On the discussion board, using a minimum of two articles that are supporting your PICOT question, submit one paragraph synthesizing the research into clear, concise statements without separately revie

Applied nutritional investigation Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes Talib A. Hussain M.B., Ch.B., R.C.G.P. a, Thazhumpal C. Mathew M.Sc., Ph.D., F.R.C.Path. b, Ali A. Dashti M.Sc., Ph.D. b, Sami Asfar M.B., Ch.B., M.D., F.R.C.S., F.A.C.S. c, Naji Al-Zaid B.Sc., Ph.D. d, Hussein M. Dashti M.D., Ph.D., F.I.C.S., F.A.C.S. c,* aAl Shaab Family Medicine Medical Center, Ministry of Health, KuwaitbDepartment of MLS, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, KuwaitcDepartment of Surgery, Faculty of Medicine, Health Sciences Center, Kuwait University, KuwaitdDepartment of Physiology, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait article info Article history:

Received 13 June 2011 Accepted 16 January 2012 Keywords:

Obesity Body mass index Blood glucose Lipid pro ﬁle Ketogenic diet Low-calorie diet abstract Objective: Effective diabetic management requires reasonable weight control. Previous studies from our laboratory have shown the beneﬁ cial effects of a low-carbohydrate ketogenic diet (LCKD) in patients with type 2 diabetes after its long term administration. Furthermore, it favorably alters the cardiac risk factors even in hyperlipidemic obese subjects. These studies have indicated that, in addition to decreasing body weight and improving glycemia, LCKD can be effective in decreasing antidiabetic medication dosage. Similar to the LCKD, the conventional low-calorie, high nutritional value diet is also used for weight loss. The purpose of this study was to understand the bene ﬁcial effects of LCKD compared with the low-calorie diet (LCD) in improving glycemia.

Methods: Three hundred and sixty-three overweight and obese participants were recruited from the Al-Shaab Clinic for a 24-wk diet intervention trial; 102 of them had type 2 diabetes. The participants were advised to choose LCD or LDKD, depending on their preference. Body weight, body mass index, changes in waist circumference, blood glucose level, changes in hemoglobin and glycosylated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, uric acid, urea and creatinine were determined before and at 4, 8, 12, 16, 20, and 24 wk after the administration of the LCD or LCKD. The initial dose of some antidiabetic medications was decreased to half and some were discontinued at the beginning of the dietary program in the LCKD group. Dietary counseling and further medication adjustment were done on a biweekly basis.

Results: The LCD and LCKD had bene ﬁcial effects on all the parameters examined. Interestingly, these changes were more signiﬁ cant in subjects who were on the LCKD as compared with those on the LCD. Changes in the level of creatinine were not statistically signi ﬁcant.

Conclusion: This study shows the bene ﬁcial effects of a ketogenic diet over the conventional LCD in obese diabetic subjects. The ketogenic diet appears to improve glycemic control. Therefore, diabetic patients on a ketogenic diet should be under strict medical supervision because the LCKD can signi ﬁcantly lower blood glucose levels.

2012 Elsevier Inc. All rights reserved. Introduction The current increase in the rate of type 2 diabetes is quite alarming. During the past three decades, the prevalence of this disease in the middle-aged has almost doubled [1]. According to reports by the World Health Organization, approximately 170 million people worldwide have diabetes and this ﬁgure is expected to reach to 366 million by 2030 [2]. A similar trend in the increase of type 2 diabetes has been observed in the Gulf region, especially in Kuwait [3,4].

The risk of diabetes is strongly associated with obesity, and even a modest weight loss has been reported to substantially decrease the diabetic risk. According to statistics from the US Center for Disease Control and Prevention, 55% of diabetic patients are obese and 85% are overweight [5]. In several previous * Corresponding author. Tel.: þ965-2498-6226; fax: þ965-2531-9597.

E-mail address: [email protected] (H. M. Dashti).

doi: 10.1016/j.nut.2012.01.016 Contents lists available at ScienceDirect Nutrition journal homepage:www.nutritionjrnl.com Nutrition 28 (2012) 1016 –10 21 studies, we have shown that a low-carbohydrate ketogenic diet (LCKD) is quite effective in decreasing body weight[6–13 ] . The LCKD has a low-carbohydrate content (20– 30 g/d) that causes ketosis and mimics the physiologic state of fasting [6].

