Effectiveness of a multidisciplinary “2+N system therapy” in achieving remission and metabolic improvement in type 2 diabetes: A real-world study with 1,000 patients

Abstract

Background

Type 2 diabetes mellitus (T2DM) is a major global health challenge characterized by insulin resistance and β-cell dysfunction. Traditional treatments often fail to achieve sustained remission. This study evaluated a comprehensive “2 + N system therapy” combining Western and traditional Chinese medicine (TCM) with individualized lifestyle interventions to promote T2DM remission and improve metabolic health.

Methods

In a real-world observational study, 1000 T2DM patients (disease duration ≤5 years; BMI ≥24 kg/m² or elevated waist circumference; preserved C-peptide) were treated with 2 + N therapy at Guangdong Second Provincial General Hospital (2015–2022). The “2” phase involved intensive insulin therapy transitioning to non-insulin agents with tailored TCM; the “N” phase included calorie-restricted low-carbohydrate diet, exercise, and psychological support. Primary outcome was diabetes remission (HbA₁c < 6.5 % for ≥3 months without medication). Secondary outcomes included changes in weight, BMI, waist/hip circumference, glycemic indices, insulin resistance (HOMA-IR), β-cell function (HOMA-β), lipids, uric acid, and MRI-assessed hepatic and pancreatic fat in a subset.

Results

At 6 months, 70.5 % of participants achieved remission. Significant metabolic improvements were observed, including mean weight reduction (9.2 ± 4.3 kg), BMI decrease (3.2 ± 1.4 kg/m²), waist circumference reduction (11.0 ± 4.2 cm), and notable improvements in glycemic control (HbA₁c decreased from 7.3 ± 1.3 % to 5.3 ± 0.4 %). Lipid profiles significantly improved, with triglycerides declining from 6.34 ± 3.25 to 1.39 ± 0.95 mmol/L and total cholesterol from 7.41 ± 2.20 to 3.76 ± 0.86 mmol/L. MRI analysis of a subgroup (n = 26) showed significant reductions in hepatic fat (28.8 %) and pancreatic fat (25.0 %).

Conclusions

The “2+N system therapy” demonstrated a high remission rate and extensive metabolic benefits, including substantial weight loss, improved glycemic control, enhanced insulin sensitivity, and reductions in ectopic fat. However, causality cannot be established without a control group and further prospective controlled trials are required to confirm its efficacy.

Highlights

• •“2+N system therapy” achieved 70.5 % remission at 6 months in 1000 T2DM patients.
• •Average weight loss was 9.2 kg, with marked reductions in liver and pancreatic fat.
• •HbA1c dropped from 7.3 % to 5.3 %; triglycerides and cholesterol improved significantly.
• •Hybrid care model used online tools and team-based education to boost adherence.
• •The approach offers scalable, non-surgical diabetes remission; further trials warranted.

1. Introduction

Type 2 diabetes mellitus (T2DM) represents one of the most significant public health challenges globally, with its prevalence increasing dramatically due to rapid lifestyle changes and growing rates of obesity [1,2]. According to the latest estimates from the International Diabetes Federation, approximately 537 million adults were affected by diabetes worldwide in 2021, and this figure is expected to rise to 783 million by 2045 [2]. China bears a substantial proportion of this burden, with around 141 million adults diagnosed with diabetes and another 197 million exhibiting prediabetic conditions such as impaired glucose tolerance or impaired fasting glucose [2,3]. This escalating epidemic has critical implications for public health, given the strong association between diabetes and increased risk of cardiovascular diseases, neuropathy, nephropathy, and retinopathy, which significantly raise morbidity and mortality rates [4,5].

Conventional management strategies for T2DM predominantly involve pharmacological interventions aimed at glycemic control, including metformin, insulin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT-2) inhibitors [6,7]. While these pharmacological treatments effectively manage hyperglycemia, they typically do not address the underlying insulin resistance and β-cell dysfunction, resulting in lifelong dependence on medication and an increased risk of associated complications [8,9]. Thus, there is a growing clinical interest in interventions that not only control glucose levels but potentially reverse the underlying pathophysiological mechanisms of T2DM.

Recent landmark trials, such as the Diabetes Remission Clinical Trial (DiRECT) [10], have demonstrated the potential for substantial diabetes remission through intensive weight management and lifestyle modification strategies, particularly in patients with relatively short disease duration [11,12]. These findings align with the twin-cycle hypothesis proposed by Taylor et al., suggesting that reducing ectopic fat accumulation in the liver and pancreas can restore β-cell function and insulin sensitivity, potentially leading to diabetes remission [13]. However, despite promising outcomes, the widespread implementation of such intensive lifestyle interventions faces challenges related to adherence, resource intensity, and variability in real-world effectiveness [14,15].

