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Medicine (Baltimore). 2023 Oct 27; 102(43): e35753.
Published online 2023 Oct 27. doi:10.1097/MD.0000000000035753
PMCID: PMC10615408
PMID: 37904380
Sumei Li, MD,
a,* Shouping Yuan, BD,a Guoxin Lin, BD,a and Jintian Zhang, MDb
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
To investigate the effects of a two-meals-a-day energy-restricted ketogenic diet (KD) on newly diagnosed obese patients with type 2 diabetes mellitus. In total, 60 obese patients with newly diagnosed type 2 diabetes mellitus were divided into 2 groups: 1 group followed a 2-meals-a-day KD and the other group followed a conventional diabetic diet. Changes in weight, blood glucose, blood lipids, insulin resistance, and uric acid levels were observed before and after 2 months of adhering to the respective diets under energy restriction. Both groups showed significant reductions in weight, waist circumference, body mass index, total cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, fasting blood glucose, fasting insulin, and glycated hemoglobin (P < .05). The twice-daily KD group showed more significant improvements in these parameters compared to the conventional diabetic diet group. In addition, the 2-meals-a-day KD group showed a slight increase in uric acid levels compared to the conventional diabetic diet control group (P < .05). The 2-meals-a-day KD can significantly improve weight, blood glucose, and lipid control in newly diagnosed obese patients with type 2 diabetes mellitus.
Keywords: ketogenic diet, obesity, type 2 diabetes mellitus
1. Introduction
In 2017, an estimated 46.22 billion individuals worldwide were suffering from type 2 diabetes mellitus. The prevalence of type 2 diabetes mellitus is projected to increase at an alarming rate worldwide by 2030.[1] Obesity is a major risk factor for noncommunicable diseases such as cardiovascular disease and diabetes mellitus.[2,3]
The ketogenic diet (KD), a dietary pattern characterized by high fat, low carbohydrate, and adequate protein, was initially used to treat refractory epilepsy.[4] However, it has been shown to be effective for weight loss in obese adults and for the management of obesity-related diseases.[5–8] In recent years, studies have found that this dietary pattern is beneficial in promoting weight loss and improving glycemic control in patients with diabetes mellitus.[9–11] However, the strict adherence required for a KD poses challenges for most patients with diabetes mellitus, limiting their ability to benefit fully from this approach.
In contrast, patients on a 2-meals-per-day KD have better adherence and willingness to adhere to the diet in the long term, suggesting that patients with diabetes mellitus may further benefit from adopting this modified KD. This study aimed to evaluate the efficacy of a 2 meals-a-day KD intervention in newly diagnosed obese patients with type 2 diabetes mellitus.
2. Data and methods
2.1. General background
This retrospective observational study involved 60 newly diagnosed obese patients with type 2 diabetes mellitus who were undergoing treatment at our endocrinology clinic from June 1, 2020 to May 1, 2023. The patients were consecutively selected, and all of them provided informed consent for participation in the study. The study was approved by the Ethics Committee of the First Hospital of Putian City, Fujian Province, China. The cohort was divided into 2 groups: a 2-meals-per-day KD group and a conventional diabetic diet control group, each consisting of 30 patients. Both diets were energy-restricted, and we aimed to compare and assess the significance of changes in various parameters before and after 2 months of adhering to the respective diets. The inclusion criteria for the study were as follows: age 20 to 60 years, body mass index (BMI) ≥ 28 kg/m2, newly diagnosed type 2 diabetes mellitus, no use of glucose-lowering medication, and glycated hemoglobin (HbA1c) < 9%. Patients were excluded from the study if they had diseases or were taking drugs that could affect glucose and lipid metabolism; if they had severe acute or chronic complications of diabetes mellitus; or if they had concurrent infections, trauma, surgeries, pregnancy, or other similar conditions.
2.2. Methods
The study included 60 newly diagnosed obese patients with type 2 diabetes mellitus who were not yet taking glucose-lowering medication and who followed different dietary patterns. These patients were divided into 2 groups, the KD group and the conventional diabetic diet control group, with 30 patients in each group. Both groups followed an energy-restricted diet, with a total mean caloric intake of 1500 ± 50 kcal per day. The KD group consumed meals containing ingredients such as butter, olive oil, kebabs, fried eggs, sardines, swordfish, avocado, broccoli, etc. This diet was designed to provide approximately 230 to 280 g of carbohydrates, 20 g of fat, and 60 g of protein per day. The conventional diabetic diet control group adhered to a daily carbohydrate intake of 30 to 35 g, 130 g of fat, and 60 g of protein. In the 2-meals-a-day KD group, 2 meals were randomly assigned to the KD, providing approximately 2-thirds of the total daily caloric intake. The remaining 1 meal consisted of a regular diabetic diet, accounting for about one-third of the total daily caloric intake. No additional caloric intake was allowed outside of the 3 designated meals during the diet control period for both groups throughout the study period. Both groups consumed more than 2000 mL of water daily. Data of the study subjects were collected before and after 2 months of starting the study. Measurements included fasting blood glucose (FBG) and fasting insulin (FINS), and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using the formula HOMA-IR = FBG × FINS/22.5. The height, weight, and waist circumference of the patients were measured to calculate the BMI. Other measurements included HbA1c, uric acid (UA), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). The number of hypoglycemic episodes in the study subjects was evaluated based on the presence of hypoglycemic symptoms such as hunger, palpitations, cold sweat, weakness, etc. Hypoglycemia event: blood glucose < 3.9 mmol/L.