Before the advent of exogenous insulin, dietary modi ﬁcation was the main therapy for diabetes. However, the diet recom- mendations during that time were completely different from the current low-fat, high-carbohydrate dietary recommendations for patients with diabetes [14,15]. For example, Dr. Elliot Joslin ’s Diabetic Diet in 1923 consisted of meats, poultry, ﬁsh, clear soups, gelatin, eggs, butter, olive oil, coffee, and tea, providing approx- imately 5% of energy from carbohydrates, 20% from protein, and 75% from fat [16]. During that time, a diabetic diet with a similar composition was advocated by Dr. Frederick Allen [17].

In a previous study from our laboratory, we quite convinc- ingly showed the beneﬁ cial effects of a ketogenic diet in obese diabetic subjects [9]. Furthermore, in recent studies in an animal model of diabetes, we showed that the LCKD has a signi ﬁcant beneﬁ cial effect on ameliorating the diabetic state and helping to stabilize hyperglycemia [11,13]. From the results of these studies, we recommended that the LCKD may be effective in diabetes management by improving glycemia and decreasing the need for medication. The present study, therefore, is a continuation of our previous studies in diabetic patients and experimental diabetic animals. The main purpose of the therapeutic plan of this study was to evaluate the effects of administering a low-calorie diet (LCD) and an LCKD for 24 wk in improving glycemia and decreasing the need for diabetic medication in overweight and obese patients with type 2 diabetes. Materials and methods Participants In this study, the participants were recruited from the Al-Shaab Family Medicine Medical Center, Kuwait. The participants were included in this study if they were at least 18 y old, had a body mass index higher than 25 kg/m 2and a fasting serum glucose level higher than 125 mg/dL ( >6.9 mmol/L). Patients with evidence of renal insuf ﬁciency, liver disease, or unstable cardiovascular disease by history, physical examination, and laboratory tests were excluded from the study. All participants provided written informed consent, and the study was approved by Kuwait University.

Intervention The participants were given detailed information on the LCKD and LCD during their initial visit. They were then advised to take choose an LCD or an LCKD, depending on their preference. Initially, participants in the LCKD group were instructed to follow the LCKD as individuals or in small groups, with an initial goal of w20 g/d of carbohydrate. The list of recommended and restricted foods in the LCKD is presented in Table 1.