In response to these challenges, we developed the innovative “2+N system therapy,” a multidisciplinary approach integrating pharmacological treatment—including both Western and traditional Chinese medicine(TCM)—with personalized nutritional interventions, structured physical exercise programs, and psychological support. The “2″ symbolizes the combination of pharmacological strategies, while “N” represents multiple tailored lifestyle and behavioral components. Since its initiation in 2015, this integrative therapy has shown promising preliminary results in clinical practice, achieving significant improvements in glycemic control, weight reduction, and metabolic parameters among patients with T2DM [16].

Therefore, the objective of this observational study is to systematically evaluate the real-world data in relation to the effectiveness of the “2+N system therapy” in achieving metabolic improvements and clinical remission in a large cohort of T2DM patients. We hypothesize that this comprehensive, multidisciplinary approach will provide superior clinical outcomes compared to conventional treatments, offering a scalable and sustainable model for diabetes management that could significantly alter the trajectory of the global diabetes epidemic.

2. Materials and methods

2.1. Study design

This real-world study evaluated the effectiveness of a comprehensive 2+N intervention program in adults with T2DM. A total of 1000 patients undergoing 2+N treatment at the Diabetes and Obesity Reversal Center of Guangdong Second Provincial General Hospital (Guangzhou, China) from May 2015 to January 2022 were included. Fig. 1 shows the design of the study and key steps involved. Baseline clinical and biochemical data were collected prior to intervention, and follow-up assessments were performed at 3 and 6 months. The study was approved by the institutional ethics committee (No.2024-KY-KZ-226-02) and all participants provided written informed consent. The study was performed in accordance with the Declaration of Helsinki. We compared outcomes before vs. after the interventions, with changes in metabolic parameters analyzed relative to baseline.

Fig. 1.

Flow chart showing the design of the study and key steps involved.

2.2. Participants

Adult patients were eligible if they had established T2DM according to standard diagnostic criteria. Diagnosis was based on the 2020 American Diabetes Association and Chinese guidelines [8]: fasting plasma glucose ≥7.0 mmol/L, 2-h postload glucose ≥11.1 mmol/L, or HbA1c ≥ 6.5 %. Obesity and overweight was defined per Chinese criteria [17] as BMI ≥28 kg/m² and ≥24 kg/m², respectively. Inclusion criteria required patients to be overweight or obese adults with T2DM and the ability to participate in intensive lifestyle and medical interventions. Exclusion criteria were applied to ensure suitability for reversal therapy, including:

Secondary or atypical diabetes: e.g. glucocorticoid-induced diabetes, Cushing's syndrome, acromegaly, glucagonoma, or monogenic diabetes (these require targeted treatment of the underlying cause).

Autoimmune diabetes: Presence of islet autoantibodies (e.g. GAD antibody) consistent with type 1 diabetes, in which irreversible β-cell loss precludes remission.

Long-standing disease or end-organ damage: Duration of T2DM > 5 years, or presence of advanced complications (severe cardiovascular disease, proliferative retinopathy, etc.), or markedly impaired β-cell reserve (fasting C-peptide <1.0 ng/mL).

These criteria are consistent with the national “ABCD” assessment framework for diabetes remission, which emphasizes Absence of autoimmunity, Body weight, C-peptide levels, and Disease Duration as key factors in selecting suitable candidates.

2.3. Interventions: the “2+N system therapy”

The “2+N system therapy” was implemented per the “SOP of 2+N for T2DM Diabetes Reversal Treatment” (T/LNBJ 002–2024) [16]. It comprised Parmacotherapy (“2”)—Western medicine and TCM and Lifestyle Interventions (“N”). The 2+N intervention program was delivered by a multidisciplinary care team and included intensive management of nutrition, physical activity, medication, and psychosocial support. The care team comprised endocrinologists, nutritionists (medical dietitians), exercise physiologists, diabetes educators/health managers, and psychological counselors. Management was structured as weekly in-person consultations supplemented by daily remote monitoring and support (via telephone or mobile apps) to track diet, exercise, sleep, and mood. Each team member had defined roles:

Endocrinologists: developed and adjusted the overall treatment plan, explained the rationale for remission therapy to patients, and monitored clinical response and safety.

Nutritionists: provided individualized medical nutrition therapy (MNT) based on patients’ habits and goals, designed calorie-restricted diets, and conducted regular follow-up to ensure adherence. Dietary plans emphasized balanced, reduced-calorie intake (typically 30–50 % below baseline, or ∼1000–1500 kcal/day) and incorporated short-term ketogenic or very-low-carbohydrate phases (4–12 weeks) as appropriate. Low-carbohydrate diets were preferentially used in patients with normal BMI.

Exercise Therapists: performed baseline fitness evaluations and prescribed structured physical activity programs. Patients were counseled to engage in moderate-intensity aerobic exercise ≥150 min per week (e.g. brisk walking, jogging, swimming, divided into ≥3 sessions/week), plus resistance training twice weekly (30 min/session). Detailed weekly exercise schedules (weekdays vs. weekends) were developed and supervised.

Diabetes Educators/Health Managers: reinforced patient education on T2DM management, self-monitoring of blood glucose, and lifestyle modification skills to enhance compliance.