2.3. Statistical analysis
Statistical analysis was performed using the SPSS 22.0 software (SPSS Inc. Armonk, NY), and the results are expressed as x ± s for normally distributed data. For non-normally distributed data, the results are expressed as the median and interquartile range. The t test or rank sum test was used to compare data between and within groups, and P < .05 was considered statistically significant.
3. Results
3.1. Comparison of general data at enrollment
There were no statistically significant differences between the 2 groups in terms of gender, age, and disease duration at enrollment. In addition, there were no statistically significant differences in the baseline measurements of weight, waist circumference, BMI, TC, TG, HDL, LDL, FBG, FINS, HbA1c, and UA between the groups (P > .05), as shown in Table Table11.
Table 1
Comparison of general data between the 2 groups before intervention (±s).
| Project | The 2-meals-a-day ketogenic diet group | The diabetic diet group | P |
|---|---|---|---|
| Age (yr) | 37.80 ± 12.23 | 37.40 ± 12.72 | .325 |
| Course (mo) | 5.51 ± 1.52 | 5.92 ± 1.67 | .526 |
| Waist (cm) | 109.87 ± 12.92 | 108.45 ± 13.26 | .452 |
| Weight (kg) | 84.52 ± 16.85 | 85.94 ± 15.77 | .248 |
| BMI (kg/m2) | 30.15 ± 5.14 | 30.75 ± 5.84 | .254 |
| UA (µmol/L) | 398.2 ± 25.31 | 401.4 ± 28.27 | .643 |
| HbA1C (%) | 8.54 ± 1.61 | 8.53 ± 1.54 | .457 |
| FBG (mmol/L) | 9.03 ± 2.57 | 8.91 ± 2.36 | .782 |
| FINS (pmol/L) | 52.64 ± 17.57 | 53.19 ± 16.78 | .638 |
| LDL (mmol/L) | 2.76 ± 0.64 | 2.77 ± 0.71 | .725 |
| HDL (mmol/L) | 1.07 ± 0.14 | 1.10 ± 0.18 | .549 |
| TG (mmol/L) | 1.86 ± 0.54 | 1.84 ± 0.68 | .545 |
| TC (mmol/L) | 4.84 ± 0.69 | 4.86 ± 0.61 | .571 |
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3.2. Changes after KD intervention
After 2 months of following an energy-restricted diet, both groups demonstrated significant reductions in weight, waist circumference, BMI, TC, TG, HDL, LDL, FBG, FINS, and HbA1c (P < .05). Notably, the 2-meals-a-day KD group showed significantly greater reductions in blood glucose levels, body mass, and blood lipids compared to the control group (P < .05). The UA levels in the 2-meal-a-day KD group showed a certain increase, whereas the change in UA levels in the control group was not statistically significant (P > .05), as shown in Table Table22.
Table 2
Changes of indicators before and after intervention of different dietary patterns in the 2 groups (±s).