The participants were given previous reports on the LCKD from our labora- tory, a handout, and a handbook [6–13 ] concerning the type and amount of foods Table 1 Recommended and restricted food in a low-carbohydrate ketogenic diet and a sample low-calorie diet Recommended food in low-carbohydrate ketogenic diet Proteins ﬁsh: tuna, sardine prawns, shrimps, lobster meat; kebabs; sausages; minced poultry; chicken; eggs; cheese: full-fat cheese Vegetables/fruits spinach, watercress, eggplant, parsley, mulberry, coriander, mint, artichoke, okra, cabbage, mushroom, avocado, leek, carrot, radish, celery, cauli ﬂower, green pepper, lettuce, cucumber, tomato, 10 –15 olives/d, lemon, strawberry 6/d, avocado, berries 10/d Oil olive oil (5 tbsp, added to salad),ﬂax seed oil Restricted food in low-carbohydrate ketogenic diet ﬂour, potato, macaroni spaghetti, noodles, bread, rice, sugar, sweets, honey, cakes, all fruit juices, all soft drinks Sample 2200-calorie low-calorie diet Breakfast coffee with caffeine (12 oz); cottage cheese 1% fat (1.5 cup); cream, ﬂuid, half and half (1 tbsp); fruit cocktail (0.5 cup) Morning snack medium apple with peel, medium banana (1 each) Lunch medium apple with peel (1 each); bread whole wheat slice (2 each); cheddar cheese (2 in. 3); mayonnaise (tuna salad, 0.15 cup); turkey breast/white meat (3 oz) Afternoon snack Bread slice rye 7 grain (2 each); jelly: any fruit ﬂavor (4 tsp); peanut butter (2 tbsp) Dinner chicken breast/white meat (4 oz); rice: white cook steamed (1.5 cups); low-calorie thousand island dressing (salad); Kraft mayonnaise (4 tbsp); croutons (cook cuts bred into small cubes) plain (0.25 cup); 1 small garden salad with tomato, onion Table 2 Baseline values of different physical and biochemical parameters monitored in diabetic and non-diabetic subjects consuming an LCD or an LCKD Total Diabetic Non-diabeticLCD LCKD LCD LCKD Age 37.2 0.4 45.1 1.1 39.2 0.7 34.8 0.7 36.8 0.6 Weight 96.0 0.9 95.7 2.0 104.0 2.1 91.0 1.6 95.7 1.3 Fasting blood sugar 6.3 0.1 9.0 0.6 9.1 0.3 5.3 0.1 5.4 0.1 Triacylglycerols 1.8 0.1 2.5 0.2 2.2 0.1 1.5 0.1 1.7 0.1 Total cholesterol 5.3 0.1 5.5 0.2 5.7 0.1 5.0 0.1 5.2 0.1 LDL 3.0 0.1 3.4 0.2 3.4 0.1 2.7 0.1 2.8 0.1 HDL 1.0 0.0 1.0 0.1 1 0.1 1.1 0.0 1.0 0.0 Uric acid 303.2 4.0 328.5 12.0 307.8 9.0 284.8 7.0 311.8 6.4 Creatinine 75.0 0.8 76.7 2.9 74.2 1.6 76.1 1.6 74.2 1.1 Urea 4.5 0.1 4.7 0.2 5.0 0.2 4.4 0.1 4.4 0.1 Waist circumference 110.2 0.6 113 1.7 115.3 1.2 107.7 1.1 108 0.9 HbA1c 7.9 0.1 8.2 0.3 7.8 0.1 Body mass index 37.3 0.3 36.3 0.5 40.0 0.7 36.0 0.6 37.2 0.5 HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LCD, low-calorie diet; LCKD, low-carbohydrate ketogenic diet; LDL, low-density lipoprotein Data are expressed as mean SE T. A. Hussain et al. / Nutrition 28 (2012) 1016 –10 21 1017 they could eat and the types of food that should be avoided. Initially, the participants were allowed to eat unlimited amounts of meats, poultry,ﬁsh, and eggs. In addition, the participants were asked to take 2 cups of salad vegetables per day, hard cheese (100 –120 g), and limited amounts of cream, olives, and lemon juice. Although fats and oils were allowed, the participants were instructed not to take trans-fats. Antidiabetic medications were decreased with the diet initiation. In general, the insulin doses were halved and the sulfonylurea doses were halved or discontinued. The participants also were instructed to take a standard multivitamin/multimineral tablet and drink approximately six to eight glasses of water daily. The participants returned every other week for 24 wk for further counseling on diet and medication. When a participant neared half the weight loss goal or developed cravings, he or she was advised to increase the carbohydrate intake by approximately 5 g/d each week as long as the weight loss continued. The participants could choose 5-g carbohydrate portions from one of the following foods each week: salad vegetables, low-carbohydrate vegetables, hard or soft cheese, nuts, or low-carbohydrate snacks. The participants in the LCD group were given appropriate guidelines and a sample LCD menu of 2200 calories is pre- sented in Table 1.

The initial dose of some antidiabetic medications was decreased to half in the LCKD group at the beginning of the dietary program. The antidiabetic medication dosage was modi ﬁed based on twice-daily glucometer measurements and hypoglycemic episodes, and diuretic and other antihypertensive medication adjustments were based on the orthostatic symptoms, blood pressure, and lower extremity edema.

Measurements The participants were given written instructions on how to complete the food records. All participants completed the take-home food record according to the directions. These food records were collected at the beginning of the study and at weeks 2, 8, 12, 16, 20, and 24. The anthropometric and vital sign measurements and assessments for hypoglycemic episodes and other symptomatic side effects were performed every other week. Weight was measured on a standardized digital scale while the participant was wearing light clothes and without shoes. Blood pressure was measured after the participant had been seated quietly without talking for 3 min.