Psychological Counselors: provided ongoing emotional support and motivation, addressing stress or behavioral barriers and helping maintain a positive outlook on the intensive treatment process.

The intensive intervention period lasted 3–6 months. Throughout this time, therapy was tailored to patient response. Key components included:

Nutrition Therapy: Nutrition therapy was delivered by certified clinical nutritionists and constituted a core component of the “N” phase of the 2+N system therapy. Although each patient received an individualized dietary plan, a standardized framework guided all prescriptions. The program employed a calorie-restricted diet aiming for a 30–50 % reduction from each patient's baseline energy intake, with typical daily targets of ∼1200 kcal/day for women and ∼1400 kcal/day for men, adjusted for BMI, physical activity level, and weight-loss trajectory. Macronutrient composition was designed to be balanced, generally beginning with ∼40 % of total energy from carbohydrates, 30 % from protein, and 30 % from fat. Refined carbohydrates were strictly limited, and whole-food, minimally processed sources of protein, vegetables, and healthy fats were emphasized.

A structured meal template was provided to all participants, and a representative 1400 kcal/day sample menu was included in the Supplementary Materials (e.g., breakfast of oatmeal [30 g] with egg whites; lunch of chicken breast salad with olive oil and minimal whole grains; dinner comprising fish and steamed vegetables; optional protein-rich snacks). Nutritionists conducted weekly reviews of dietary adherence and metabolic response using food logs and app-based photo submissions.

Diet intensity was dynamically adjusted based on clinical progress. For patients who did not achieve expected weight loss or glycemic improvement, caloric intake was further reduced by approximately 10–15 %, or daily carbohydrate intake was restricted to <100 g/day. Conversely, to prevent excessive weight loss—defined as >1 kg/week after month 3—energy targets were recalibrated upward in a stepwise fashion. Throughout the program, dietitians ensured adequate micronutrient intake and monitored for symptoms of hypoglycemia or intolerance. This adaptive, closely supervised nutrition strategy provided both standardization and personalization, supporting both adherence and metabolic optimization.

Two sample daily meal plans (Low-carbohydrate diet meal plan and ketogenic diet meal plan) are presented in Supplementary Table 1.

Physical Exercise: A structured physical activity program was prescribed for all participants and delivered by certified exercise physiologists as part of the “N” component of the 2+N system therapy. The regimen emphasized moderate-intensity aerobic training combined with resistance exercise. In accordance with international guidelines, patients were instructed to complete ≥150 min per week of moderate aerobic activity, distributed over at least 3 days to avoid prolonged inactivity. Examples provided included brisk walking, cycling, treadmill training, or swimming, selected according to each patient's physical capacity and comorbidities. Aerobic intensity was targeted at 50–70 % of the age-predicted maximal heart rate, corresponding to a level that increased breathing rate while still allowing conversation.

Daily ambulation goals were incorporated into the program; a typical prescription aimed for 10,000 steps per day, with step targets gradually increased from the patient's baseline. In addition, resistance training was performed twice weekly, using body weight, resistance bands, or gym-based equipment when available. Standardized routines consisted of 3 sets of 10–15 repetitions involving major muscle groups (e.g., quadriceps, gluteal muscles, chest, back, and core). Progressions were individualized based on tolerance and functional assessment.

To ensure safety and correct movement patterns, initial training sessions were supervised by physiotherapists, who provided instruction on technique, injury prevention, and appropriate intensity adjustment. Based on baseline fitness evaluation, each patient received a personalized exercise prescription, including a printed weekly schedule detailing the type, duration, and intensity of aerobic and resistance activities. Adherence was monitored through weekly check-ins and mobile app–based activity tracking, with exercise plans modified as needed to accommodate musculoskeletal limitations, fatigue, or changes in metabolic status.

Pharmacological Management: Pharmacologic therapy constituted the core component of the “2” phase of the 2+N system protocol. A standardized medication algorithm was applied to all participants, with adjustments based on baseline glycemia, comorbidities, and individual tolerance. The overarching goal was to rapidly correct glucotoxicity, enable early glycemic stabilization, and subsequently de-intensify medications in a structured manner as metabolic health improved.

• Step 1: Initial Glycemic Stabilization with Insulin (when indicated). Patients presenting with marked hyperglycemia (HbA1c ≥ 10 % or fasting plasma glucose ≥11.1 mmol/L) were started on short-term basal–bolus insulin therapy to promptly reduce glucose levels. Basal insulin typically began at 0.2–0.3 U/kg/day, while bolus insulin was initiated at 0.05–0.1 U/kg per meal, with daily titration based on fasting and pre-meal glucose targets. Patients with less severe hyperglycemia generally proceeded directly to non-insulin pharmacotherapy.

