.3 g sugars. So if, for example, a patient weighs 20 kg, he/she should receive 20 1.75 ¼ 35 g sugar which will be present in (35 100) O 77.3 ¼ 45.3 g honey. Venous blood was sampled just before ingestion and then every 30 min postprandial for 2 h thereafter. Samples were left to clot, centrifuged and glucose assay was performed chemically on the Synchron CX5 autoanalyser (Beckman instruments Inc.).c
c
Beckman, 200 S. Kraemer Blvd, Brea, CA 92621, USA.
Maximal increment is the difference between the peak point and the fasting point. 3. Statistical analysis The collected data were revised, coded, tabulated and introduced to a PC using Statistical package for Social Science (SPSS 15.0.1 for windows; SPSS Inc, Chicago, IL, 2001). All numeric variables were expressed as mean standard deviation (SD). Student ttest was used to assess the statistical significance of the difference between two study group means. Paired t-test was used to assess the statistical significance of the difference between two means measured twice for the same study group. Chi-square (c2) test was used to compare frequency of qualitative variables amongst the different groups. For statistical power calculation STATAÒ version 11 program was used. 4. Results No significant difference was found between patients with type 1 DM and controls without diabetes as regards the age, sex and anthropometric measures. The fasting serum glucose level did not differ significantly between subjects in both groups (Table 1 and 2).
d
Biosource Europe S. AdRue de l’industrie 8, 1400 Nivelles, Belgium.
M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19 Table 1 Mean serum glucose (SD) (mg/dl) in subjects without diabetes (control) following equivalent amount of glucose, sucrose or honey. Time (min)
Glucose
0 30 60 90 120
80.47 94.43 111.43 116.40 97.27
a b c d e f g h
Sucrose 12.78 15.82 17.22 17.47 14.45h
78.50 100.97 118.40 124.90 109.13
80.60 90.50 100.23 100.47 87.50
Honey
10.84 11.10a 13.71b,c 14.07d,e 9.50f,g
P ¼ 0.0120 compared to sucrose (95% CI of this difference: From 18.55 to 2.39). P ¼ 0.0072 compared to glucose (95% CI of this difference: From 19.24 to 3.16). P < 0.0001 compared to sucrose (95% CI of this difference: From 25.98 to 10.36). P ¼ 0.0003 compared to glucose (95% CI of this difference: From 24.13 to 7.73). P < 0.0001 compared to sucrose (95% CI of this difference: From 33.15 to 15.71). P ¼ 0.003 compared to glucose (95% CI of this difference: From 16.09 to 3.45). P < 0.0001 compared to sucrose (95% CI of this difference: From 29.53 to 13.73). P ¼ 0.0095 compared to sucrose (95% CI of this difference: From 20.71 to 3.01).
The mean (SD) fasting C-peptide of patients and controls were 0.19 (0.10) and 1.41 (0.61), respectively (P < 0.01). The GI and PII of either sucrose or honey did not differ significantly between patients and controls (P > 0.05). Both the GI and PII of honey were significantly lower when compared with sucrose in patients and controls (P < 0.01) (Table 3). In both patients with diabetes and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01; with a statistical power of 98%) (Table 4 and Fig. 1). 5. Discussion The glycemic index of foods was developed to compare the postprandial responses to constant amounts of different carbohydrate-containing foods. A meta-analysis of loweglycemic index diet trials in subjects with diabetes14 showed that such diets produced a 0.4% decrement in HbA1C when compared with higheglycemic index diets. Moreover, the low glycemic index diet reduced episodes of hypoglycemia in patients with either type 1 or type 2 diabetes.15 Oxidative stress and its contribution to low-density lipoprotein oxidation have been implicated in the pathogenesis of vascular complications in diabetes. The results of the study done by Ceriello et al.16 suggested that postprandial hyperglycemia may contribute to oxidative stress in patients with diabetes, providing a mechanistic link between hyperglycemia and vascular disease. C-peptide or connecting peptide is a 31-amino acid segment that links the A and B chains of proinsulin and serves to promote the efficient folding, assembly and processing of the insulin
Table 2 Mean serum glucose (SD) (mg/dl) in patients with diabetes following equivalent amount of glucose, sucrose or honey. Time (min)
Glucose
0 30 60 90 120
155.18 220.28 294.62 294.38 273.84
Sucrose 78.84 74.33 78.72 78.22 85.92h
147.66 236.90 293.90 320.78 318.70
Table 3 Glycemic index (GI) mean (SD) and peak incremental index (PII) of honey and sucrose (glycemic index of glucose ¼ 1; peak incremental index of glucose ¼ 1).