Hypoglycemic episodes and symptomatic side effects were assessed by direct questioning of the participant. Blood specimens were collected after the participant had fasted overnight at weeks 0, 4, 8, 12, 16, 20, and 24. The following serum tests were performed in the hospital laboratory using standardized methods: complete blood cell count and lipid, liver, and renal pro ﬁles.

For statistical analysis of the data, a paired ttest was used to determine the statistical signi ﬁcance between weeks 1 and 24 in the different groups and an independent ttest was used to analyze the signiﬁ cance between the LCD and LCKD groups using SPSS 16 (SPSS, Inc., Chicago, IL, USA). The method used in this study for estimating the treatment effects was with completers only, rather than an intent-to-treat analysis.

Results Three hundred sixty-three participants were enrolled in the study and completed the 24 wk of follow-up. Adherence to the two dietary programs was discussed with the participants and recorded. Adequate food records were available to determine each participant ’s adherence to the dietary program (data not shown). Among the 363 participants, 86 were men (23.7%) and 277 were women (76.3%). Among the men, 28 were diabetic and 58 were non-diabetic; among the women, 74 were diabetic and 203 were non-diabetic. In total, 102 participants were diabetic and 261 were non-diabetic. Concerning diet, 143 (27 men and 116 women) of the 363 participants were on a low-calorie diet, whereas 220 (59 men and 161 women) were on a ketogenic diet.

In the LCD group, 24 participants (16.8%) were diabetic, whereas in the LCKD group 78 (35.5%) were diabetic. The baseline values of the clinical parameters examined are listed in Table 2.

Effect on body weight, body mass index, and waist circumference There was a signi ﬁcant difference ( P< 0.0001) in the body weight, body mass index, and waist circumference of the diabetic and non-diabetic participants in the LCD and LCKD groups compared with their initial (week 1) and ﬁnal (week 24) measurements ( Fig. 1A,Table 3 ). The effectiveness of the LCKD over the LCD is quite evident in Figure 1A, which shows the percentage of weight loss in the different groups. Fig. 1. Changes in the percentage of body weight (A), blood glucose level (B), and level of glycosylated hemoglobin (C) in diabetic and non-diabetic subjects after the administration of a low-calorie diet or a low-carbohydrate ketogenic diet for 24 wk.

A signi ﬁcant difference (P <0.0001) in body weight was noticed in the low-calorie and low-carbohydrate ketogenic diet groups compared with their initial (week 1) and ﬁnal (week 24) measurements. The ketogenic diet was more effective than the low-calorie diet. The blood sugar level signi ﬁcantly decreased in the two groups.

The effectiveness of the low-carbohydrate ketogenic diet was much greater (P < 0.0001) in the diabetic group on the low-carbohydrate ketogenic diet than on the low-calorie compared with week 1 and week 24 blood glucose levels. In the dia- betic group, the glycosylated hemoglobin level signi ﬁcantly decreased with the low-carbohydrate ketogenic diet compared with the two diets. Black circles, ketogenic and non-diabetic; black triangles, ketogenic and diabetic; white circles, low calorie andnon-diabetic; white triangles, low calorie and diabetic.

T. A. Hussain et al. / Nutrition 28 (2012) 1016 –1021 1018 Effect on blood glucose and glycosylated hemoglobin levelsAlthough the initial dose of some antidiabetic medications was decreased to half and some were discontinued at the beginning of the dietary program in the LCKD group, the blood sugar level signi ﬁcantly decreased in the two groups (Fig. 1 B,C).

However, the effectiveness of the LCKD was much greater ( P < 0.0001) in the diabetic LCKD group than in the LCD group compared with the initial (week 1) and ﬁnal (week 24) blood glucose levels. Similarly, the glycosylated hemoglobin (HbA1c) level signi ﬁcantly decreased with the LCKD compared with the two diets in the diabetic group (Fig. 1 C).