• Step 2: Transition to Non-Insulin Therapy. Once fasting glucose improved to <8.0 mmol/L, insulin was tapered and patients were transitioned to metformin combined with a GLP-1 receptor agonist (GLP-1 RA) as first-line therapy unless contraindicated. Metformin was titrated to 1500–2000 mg/day, while GLP-1 RAs were selected for their benefits on weight, appetite regulation, and β-cell preservation. When GLP-1 RAs were unsuitable, alternatives included SGLT-2 inhibitors or thiazolidinediones, particularly after weight reduction. Insulin tapering occurred every 2–3 days based on capillary glucose, with most patients discontinuing insulin within 2–4 weeks.

• Step 3: Medication Withdrawal Standardization. Systematic withdrawal of glucose-lowering medications was initiated once a patient achieved near-normoglycemic values on therapy, defined as HbA1c <6.5 %, fasting glucose <7 mmol/L, and 2-h postprandial glucose <10 mmol/L. Tapering followed a fixed sequence to minimize hypoglycemia and metabolic rebound: 1) Insulin was reduced first and discontinued once fasting glucose remained stable. 2) Sulfonylureas, which were discouraged in this program and rarely used chronically, were stopped immediately if present. 3) Other oral agents (e.g., metformin, SGLT-2 inhibitors, thiazolidinediones) were withdrawn individually over 1–2 weeks per agent. 4)GLP-1 RAs were tapered last, only after all other medications had been stopped and glycemic values remained within target for ≥2 weeks.

During the withdrawal phase, participants monitored fasting and postprandial glucose at least twice weekly, with additional checks as needed. If blood glucose increased above target (e.g., fasting >7.0 mmol/L or projected HbA1c >6.5 %), medication tapering was paused, and the previous agent was reinstated. Such reversals were uncommon within the first 3 months, as patients meeting withdrawal criteria typically maintained stable glycemic control.

In alignment with ADA consensus definitions, participants were considered in diabetes remission only after ≥3 months completely off all glucose-lowering medications with sustained normoglycemia.

Management of Comorbidities. All participants received guideline-directed pharmacologic therapy for hypertension, dyslipidemia, hyperuricemia and other cardiometabolic comorbidities. As a principle in the management of these comorbidities, they were generally managed with lifestyle first, and new medications for these conditions were generally not introduced during the 6-month intervention period unless absolutely necessary.

TCM Protocol: TCM was incorporated as an adjunctive component of the 2+N system therapy and was offered selectively based on clinical judgment and patient preference. TCM therapy—predominantly acupuncture, rather than herbal formulations—was recommended for patients who aimed for optimal metabolic improvement with core lifestyle and pharmacologic therapy alone or who experienced coexisting conditions amenable to TCM support, such as diabetic neuropathy, stress-related insomnia, chronic pain, or high treatment-related anxiety. In addition, highly motivated participants who explicitly requested integrative therapy were considered eligible. These selection decisions were made by attending endocrinologists in consultation with TCM specialists, and no rigid inclusion criteria were used. We acknowledge that these selection decisions were subjective and not based on predefined criteria. Approximately 80 % of the cohort received at least one form of adjunctive TCM intervention during the study. Among these patients, acupuncture was the primary modality, with herbal medicine used only in rare instances. Treatments were administered by certified acupuncturists following national practice guidelines for diabetes-related acupuncture therapy.

For patients receiving acupuncture, the protocol was largely standardized across the program. Sessions were delivered 1–2 times per week, each lasting approximately 30 min. Sterile, single-use 0.25 × 40 mm needles were used in all treatments. Acupuncture points targeted meridians traditionally associated with glycemic regulation, metabolic balance, and autonomic modulation, including but not limited to Zusanli (ST36), Qihai (CV6), Guanyuan (CV4), Sanyinjiao (SP6), Zhongwan (CV12), Quchi (LI11) and Taixi (KI3). Needle insertion depth and stimulation techniques followed conventional practice standards, and moxibustion was applied at select points when indicated. Acupuncture frequency and duration were adjusted based on symptom response, tolerance, and weekly evaluations. Participants receiving acupuncture underwent an average of 8 sessions over a 3-month period. Both men and women were equally represented in the acupuncture subgroup (≈50 % each), mirroring the sex distribution of the overall cohort.

While TCM was widely used, it was not administered to all patients; therefore, the extent and duration of exposure varied among individuals. Nonetheless, among those who received treatment, the procedural elements of acupuncture were highly standardized, ensuring consistency and reproducibility of the adjunctive TCM intervention.

The major components of the intervention and the proportion of patients who received each are presented in Supplementary Table 2.

2.4. Features of the comprehensive precision intervention

A “2+N” system therapy protocol for each participant was established under the leadership of an endocrinologist, integrating health managers, dietitians, physiotherapists, sports medicine specialists, specialist nurses and psychological counselors into a multidisciplinary care team. Employing a hybrid “online + offline” management model, the team delivered personalized and adaptive diabetes care across five core modules: diet, exercise, medication, monitoring, and education.