| Project | The 2-meals-a-day ketogenic diet group (n = 30) | P | The diabetic diet group (n = 30) | P | ||
|---|---|---|---|---|---|---|
| Before the intervention | After 2 mo of intervention | Before the intervention | After 2 mo of intervention | |||
| Waist (cm) | 109.87 ± 12.92 | 101.21 ± 10.48 | .000 | 108.45 ± 13.26 | 104.26 ± 11.78 | .000 |
| Weight (kg) | 84.52 ± 16.85 | 77.16 ± 11.49 | .000 | 85.94 ± 15.77 | 81.14 ± 10.22 | .000 |
| BMI (kg/m2) | 30.15 ± 5.14 | 27.74 ± 4.71 | .000 | 30.75 ± 5.84 | 28.72 ± 5.31 | .000 |
| UA (µmol/L) | 398.2 ± 25.31 | 432.41 ± 34.14 | .000 | 401.4 ± 28.27 | 388.15 ± 28.12 | .242 |
| HbA1C (%) | 8.54 ± 1.61 | 7.52 ± 1.61 | .000 | 8.53 ± 1.54 | 7.94 ± 2.01 | .000 |
| FBG (mmol/L) | 9.03 ± 2.57 | 7.5 ± 1.85 | .000 | 8.91 ± 2.36 | 7.9 ± 1.91 | .000 |
| FINS (pmol/L) | 52.64 ± 17.57 | 46.31 ± 9.55 | .000 | 53.19 ± 16.78 | 48.24 ± 10.62 | .000 |
| LDL (mmol/L) | 2.76 ± 0.64 | 2.44 ± 0.41 | .124 | 2.77 ± 0.71 | 2.58 ± 0.51 | .147 |
| HDL (mmol/L) | 1.07 ± 0.14 | 1.18 ± 0.24 | .000 | 1.10 ± 0.18 | 1.14 ± 0.23 | .000 |
| TG (mmol/L) | 1.86 ± 0.54 | 1.44 ± 0.26 | .000 | 1.84 ± 0.68 | 1.66 ± 0.46 | .000 |
| TC (mmol/L) | 4.84 ± 0.69 | 4.22 ± 0.45 | .000 | 4.86 ± 0.61 | 4.43 ± 0.42 | .000 |
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3.3. Blood glucose levels
During the first 3 weeks of the intervention, 4 hypoglycemic episodes occurred in the 2-meals-a-day KD, with 2 person-times of hypoglycemia events (peripheral blood glucose < 3.9 mmol/L). In contrast, the control group exhibited 2 hypoglycemic episodes, and no end-point glucose measurements were <3.9 mmol/L. No other hypoglycemic events occurred during Weeks 4 to 8 of the intervention. However, at the end of the intervention, 5 patients in the 2-meals-a-day KD group and 2 patients in the diabetic diet control group had normal blood glucose levels.
3.4. Follow-up of the willingness to adhere to the diet
Table Table33 presents the results of the follow-up on adherence to dietary patterns after the study concluded. The findings showed that the willingness to comply with the assigned dietary patterns was lower in the 2-meals-a-day KD group than in the diabetes diet control group. The majority of patients thought that low-carbohydrate foods were unpleasant.
Table 3
Differences in intentions after completion of projects between the 2 groups
| The 2-meals-a-day ketogenic diet group | The diabetic diet group | P | |
|---|---|---|---|
| Number of people who cannot stick to it (percentage) | 4 (13.3%) | 2 (6.7%) | <.05 |
| Number of people willing to stick with it in the short term (proportion) | 18 (60.0%) | 6 (20.%) | <.05 |
| Number of people willing to stick with it for the long term (proportion) | 8 (26.7%) | 22 (73.3%) | <.05 |
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4. Discussion
Effective treatment of obesity can reduce the prevalence and mortality rates of various diseases, including cardiovascular disease, diabetes mellitus, and tumors, thereby leading to substantial cost savings associated with healthcare expenses related to these diseases.[12,13] Exercising daily dietary control has been shown to reduce the incidence of type 2 diabetes mellitus and obesity, while also reducing the risk of cardiovascular-related deaths, all-cause mortality, and other endpoint events.[14] This study aimed to observe changes in blood glucose levels, body weight, lipid profiles, insulin resistance, and UA levels in patients with newly diagnosed type 2 diabetes mellitus and obesity who were placed on a KD with 2 meals per day for 2 months.
A study by Dehghan et al,[15] published in The Lancet, suggested that a lifestyle characterized by excessive carbohydrate intake may be associated with an increased risk of all-cause mortality and that a KD may serve as a therapeutic dietary approach, offering some practicality and theoretical advantages.[9,15]
Research studies have demonstrated the benefits of following a KD in patients with type 2 diabetes mellitus.[16,17] The KD provides energy through fat oxidation. When the body experiences extreme starvation or very low carbohydrate intake, the liver converts fatty acids into ketone bodies, which are then released into circulation.[18,19] It is important to differentiate between nutritional ketosis and severe pathological diabetic ketosis. In nutritional ketosis, blood ketone bodies are maintained in a range of 0.5 to 3.0 mmol/L, blood glucose levels are reduced, blood pH remains normal, and there are no symptoms of pathological ketosis.[20] When the body is in a state of ketosis induced by a strict KD, it uses ketone bodies as the main source of energy instead of carbohydrates. However, the anorexic effect and hunger caused by ketone bodies can render long-term compliance challenging for patients. By ensuring a proper carbohydrate intake, this metabolic shift can help reduce hunger and cravings, making it easier for patients to adhere to the prescribed diet.[21] Considering these factors, we focused on patients with type 2 diabetes who followed a 2-meals-a-day KD.