Honey 13.06 19.11 16.40 19.27 19.43
Honey 68.87 65.38 58.98 56.94 76.75
156.82 197.36 246.38 232.48 203.66
17
76.56 79.34a 66.31b,c 66.96d,e 59.75f,g
GI
Sucrose PII
GI
PII
Subjects without 0.614 0.194a 0.60 0.160a 1.39 0.331 1.28 0.297 diabetes Patients with 0.59 0.332b 0.613 0.263b 1.28 0.473 1.26 0.423 diabetes a P < 0.0001 compared to sucrose (GI: 95% to 0.64) (PII: 95% CI of difference: From 0.80 b P < 0.0001 compared to sucrose (GI: 95% to 0.53) (PII: 95% CI of difference: From 0.79
CI to CI to
of this difference: From 0.92 0.56). of this difference: From 0.85 0.51).
molecule in the beta cell endoplasmic reticulum in the course of insulin biosynthesis.17 Equimolar amounts of insulin and C-peptide are subsequently stored in secretory granules of the beta cells and eventually released into the portal and systemic circulations. Since its discovery in 1967, there has been a general view that the C-peptide was devoid of physiological effects other than its role in insulin biosynthesis. C-peptide is co-secreted with insulin by the pancreatic cells as a by-product of the enzymatic cleavage of proinsulin to insulin and thus plasma concentrations of C-peptide effectively reflect the endogenous insulin secretion.2 Thus Cpeptide is considered to be a good marker of insulin secretion. The study of Panero et al.,18 which involved a large cohort of patients with type 1 diabetes, showed that a remaining fasting Cpeptide level above 0.06 nM/L (0.02 ng/mL) conferred a statistically significant protective effect against the development of microvascular complications independently of glycemic control, duration of diabetes, age, and sex. Studies evaluating the effect of honey ingestion on insulin and C-peptide levels in type 2 DM showed controversial results.19,20 To our knowledge, our previous study10 was the first and only study which evaluated the effect of honey on C-peptide level in type 1 DM. In this study honey caused significant postprandial rise of plasma C-peptide levels when compared to glucose and sucrose in subjects without diabetes, but the rise was not significant in patients with diabetes. However the limitation of this study was that it involved small number of subjects. Based on the results of the present study it may be hypothesized that: “honey might have the ability to stimulate not only the healthy but as well the diseased beta cells of pancreas”. In both patients with diabetes and controls without diabetes, although the glycemic and peak incremental indices of honey were significantly lower, as compared with either glucose or sucrose, the rise of Cpeptide levels after honey ingestion in both patients with diabetes and controls was highly statistically significant, as compared with either glucose or sucrose. Whether the sugar or the non-sugar components of honey or both are responsible for stimulation of the diseased beta cells, needs further studies. We hypothesize that the non-sugar part of honey might be the main factor responsible
Table 4 Mean C-peptide (SD) (ng/mL) following equivalent amount of glucose, sucrose or honey in subjects without diabetes and in patients with diabetes.
a
P ¼ 0.0077 compared to sucrose (95% CI of this difference: From 68.39 to 10.69). P ¼ 0.0013 compared to glucose (95% CI of this difference: From 77.13 to 19.35). P ¼ 0.0003 compared to sucrose (95% CI of this difference: From 72.43 to 22.61). d P < 0.0001 compared to glucose (95% CI of this difference: From 90.80 to 33.00). e P < 0.0001 compared to sucrose (95% CI of this difference: From 112.97 to 63.63). f P < 0.0001 compared to glucose (95% CI of this difference: From 99.55 to e 40.81). g P < 0.0001 compared to sucrose (95% CI of this difference: From 142.34 to e 87.74). h P ¼ 0.007 compared to sucrose (95% CI of this difference: From 77.19 to 12.53). b
Group
C- peptide (ng/mL)
c
Subjects without diabetes Patients with diabetes a b c d
P P P P
< < ¼ <
0.0001 0.0001 0.0003 0.0001
compared compared compared compared
to to to to
After glucose
After sucrose
After honey
4.15 0.53 0.33 0.18
4.21 0.67 0.36 0.20
5.99 0.83a,b 0.60 0.41c,d
sucrose (95% glucose (95% sucrose (95% glucose (95%
CI CI CI CI
of this of this of this of this
difference: difference: difference: difference:
From 1.39 to From 1.48 to From 0.11 to From 0.14 to
2.17). 2.20). 0.37). 0.40).