Systematic Diabetes Education: Each participant received structured instruction on nutrition, dietary planning, and physical activity, designed to deepen their understanding of the physiological principles underlying glycaemic control. This educational framework empowered patients to self-manage more effectively, leading to a marked reduction in pharmacological dependence. To ensure mastery of key self-care skills, we implemented a competency-based assessment—akin to a driver's license examination—requiring patients to pass a formal test demonstrating both knowledge and practical application. This evaluative process not only verified learning outcomes but also motivated adherence to evidence-based lifestyle modifications, thereby mitigating the risk of glycaemic rebound.

Use of AI-Enabled Mobile Application: To maintain continuous support, a bespoke app was used for each participant to offer the following. First, it is friendly platform to ask questions and to get answers from experts, connecting patients with the care team instantly. Second, to personalize meal plans tailoring to individual glycaemic targets and nutritional profiles. Third, through the app to do custom exercise coaching, with in-app prompts to adjust intensity and duration. Fourth, to enable activity & energy tracking, integrating wearable step counters and energy-expenditure estimates. Firth, we also could use to do real-time data visualization and trend analysis allowed automated adjustments to dietary and exercise recommendations, ensuring interventions stayed aligned with each patient's evolving needs.

Integrated Follow-Up: Regular virtual group sessions fostered peer support and reinforced education, while scheduled in-person visits enabled physical assessments and fine-tuning of treatment plans. Continuous data monitoring informed timely modifications, maintaining adherence and optimizing outcomes.

By weaving together systematic education, rigorous competency evaluation, AI-driven digital tools, and coordinated follow-up, this system achieved high-efficiency, patient-centered management and sustained therapeutic benefits.

2.5. Outcome measures and definitions

Clinical and metabolic outcomes were evaluated at baseline, 3 months, and 6 months. The primary endpoint was T2DM remission, defined according to ADA 2021 consensus [11] criteria. Remission required normoglycemia (HbA1c <6.5 %) sustained for at least 3 months after complete withdrawal of glucose-lowering medications. In practice, glycemic status was monitored by HbA1c and fasting glucose; patients meeting criteria had medications discontinued and continued without pharmacotherapy. Secondary outcomes included changes in body weight, BMI, and waist/hip circumference; glycemic indices (HbA1c, fasting plasma glucose, 2-h postload glucose); insulin sensitivity (HOMA-IR) and β-cell function (HOMA-β); and serum lipids and uric acid.

To assess changes in ectopic fat, a subset of 26 patients underwent MRI quantification of liver and pancreatic fat content. This cohort was established using a convenience sampling method, comprising the first 26 consecutive patients who volunteered for the imaging substudy and provided specific informed consent. Inclusion was strictly based on patient willingness and the absence of absolute contraindications to MRI (e.g., metallic implants or severe claustrophobia). The selection process was driven primarily by logistical factors, such as scanner availability, and was independent of baseline disease severity, metabolic status, or subsequent treatment outcomes. Imaging was performed at baseline and after 1.5 months of intervention using a 3.0-T scanner (uMR 780, United Imaging Healthcare) with a 12-channel body coil. A multi-echo gradient-echo sequence was acquired in one breath-hold; hepatic fat fraction was measured by placing multiple ROIs (∼158.7 mm² each) on three liver slices, and pancreatic fat by ROIs (∼87.9 mm²) in the head, body, and tail of the pancreas.

Weight loss ≥10 kg (or ≥10 % of body weight) and a reduction in BMI to ≤24 kg/m^2 were used as additional indicators of successful metabolic improvement. Resolution of fatty liver (by ultrasound or MRI) and an increase in relative muscle mass were also noted as markers of health restoration. All anthropometric and laboratory measurements were obtained using standardized protocols.

2.6. Statistical analysis

Data analysis was conducted using R software (v4.2.0) and GraphPad Prism 8. Continuous variables were expressed as mean ± standard deviation (or median and interquartile range, if non-normally distributed), and categorical variables as counts (percentages). Paired or repeated-measures t-tests (or ANOVA) were used to compare continuous outcomes over time, and chi-square tests for categorical variables. All statistical tests were two-sided, and p-values <0.05 were considered statistically significant.

3. Results

3.1. Baseline characteristics of the participants

A total of 1000 diabetic participants were included in the study, with 295 in the Non-Remission Group and 705 in the Remission Group. The baseline characteristics of the participants are presented in Table 1. The mean age was similar between the two groups (58.0 ± 11.1 years in the Non-Remission Group vs. 58.2 ± 10.3 years in the Remission Group, p = 0.691). However, there was a significant difference in sex distribution, with a higher proportion of females in the Non-Remission Group (63.1 % vs. 54.6 %, p = 0.014). The duration of diabetes also differed significantly, with the Non-Remission Group showing a longer duration (median 4.5 years [IQR 4.5–5.0] vs. 4.5 years [IQR 2.0–4.5], p < 0.001).

Table 1.

Baseline characteristics of all participants before treatment.

