INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder marked by elevated blood sugar levels ¹. T2DM is linked to metabolic syndrome and insulin resistance. It is influenced by genetics, obesity, inactivity, and ethnicity ^2,3. The prevalence of T2DM varies globally, with a higher incidence in developed countries. As per the most recent report from the International Diabetes Federation (IDF), the worldwide incidence of T2DM among adults stood at 536.6 million individuals (10.5%) in 2021. It is projected that the number of individuals living with diabetes will reach 783.2 million people (12.2%) globally by the year 2045 ⁴.

From a pathophysiological perspective, T2DM is associated with insulin resistance, wherein the body’s cells are less responsive to insulin, and a gradual failure of pancreatic β-cells to compensate for this increased demand ⁵. This dysfunction is reflected in the hallmark signs and symptoms of T2DM, which include polyuria, polydipsia, polyphagia, and weight loss ⁶.

Long-term complications of T2DM are broad-ranging and include microvascular damage leading to retinopathy, neuropathy, and nephropathy, as well as macrovascular complications such as coronary artery disease, peripheral arterial disease, and cerebrovascular disease ^7,8.

Diagnosis of T2DM is typically confirmed through several tests, including fasting plasma glucose (FPG), 2-hour plasma glucose (2-h PG) during an oral glucose tolerance test (OGTT), and hemoglobin A1c (HbA1c) levels, which reflect the mean blood glucose levels over the previous two to three months ⁹.

Treatment modalities for T2DM include lifestyle interventions, oral hypoglycemic agents, non-insulin injectables, and insulin therapy ^10,11. Among the dietary strategies, the KD (a high-fat, adequate-protein, low-carbohydrate diet) has emerged as a potential therapeutic option ^12,13. This diet aims to induce a state of ketosis, where the body utilizes fat as a primary energy source instead of glucose ¹⁴.

The KD has been associated with alterations in the gut microbiota, which play a crucial role in metabolic health ¹⁵. A shift in intestinal flora could potentially influence the incretin hormone glucagon-like peptide-1 (GLP-1), which promotes insulin secretion and improves glycemic control. Furthermore, the KD could influence HbA1c levels, providing a broader metabolic benefit for patients with T2DM ^16,17.

However, the literature presents a paucity of comprehensive studies that holistically examine the effects of a KD on both the intestinal microbiota and the serum levels of GLP-1 and HbA1c in patients with T2DM. Therefore, this study aims to explore the effects of a KD on intestinal flora and serum GLP-1 and glycosylated hemoglobin levels in T2DM patients.

PATIENTS AND METHODS

This study was conducted as an interventional study with a randomized controlled trial (RCT) design. The study spanned over six months, from June 2021 to June 2022, at the South of Guang’anmen Hospital.

Based on the random number table method, 100 T2DM patients were selected and divided into a control group (CG) and an observation group (OG), with 50 patients in each group. As shown in Table 1, there were no significant differences between the two groups in general data (P>0.05).

Our hospital’s Ethics Committee reviewed and approved the study, and patients signed the informed consent form.

Inclusion criteria: ① Patients with T2DM were initially diagnosed through clinical signs and symptoms (polyuria, polydipsia, polyphagia, unexplained weight loss, fatigue, and blurred vision), and serological indicators (FPG >7.0 mmol/L or 126 mg/dL; a plasma glucose concentration equal to or exceeding ≥11.1 mmol/L or 200 mg/dL two hours after a 75-g oral glucose tolerance test (OGTT); HbA1c >6.5% or higher was also indicative of T2DM) ^18,19, ② Patients with good treatment compliance; ③Complete and accurate medical records.

Exclusion criteria: ① Patients with other serious diabetic complications such as ketoacidosis; ② Patients with other endocrine diseases; ③ Heart, liver, and kidney failure patients; ④ Patients with drug allergy episodes in the past.

The patients in the CG were given standard treatment: patients were instructed to control their diet, exercise appropriately, quit smoking, and limit alcohol consumption, and blood glucose was closely monitored. Patients in the OG were given a KD based on treatment in the CG. High-protein and low-carbohydrate KD treatment included 1/5-2/5 of fat, 2/5 of protein, 1/5 of carbohydrate, keeping regular three meals. This diet limits carbohydrate intake to around 20-50 grams daily and increases fats such as meat, fish, eggs, nuts, and healthy oils. On the other hand, adjusting protein consumption is also part of this diet; if much protein is consumed, it can be converted to glucose and may slow the transition to ketosis. The intake of fat was rich in ω-3 mainly, such as sardines, salmon, tuna, and other sources of this fat. The amount of drinking water was more than 2000 mL/d, multiple mineral vitamins needed to be supplemented, and the amount of exercise remained at the previous level. Both groups of patients were treated continuously for six months.