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M. Abdulrhman et al. / Complementary Therapies in Clinical Practice 19 (2013) 15e19
Fig. 1. Per cent increase of C-peptide following equivalent amount of glucose, sucrose or honey in subjects without diabetes (controls) and in patients with diabetes (p < 0.01).
for stimulation of beta cells. This is because despite its lower glycemic and peak incremental indices when compared to either glucose or sucrose, honey caused significant postprandial increase in the C-peptide level. We considered this finding important in patients with type 1 DM because patients who retain a low but detectable level of Cpeptide are less prone to develop microvascular complications of the eyes, kidneys, and peripheral nerves.18,21 The question: Would long term use of honey have a potential beneficial effect that might allow preservation of at least a modest beta cell function over time? To answer this question further studies are recommended. To our knowledge, no studies were done to evaluate the effects of long term use of honey in type 1 DM. However, in patients with type 2 DM, Bahrami et al.22 investigated the effect of 8-week honey consumption on body weight and blood lipids, and they found that body weight, total cholesterol, low-density lipoprotein-cholesterol and triglyceride decreased (P ¼ 0.000), and high-density lipoprotein-cholesterol increased significantly (P < 0.01) in honey group; but the levels of HbA1C increased significantly in this group (P < 0.01). In their study the levels of C-peptide were not measured. Further more, Oizumi et al.23 reported the beneficial effects of a palatinose based formula (PBF) on metabolic syndrome related parameters in subjects with impaired glucose tolerance. Palatinose is a disaccharide present in honey, which has the characteristics of delayed digestion and absorption. They reported that a 12-week PBF consumption suppressed postprandial hyperglycemia indicated as 2h-postprandial glucose levels, improved the lipid profile such as serum free fatty acid (FFA) levels, and at least in a viscerally obese population, reduced visceral fat accumulation indicated as visceral fat area. Recently, Zmys1owska et al.24 found a negative correlation between FFA and C-peptide measurements in patients with type 1 DM. Whether or not ingestion of honey for an extended period of time in patients with type 1 diabetes would have similar effects needs further studies. Type 1 DM is a complex autoimmune disease that is untimely caused by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Buschard et al.25 focused in their review on the possible environmental factors leading to type 1 DM in genetically susceptible individuals. Amongst these factors are viral induced autoimmune inflammatory insulitis with subsequent beta cell destruction, and increased intestinal permeability due to inflammation that might be also induced by viruses. Also Pietropaolo et al.26 stated that chronic inflammation of pancreatic islets is a central aspect of type 1 DM pathogenesis. Further more Bonnefont-Rousselot et al.27 discussed the role of oxidative stress in the origin of type 1 DM. Through its antiinflammatory,4 anti-
oxidant5 and antiviral28 properties, honey might help healing the diseased beta cells. Further more Olofsson et al.29 suggested that honey be considered a fermented food product because of the lactic acid bacteria of the genera Lactobacillus and Bifidobacterium involved in honey production. Therefore through its possible probiotic effect, honey may help reducing intestinal inflammation and permeability, and changing the composition of bacterial flora, a factor involved in the pathogenesis of type 1 DM.25 To summarize; it may be hypothesized that honey might have the ability to stimulate beta cells through the following possible mechanisms; (a) direct stimulatory effect, as more evident in subjects without diabetes where the beta cells are supposed to be healthy, and (b) indirect stimulatory effect through its antiinflammatory, antioxidant, antiviral and probiotic effects, as more evident in patients with type 1 diabetes where the cells are supposed to be unhealthy. Beta-Cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Human and animal studies of beta-cell destruction and regeneration