Variable	All participants	Non-Remission Group	Remission Group	P value
	(n = 1000)	(n = 295)	(n = 705)
Age (years)	58.1 ± 10.5	58.0 ± 11.1	58.2 ± 10.3	0.691
Sex				0.014
Female	571 (57.1 %)	186 (63.1 %)	385 (54.6 %)
Male	429 (42.9 %)	109 (36.9 %)	320 (45.4 %)
Duration of diabetes (y)	4.5 (2.0–5.0)	4.5 (4.5–5.0)	4.5 (2.0–4.5)	<0.001
BMI (kg/m2)	25.5 (24.0–27.3)	27.3 (25.2–29.4)	25.0 (24.0–26.6)	<0.001
Weight (kg)	72.0 (66.4–78.0)	78.0 (69.8–91.4)	70.1 (65.0–76.0)	<0.001
HbA1c (%)	6.9 (6.5–7.8)	7.2 (6.7–8.1)	6.9 (6.4–7.7)	<0.001
FBG (mmol/L)	8.6 (7.2–10.2)	9.2 (7.7–10.6)	8.4 (7.0–9.9)	<0.001
2h glucose (mmol/L)	15.6 (13.2–19.6)	19.0 (15.2–21.4)	15.0 (12.9–18.2)	<0.001
FINS (μU/ml)	13.1 (9.5–17.6)	15.1 (10.1–19.0)	12.3 (9.2–16.7)	<0.001
2h insulin (μU/ml)	66.1 (47.4–98.3)	86.3 (58.4–121.1)	59.1 (45.5–86.5)	<0.001
Fasting C-peptide (ng/mL)	3.5 (3.0–4.0)	3.6 (3.0–4.0)	3.4 (2.9–4.0)	0.260
2h C-peptide (ng/mL)	14.5 (10.3–18.4)	16.7 (11.5–21.6)	13.7 (9.9–17.0)	<0.001
Waist Circumference (cm)	98.0 (94.0–105.0)	102.0 (96.0–115.0)	97.0 (93.0–102.0)	<0.001
Hip Circumference (cm)	106.0 (100.0–112.0)	109.0 (103.0–118.0)	105.0 (100.0–110.0)	<0.001
TG (mmol/L)	6.04 (3.70–8.66)	9.63 (6.54–11.57)	5.20 (3.32–7.23)	<0.001
TC (mmol/L)	7.46 (5.87–8.85)	7.90 (6.49–9.25)	7.26 (5.59–8.58)	<0.001
LDL-c (mmol/L)	3.43 (2.76–4.02)	3.40 (2.64–4.12)	3.43 (2.80–4.00)	0.324
HDL-c (mmol/L)	1.00 (0.86–1.20)	0.99 (0.86–1.21)	1.00 (0.86–1.19)	0.778
Uric acid (μmol/L)	386.0 (333.0–449.0)	421.0 (380.0–495.0)	369.0 (322.0–421.0)	<0.001
HOMA-IR	4.8 (3.4–7.0)	5.9 (4.0–7.9)	4.5 (3.2–6.4)	<0.001
HOMA-β	51.3 (36.1–74.7)	51.9 (36.5–74.3)	50.9 (35.5–74.7)	0.800

Data are presented as median (25–75 percentile) for continuous variables and n (%) for categorical variables.

Abbreviation: BMI, body mass index; FBG, fasting blood glucose; FINS, fasting insulin; TG, total triglyceride; TC, total cholesterol; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; Significant P values (P < 0.05) are presented in bold.

Participants in the Non-Remission Group exhibited significantly higher values for several anthropometric measures compared to the Remission Group. Glycemic parameters were significantly elevated in the Non-Remission Group. The Non-Remission Group showed higher insulin and C-peptide levels, except for fasting C-peptide. Significant differences were observed in lipid parameters. Levels were higher in the Non-Remission Group.

In summary, participants who later achieved remission had a generally more favorable baseline metabolic profile. The remission group exhibited lower median measures of adiposity (BMI, weight, waist and hip circumferences), lower glycemic levels (HbA1c, fasting and 2h glucose), and lower insulin and triglyceride levels than the non-remission group. In contrast, LDL and HDL cholesterol and β-cell function (HOMA-β) were similar between groups. These trends indicate that the remission group was characterized by lower body fat and insulin resistance and better baseline glucose control compared to the non-remission group.

3.2. Weight loss and anthropometric favorable changes following interventions

Participants experienced substantial weight loss and reduction in central adiposity during the intervention. Mean body weight decreased from 73.1 ± 10.9 kg at baseline to 63.9 ± 8.6 kg at 6 months, a net loss of 9.2 ± 4.3 kg (P < 0.05 vs baseline). This corresponded to a drop in BMI from 25.7 ± 2.6 to 22.5 ± 1.9 kg/m² (Δ −3.2 ± 1.4 kg/m², P < 0.05). Notably, most of the weight reduction occurred in the first 3 months (−5.3 ± 2.6 kg, P < 0.05), with additional loss by 6 months (Table 2). Consistent with weight loss, waist circumference was reduced from 100.1 ± 9.5 cm at baseline to 89.1 ± 7.4 cm at 6 months (−11.0 ± 4.2 cm, P < 0.05). Hip circumference showed a similar decline (106.6 ± 8.9 cm to 94.7 ± 7.6 cm, −12.0 ± 4.2 cm; P < 0.05). These anthropometric improvements are illustrated in Fig. 2, which shows the progressive decrease in body weight, BMI, and circumferences over 3 and 6 months.