Effect on lipid pro ﬁle The effects of the LCD and LCKD on the lipid pro ﬁle of diabetic and non-diabetic participants are shown in Figure 2. Diabetic and non-diabetic participants in the LCKD group showed a signi ﬁcant decrease ( P< 0.0001) in triglycerides, total cholesterol, and low-density lipoprotein levels, whereas the Table 3 Effect of an LCD and an LCKD on body weight, body mass index, and waist circumference in diabetic and non-diabetic subjects Group Initial, mean SD Week 24, mean SD Change (%) P * Body weight (kg) Diabetic and LCD 95.71 9.56 89.02 5.97 7.0 <0.0001 Diabetic and LCKD 104.01 18.89 91.56 17.45 12.0 <0.0001 P y 0.005 0.275 <0.001 Non-diabetic and LCD 91.01 17.77 86.38 17.08 5.1 <0.0001 Non-diabetic and LCKD 95.71 15.58 83.87 14.82 12.4 <0.0001 P y 0.024 0.026 <0.001 Body mass index (kg/m 2) Diabetic and LCD 36.31 2.63 33.87 2.75 6.7 <0.0001 Diabetic and LCKD 39.84 6.40 35.05 5.90 12.0 <0.0001 P y 0.001 0.180 <0.001 Non-diabetic and LCD 35.97 6.06 34.14 5.86 5.1 <0.0001 Non-diabetic and LCKD 37.19 5.73 32.59 5.40 12.4 <0.0001 P y 0.097 0.026 Waist circumference (cm) Diabetic and LCD 113.92 8.43 109.94 9.07 3.5 <0.0001 Diabetic and LCKD 115.27 10.45 106.81 9.83 7.3 <0.0001 P y 0.563 0.168 <0.001 Non-diabetic and LCD 107.72 11.58 104.72 11.00 2.8 <0.0001 Non-diabetic and LCKD 108.74 10.50 102.10 9.36 6.1 <0.0001 P y 0.455 0.041 <0.001 LCD, low-calorie diet; LCKD, low-carbohydrate ketogenic diet *Signi ﬁcance between weeks 1 and 24 by paired ttest.ySigni ﬁcance between LCD and LCKD groups by independent ttest. Fig. 2. Changes in the lipid pro ﬁle in diabetic and non-diabetic subjects after the administration of a low-calorie diet or a ketogenic diet for 24 wk. Diabetic and non-diabetic participants in the low-calorie ketogenic diet group showed a signi ﬁcant decrease (P <0.0001) in triglycerides (A), total cholesterol (B), and LDL (D) levels, whereas the HDL level (C) was signi ﬁcantly (P <0.0001) increased. Black circles, ketogenic and non-diabetic; black triangles, ketogenic and diabetic; HDL, high-density lipoprotein; LDL, low- density lipoprotein; white circles, low calorie and non-diabetic; white triangles, low calorie and diabetic. T. A. Hussain et al. / Nutrition 28 (2012) 1016 –10 21 1019 high-density lipoprotein level was signiﬁcantly ( P< 0.0001) increased ( Fig. 2).

Changes in urea, uric acid, and creatinine levels Urea levels were signi ﬁcantly increased for the two diet groups in diabetic and non-diabetic participants ( Fig. 3A).

Interestingly, the uric acid level increased in the LCD group, whereas it decreased in the LCKD group ( Fig. 3B). A similar change was noted for the creatinine level (Fig. 3 C).

Discussion The effect of carbohydrate restriction on type 2 diabetes was previously examined in our laboratory [9]. We found that the body weight, body mass index, and levels of blood glucose, total cholesterol, low-density lipoprotein cholesterol, triglycerides, and urea were signi ﬁcantly decreased from week 1 to week 56 ( P < 0.0001). Conversely, the level of high-density lipoprotein cholesterol was increased signi ﬁcantly ( P< 0.0001). These changes were more signi ﬁcant in subjects with a high blood glucose level as compared with those with a normal blood glucose level. Furthermore, we found that the cardiac protective and ultrastructural changes in the cardiac muscles of laboratory rats that were fed normal, high-carbohydrate, and low- carbohydrate ketogenic diets [10]. We convincingly showed the therapeutic and protective effects of the LCKD in a diabetic rat model [11,13].