RESULTS

DISCUSSION

The ketogenic diet (KD) has been increasingly studied for its potential therapeutic effects in various health conditions, including type 2 diabetes mellitus (T2DM) ²⁰. T2DM is a chronic condition characterized by insulin resistance and impaired glucose metabolism ²¹. This study aimed to investigate the impact of a KD on the intestinal microbiota and the serum levels of glucagon-like peptide-1 (GLP-1) and glycosylated hemoglobin (HbA1c) in patients with T2DM. The present study’s findings suggest that patients with T2DM who followed a KD for six months exhibited significant improvements in their serum levels of GLP-1 and HbA1c, as well as their blood glucose and lipid profiles, compared to the control group receiving standard treatment. Additionally, there were notable changes in the composition of the intestinal microbiota, with an increase in beneficial bacteria such as Bifidobacterium and Lactobacillus, and a decrease in potentially harmful bacteria like E. faecalis and E. coli.

Several studies have investigated the impact of a KD on weight, blood glucose levels, and lipid profiles in patients with T2DM. In line with the present study, the research findings suggest that a KD can induce positive changes in these parameters, offering potential benefits for managing T2DM. Li et al.’s study results show that following a KD can lead to a decrease in fasting blood glucose and glycosylated hemoglobin levels in T2DM patients, which indicates an improvement in blood glucose management ²². Zhou et al.²³ also conducted a meta-analysis to investigate the role of KD in controlling body weight and managing blood sugar in overweight patients with T2DM. The results show that the KD significantly reduces body weight, reduces waist circumference, reduces glycosylated hemoglobin and triglycerides, and increases high-density lipoproteins (HDL)²³.

Additionally, the improvement in lipid profiles, particularly the reduction in triglyceride levels, is corroborated by Yuan et al. ²⁴. The KD’s impact on lipid profiles, especially triglyceride levels, is likely due to its effects on insulin secretion and lipid metabolism. By reducing carbohydrate intake and increasing fat intake, the diet leads to a decrease in insulin secretion, which in turn reduces the conversion of excess carbohydrates into triglycerides in the liver ²⁵. Additionally, the diet’s high-fat content provides a source of energy that is less likely to be stored as triglycerides in adipose tissue, further contributing to the reduction in triglyceride levels ²⁶.

The efficacy of insulin action is ensured through a cellular signalling cascade, which encompasses membrane insulin receptors (IRS) and intracellular proteins (PI3K and AKT). Critical for the uptake of plasma glucose into tissues, these interactions between proteins play a vital role. Conversely, deficiencies in cellular signal transduction and insulin responses to insulin stimulation (IR) can disrupt glucose regulation, consequently contributing to the onset of T2DM ²⁷. The reduction in carbohydrate intake in a KD induces a state of nutritional ketosis, which alters the body’s metabolism, leading to improved blood glucose levels and insulin sensitivity ^28,29. In line with the present study, a systematic study by Huang et al. revealed that the ketogenic diet can improve insulin sensitivity in individuals with type 2 diabetes, with the most significant effect resulting from a ketogenic diet paired with exercise ³⁰. The study by Paoli et al. also confirms these findings and states that a ketogenic diet can improve blood sugar control and insulin sensitivity ³¹.

The reduction in HbA1c levels in the observation group supports the results of a study by Rafiullah et al., which concluded that very low-carbohydrate ketogenic diets effectively reduce HbA1c in individuals with T2DM ³². A recent systematic review and meta-analysis conducted by Zaki et al.³³ found that low carbohydrate (LCD) and KD positively impact glucose regulation in individuals with Type 2 Diabetes. Nevertheless, the analysis indicated that ketogenic diets demonstrate notably higher effectiveness in lowering HbA1c levels (− 1.45%) when compared to LCD (− 0.27%) ³³.

The results of the present study showed that the ketogenic diet increases the serum level of GLP-1 in diabetic patients. GLP-1 is a hormone produced by the intestines that helps regulate blood sugar levels and stimulates insulin secretion ³⁴. Widiatmaja et al. conducted a study to analyze the long-term effect of KD on the serum levels of adiponectin and IGF-1 in rats. The results showed that long-term KD increases serum adiponectin levels and does not affect serum IGF-1 levels ³⁵. This finding is contrary to the results of the present study, which could be due to the type of participants and the type of study. Since human studies on this parameter have not been conducted in people with a KD diet, it is necessary to investigate this matter further.

Finally, the present study showed that KD improves intestinal microbiota. KD improves Bifidobacterium and Lactobacillus levels and reduces E. faecalis and E. coli levels in the intestine. Previous studies have also shown that a very low-calorie ketogenic diet (VLCKD) can lead to significant changes in gut microbiota composition in drug-naïve patients with T2DM and obesity. One study compared the effects of VLCKD and a hypocaloric Mediterranean diet (MD) on gut microbiota in patients with T2DM and obesity. The results showed that the VLCKD group had more significant changes in gut microbiota composition ³⁶. The study of Paoli et al. also supports this idea and results ³⁷. Since the number of studies in this field is limited, more studies are recommended.

In conclusion, this study confirms that a ketogenic diet significantly outperforms standard dietary treatments for type 2 diabetes mellitus over six months. It more effectively lowers blood glucose levels, improves lipid profiles, reduces body weight and waist circumference, and beneficially alters gut microbiota. These findings highlight the ketogenic diet’s potential as a superior dietary intervention for managing type 2 diabetes.