Table 2.

Changes in key parameters following 2+N system therapy.

Variable	Baseline	3 months	6 months	Changes
				3 months vs. baseline	6 months vs. baseline	3 months vs. 6 months
BMI (kg/m2)	25.7 (2.6)	23.9 (2.2)	22.5 (1.9)	−1.9 (0.9)∗	−3.2 (1.4)∗	−1.4 (0.8)∗
Weight (kg)	73.1 (10.9)	67.8 (9.6)	63.9 (8.6)	−5.3 (2.6)∗	−9.2 (4.3)∗	−3.9 (2.2)∗
HbA1c (%)	7.3 (1.3)	5.4 (0.5)	5.3 (0.4)	−2.0 (1.4)∗	−2.1 (1.4)∗	−0.1 (0.5)
FBG (mmol/L)	8.8 (2.0)	5.1 (0.5)	5.3 (0.3)	−3.7 (2.1)∗	−3.5 (2.0)∗	0.2 (0.6)
2h glucose (mmol/L)	16.5 (4.3)	7.4 (1.1)	7.4 (1.0)	9.2 (4.3)∗	9.2 (4.3)∗	0.0 (0.8)
WC (cm)	100.1 (9.5)	93.9 (8.2)	89.1 (7.4)	−6.1 (2.6)∗	−11.0 (4.2)∗	−4.9 (2.5)∗
HC (cm)	106.6 (8.9)	100.1 (7.8)	94.7 (7.6)	−6.5 (2.9)∗	−12.0 (4.2)∗	−5.4 (2.2)∗
TG (mmol/L)	6.34 (3.25)	1.59 (1.25)	1.39 (0.95)	−4.7 (3.0)∗	−4.9 (3.1)∗	−0.2 (0.6)
TC (mmol/L)	7.41 (2.20)	4.07 (1.49)	3.76 (0.86)	−3.3 (2.4)∗	−3.6 (2.2)∗	−0.3 (1.2)
LDL-c (mmol/L)	3.42 (0.82)	1.93 (0.94)	1.89 (0.92)	−1.5 (1.2)∗	−1.5 (1.2)∗	−0.0 (0.9)
HDL-c (mmol/L)	1.02 (0.24)	1.22 (0.14)	1.24 (0.15)	0.2 (0.3)	0.2 (0.3)	0.0 (0.2)
Uric acid (μmol/L)	399.2 (95.3)	376.2 (57.2)	324.0 (55.2)	−22.9 (108.1)	−75.2 (100.7)	−52.3 (62.3)
HOMA-IR	5.4 (2.6)	3.1 (1.1)	3.1 (1.2)	−2.3 (2.8)	−2.4 (2.4)∗	−0.0 (1.6)
HOMA-β	60.5 (36.2)	74.2 (31.8)	148.3 (63.9)	13.7 (48.3)∗	87.9 (66.0)∗	74.2 (69.9)∗

Data are presented as mean ± SD (n = 1000). ∗P value < 0.05.

Fig. 2.

Changes in anthropometric measurements following 2+N system therapy. (A) Body mass index (BMI; kg/m²), (B) body weight (kg), (C) waist circumference (WC; cm), and (D) hip circumference (HC; cm) at baseline, 3 months and 6 months following initiation of therapy. Data are presented as mean ± SD (n = 1000). Statistical comparisons were made by one-way repeated measures ANOVA with Bonferroni post hoc test. ∗∗∗p < 0.05. Abbreviations: BMI, body mass index; SD, standard deviation; WC, waist circumference; HC, hip circumference.

3.3. Glycemic control and diabetes remission following the 2+N system therapy

As shown in Table 2, glycemic control improved markedly following the 2+N system therapy. By 3 months, mean HbA₁c had declined from 7.3 ± 1.3 % to 5.4 ± 0.5 %, and by 6 months it reached 5.3 ± 0.4 %, well into the non-diabetic range (total Δ −2.1 ± 1.4 %, P < 0.001). Fasting blood glucose normalized, decreasing from 8.8 ± 2.0 to 5.3 ± 0.3 mmol/L at 6 months (Δ −3.5 ± 2.0 mmol/L, P < 0.05). Likewise, 2-h postprandial glucose fell dramatically from 16.5 ± 4.3 mmol/L at baseline to 7.4 ± 1.0 mmol/L at 6 months (Δ −9.1 ± 4.3 mmol/L, P < 0.05), indicating a restoration of postprandial normoglycemia. Notably, there were no significant changes between 3 and 6 months in FBG or 2h glucose (both P > 0.05 for 3 vs 6 months), suggesting that most patients achieved near-normal glycemic levels by 3 months which were then maintained. By the end of the intensive intervention, 705 of 1000 patients (70.5 %) met criteria for diabetes remission (Table 1), having an HbA₁c <6.5 % without medications, as noted above. Fig. 3 illustrates the time-course of these key glycemic parameters, with early and sustained improvements through 6 months.