in type 1 DM were reviewed by Akirav et al.30 and their conclusion was that: “residual beta cells play a significant role for the design of therapeutic trials: they not only may respond to combination therapies that include stimulants of metabolic function but are also the potential source of new beta cells.” Therefore it may be recommended to consider honey amongst the future therapeutic trials in type 1 DM aiming to target beta cells. The positive effect of a single test meal of honey in type 1 DM is not enough to recommend honey as a preferred sugar substitute or dietary supplement in these patients. Before recommending that, further studies with long term follow up are needed. 6. Conclusion In type 1 DM, honey, compared to sucrose, had lower glycemic and peak incremental indices. However, before recommending honey as a preferred sugar substitute or dietary supplement in patients with type 1 DM, further studies are needed to evaluate the effects of long term ingestion of honey in these patients. On the other hand, because of its possible ability to stimulate the diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas. Conflict of interest Nothing to be declared. No any financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work. Author disclosure statement No competing financial interests exist. Acknowledgments We thank very much all children and their parents who agreed to participate in this study. We thank Dr. Emara I, assistant professor of biochemistry at National Institute of Diabetes in Cairo, who did the laboratory tests. We also thank Dr. Ahmed W, lecturer of community medicine department, of Ain Shams University, Cairo, Egypt, who did the statistical analysis. References 1. Chiasson J, Josse R, Gomis R, Hanefeld M, Karasik A, Laakso M, STOPNIDDM. Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM trial. Lancet 2002;259:2072e7. 2. Sj€oberg S, Gunnarsson R, Gj€otterberg M, Lefvert AK, Persson A, Ostman J. Residual insulin production, glycemic control and prevalence of microvascular
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17. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science 1967;157:697e700. 18. Panero F, Novelli G, Zucco C, Fornengo P, Perotto M, Segre O, et al. Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of patients with type 1 DM. Diabetes Care 2009;32(2): 301e5. 19. Bornet F, Haardt MJ, Costagliola D, Blayo A, Slama G. Sucrose or honey at breakfast have no additional acute hyperglycemic effect over an isoglucidic amount of bread in patients with type 2 DM. Diabetologia 1985;28(4):213e7. 20. Watford M. Small amounts of dietary fructose dramatically increase hepatic glucose uptake. Nutr Rev 2002;60(8):253e7. 21. Luppi P, Cifarelli V, Wahren J. C-peptide and long-term complications of diabetes. Pediatr Diabetes 2011;12(3 Pt 2):276e92. 22. Bahrami M, Ataie-Jafari A, Hosseini S, Foruzanfar MH, Rahmani M, Pajouhi M. Effects of natural honey consumption in patients with diabetes: an 8-week randomized clinical trial [abstract]. Int J Food Sci Nutr 2009;60(7):618e26. 23. Oizumi T, Daimon M, Jimbu Y, Kameda W, Arawaka N, Yamaguchi H, et al. A palatinose based formula improves glucose tolerance, serum free fatty acid levels and body fat composition. Tohoku J Exp Med 2007;212:91e9. 24. Zmys1owska A, Wyka K, Szadkowska A, Mianowska B, Pietrzak I, M1ynarski W. Free fatty acids level may effect a residual insulin secretion in type 1 diabetes. Pediatr Endocrinol Diabetes Metab 2011;17(1):26e9. 25. Buschard K. What causes type 1diabetes? lessons from animal models. APMIS 2011;119(Suppl. 132):1e19. 26. Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes 2007;56(5):1189e97. 27. Bonnefont-Rousselot D, Bastard JP, Jaudon MC, Delattre J. Consequences of the patients with type 1 DM status on the oxidant/antioxidant balance. Diabetes Metab 2000;26(3):163e76. 28. Zeina B, Othman O, Al-Assad S. Effect of honey versus thyme on Rubella virus survival in vitro. J Alternative Compl Med 1996;2(3):345e8. 29. Olofsson TC, Vásquez A. Detection and identification of a novel lactic acid bacterial flora within the honey stomach of the honeybee Apis mellifera. Curr Microbiol 2008;57(4):356e63. 30. Akirav E, Kushner JA, Herold KC. Beta-cell mass and type 1diabetes: going, going, gone? Diabetes 2008;57(11):2883e8.