The present results showed that, in addition to its therapeutic value, an LCKD is safe to use for a longer period in obese diabetic subjects. Other investigators reported that HbA1c improved to a greater degree with an LCKD over 1 y compared with a low-fat, calorie-restricted diet [18,19]. Our results are in agreement with the previous similar studies carried out by other investigators [20– 22]. Furthermore, very LCKDs have not been found to have an adverse effect on glucose metabolism or insulin resistance [23– 25]. Also, the prolonged administration of very LCKDs has been reported to not cause any chronic dehydration [26].

In the present 6-months ’dietary intervention, the LCKD resulted in a signi ﬁcant improvement of glycemia, as measured by the fasting glucose and HbA1c levels in patients with type 2 diabetes. More importantly, this improvement was observed after some antidiabetic medications had been decreased to half in the LCKD group. The present data showed that the participants in the two dietary programs exhibited decreases in body weight. Several recent studies have indicated that an LCKD is effective in improving glycemia. A few studies have shown that, in non- diabetic individuals, LCKDs are more effective than higher- carbohydrate diets at improving fasting serum glucose [27–31] and insulin [19,31–33] and at improving insulin sensitivity as measured by the homeostasis model [5,6] .

F urthermor e, other investigators have reported that antidia- betic medications were decreased in some participants of the dietary program [19,21,22]. Based on the theoretical effects of the LCKD [34], the observed effects of the diet on body water by bioelectric impedance [35]and practical experience with the diet [35] , the continuation of antidiabetic medication in patients who are on an LCKD should be cautiously monitored. Until we learn more about using LCKDs, the medical monitoring for hypogly- cemia, dehydration, and electrolyte abnormalities is imperative in patients taking antidiabetic or diuretic medications. Although body weight decreased signi ﬁcantly in these 102 diabetic participants, the mean weight loss was less compared with what we observed in participants consuming an LCKD in a similar previous trial ( 12.0 kg) [35]. Because the diabetic participants had a higher baseline mean weight than the participants consuming an LCKD in our previous trial, this translates into an even more dramatic disparity in the percentage of change in body weight. It should be noted that in the present study, most participants were taking insulin and/or oral hypoglycemic agents that are known to induce weight gain Fig. 3. Changes in the levels of urea (A), uric acid (B), and creatinine (C) after the administration of a low-calorie diet or a ketogenic diet for 24 wk in diabetic and non-diabetic subjects. Urea levels were signi ﬁcantly increased in the two diet groups in diabetic and non-diabetic participants. Uric acid level increased in the low-calorie diet group but decreased in the low-carbohydrate ketogenic diet groups. A similar change was noticed for the creatinine level. Black circles, keto- genic and non-diabetic; black triangles, ketogenic and diabetic; white circles, low calorie and non-diabetic; white triangles, low calorie and diabetic.

T. A. Hussain et al. / Nutrition 28 (2012) 1016 –1021 1020 [36–38]. Moreover, these same agents, particularly insulin, inhibit ketosis, which is strived for in the earliest phases of the LCKD. Although it remains unclear whether ketones actually play a role in weight loss on the LCKD, previous research in non-diabetic patients has shown a positive correlation between the level of ketonuria and a success in weight loss [39]. The main limitations of our study are its small sample and short duration.

Conclusion In summary, the LCKD had signi ﬁcant positive effects on body weight, waist measurement, serum triacylglycerols, and glyce- mic control in participants with type 2 diabetes. Most impres- sively, there was an improvement in HbA1c despite the small sample and short duration of follow-up, and this improvement in glycemic control occurred after the antidiabetic medications had been decreased substantially in participants using the LCKD program. Further studies are necessary to examine the optimal adjustments, particularly for antidiabetic medications and diuretic agents, to avoid the possible complications of hypogly- cemia and dehydration because the LCKD can be very effective at lowering blood glucose. Diabetic patients who use this diet should be under close medical supervision or capable of adjusting their medication as required.

Acknowledgments The authors thank Mr. Joseph E Gomez, Department of Community Medicine, Faculty of Medicine, Kuwait University for advice and assistance in the statistical analysis of the data.

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