The KD induces a state of starvation ketosis, wherein the primary energy source of the body changes from glucose to ketone bodies. This allows the conversion of water-insoluble triglycerides to water-soluble ketone bodies, which can be excreted in the urine, while consuming energy.[22] On the other hand, the accumulation of ketone bodies in the body can lead to a decrease in appetite, decreasing caloric intake.[23] A decrease in caloric intake can also lead to a decrease in blood lipids. Therefore, the effects of the KD on lipid metabolism are multidimensional.[24] Despite its high fat content, the KD can lead to a decrease in lipid metabolism indicators such as TC, TG, and LDL-C. In this study, participants followed a 2-meals-per-day KD combined with one meal of a diabetic diet; however, the total caloric intake per day was restricted, resulting in an energy-restricted diet. This restriction in calorie consumption likely contributed to the observed decrease in lipid metabolism indicators.
The KD is extremely low in carbohydrate content, owing to which it can effectively regulate hepatic glycogen catabolism to alter the basal metabolism of blood glucose and achieve lower blood glucose levels.[25] The KD reduces the absorption of simple sugars in the intestine, which further lowers blood glucose and reduces fluctuations. Myette-Cote et al[26] demonstrated that the KD significantly improves glycemic control, lowers fasting insulin levels, and reduces blood glucose fluctuations in patients with diabetes mellitus. Partsalaki et al[27] showed that the KD can reduce weight, waist circumference, and insulin resistance. Waist circumference is an important indicator of central obesity and is closely associated with insulin resistance. In the present study, the stepwise KD with 2 meals per day resulted in weight loss, reduced waist circumference, improved glycemic control, and reduced insulin resistance; furthermore, the lipid indices of the study subjects improved compared to the baseline measurements. Previous meta-analyses have consistently shown that the KD significantly contributes to weight loss in obese patients.[10,28–36] The reduction in body weight can be attributed to the very low carbohydrate content of the KD, and also to the energy restriction that leads to negative nitrogen balance. Although the control group followed the diabetic diet with energy restriction, the KD with 2 meals per day was superior to the regular diabetic diet at every meal in reducing body weight, body fat, and blood glucose levels. It should be noted that daily caloric intake should be limited to achieve significant improvements in body composition.[37]
Clinically significant insulin resistance and some degree of islet dysfunction are commonly observed in obese patients with newly diagnosed type 2 diabetes mellitus. The KD with 2 meals per day can effectively improve insulin resistance, body weight, blood glucose, and lipid indices in such patients. Some patients may even achieve diabetes remission and glycemic control through lifestyle changes alone. The advantage of incorporating the KD into 2 meals per day, combined with a regular diabetic diet for the third meal, improves long-term compliance and allows more patients to benefit from this dietary approach.
This study has some limitations that should be acknowledged. The observation period in this study was only 2 months, so the long-term effects after discontinuing the 2-meals-per-day KD remain unclear. Further studies are needed to investigate this aspect. In addition, the risk of hypoglycemia in patients with diabetes, especially during the first 3 weeks of the KD, particularly if they are treated with glucose-lowering medications, and the potential elevation of serum UA and increased risk of gout should be taken into consideration.
In conclusion, our study demonstrates that a 2-meal-a-day KD can effectively improve weight management, glycemic control, and lipid profiles in newly diagnosed obese patients with type 2 diabetes mellitus. However, further research is necessary to address its potential limitations and long-term effects.
Acknowledgements
Thank you to all the medical staff of the Department of Endocrinology of the First Hospital of Putian City, Fujian Province.
Author contributions
Conceptualization: Sumei Li, Guoxin Lin, Jintian Zhang.
Data curation: Shouping Yuan, Jintian Zhang.
Formal analysis: Sumei Li, Shouping Yuan, Jintian Zhang.
Funding acquisition: Sumei Li.
Investigation: Sumei Li, Shouping Yuan.
Project administration: Sumei Li.
Resources: Sumei Li.
Writing – original draft: Sumei Li.
Writing – review & editing: Sumei Li, Guoxin Lin.
Abbreviations:
- BMI
- body mass index
- FBG
- fasting glucose
- FINS
- fasting insulin
- HbA1c
- glycosylated hemoglobin
- HDL-C
- high-density lipoprotein cholesterol
- KD
- ketogenic diet
- LDL-C
- low-density lipoprotein cholesterol
- TC
- total cholesterol
- TG
- triglyceride
- UA
- uric acid
This study was supported by the Putian Science and Technology Bureau Fund (2020SY002).
Written informed consent was obtained from all participants. We had complied with the Declaration of Helsinki Ethical Principles for medical research involving human subjects.[25]
Ethical clearance and approval were obtained from Ethics Committee of the first l Hospital of Putian, Fujian, China. All study participants were informed about the purpose of the study and additional information was given as they need.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
How to cite this article: Li S, Yuan S, Lin G, Zhang J. Effects of a two meals-a-day ketogenic diet on newly diagnosed obese patients with type 2 diabetes mellitus: A retrospective observational study. Medicine 2023;102:43(e35753).
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