Fig. 3.

Effects of 2+N system therapy on glycemic control. Changes in (A) fasting blood glucose (FBG; mmol/L), (B) glycosylated hemoglobin (HbA₁c; %), (C) fasting insulin (μU/mL) and (D) homeostasis model assessment of insulin resistance (HOMA-IR) at baseline, 3 months and 6 months. Data are presented as mean ± SD (n = 1000). Statistical methods and significance indicators as in Fig. 1. Abbreviations: FBG, fasting blood glucose; HOMA-IR, homeostasis model assessment of insulin resistance.

Improvements in insulin sensitivity accompanied the better glycemic control. The HOMA-IR index declined from a mean of 5.4 ± 2.6 at baseline to 3.1 ± 1.2 at 6 months (Δ −2.4 ± 2.4, P < 0.001), reflecting a significant reduction in insulin resistance. By 3 months, HOMA-IR had already dropped by ∼43 %, with no further change between 3 and 6 months (Table 2). Together with the marked reduction in glycemic load, the beta-cell function (HOMA-β) at 6 months increased significantly (as shown in Table 2), suggesting a substantial improvement in insulin secretion capacity. Taken together, these results indicate that the 2+N therapy led to near-normalization of glycemia in the majority of patients, primarily through weight loss and improved insulin sensitivity, enabling cessation of glucose-lowering medications in a large proportion of participants.

3.4. Lipid profile and uric acid improvements following the 2+N system therapy

Marked improvements in the lipid profile were observed in parallel with weight loss. Median fasting triglycerides (TG) declined dramatically from a high baseline of 6.04 mmol/L (IQR 3.70–8.66) to 1.39 mmol/L (IQR 0.95–3.22) at 6 months (P < 0.05) (mean change −4.9 ± 3.1 mmol/L). Total cholesterol was likewise reduced by nearly 50 %, from 7.41 ± 2.20 to 3.76 ± 0.86 mmol/L (Δ −3.6 ± 2.2 mmol/L, P < 0.05). LDL-C dropped from 3.42 ± 0.82 to 1.89 ± 0.92 mmol/L (Δ −1.53 ± 1.2

mmol/L, P < 0.05). HDL cholesterol showed a modest increase by 6 months (from ∼1.0 to ∼1.2 mmol/L on average), however, the increase was not statistically significant (Table 2). Fig. 4 depicts the changes in lipid parameters over time, highlighting the rapid normalization of TG and significant reductions in LDL-C and total cholesterol by 3 months of therapy.

Fig. 4.

Effects of 2+N system therapy on lipid profile and uric acid. Changes in (A) total cholesterol (TC; mmol/L), (B) triglycerides (TG; mmol/L), (C) high-density lipoprotein cholesterol (HDL-C; mmol/L), (D) low-density lipoprotein cholesterol (LDL-C; mmol/L) and (E) serum uric acid (UA; mg/dL) at baseline, 3 months and 6 months. Data are presented as mean ± SD (n = 1000). Statistical methods and significance indicators as in Fig. 1. Abbreviations: TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; UA, uric acid.

Systemic inflammation and metabolic indices also improved. Serum uric acid levels declined significantly with the intervention. Mean uric acid fell from 399 ± 95 μmol/L at baseline to 324 ± 55 μmol/L at 6 months (mean Δ −75 μmol/L, P < 0.05). The reduction in uric acid became significant by 6 months (there was a nonsignificant slight decrease at 3 months, followed by a larger drop by 6 months; Table 2). This trend suggests an improvement in metabolic health and possibly reduced insulin resistance (as hyperuricemia is often associated with insulin-resistant states). No cases of symptomatic gout were reported during the rapid weight loss phase (data not shown).

3.5. MRI-assessed hepatic and pancreatic fat reduction

As shown in Table 3 and Fig. 5, in a subset of 26 patients who underwent MRI quantification of ectopic fat, there were significant reductions in liver and pancreatic fat content after the intervention. At baseline, the median hepatic fat content was 16.3 % (IQR 12.7–28.4 %), which decreased to 11.6 % (IQR 10.1–12.3 %) following 1.5 months of 2+N therapy (P = 0.017). Pancreatic fat content was also substantially reduced. For example, median fat content in the pancreatic head fell from 5.75 % to 4.00 % (P = 0.009), and similar declines were observed in the body (5.70 %–4.72 %, P = 0.019) and tail of the pancreas (6.30 %–5.08 %, P = 0.002). Overall pancreatic fat (combined across regions) dropped from a median of 18.8 %–14.1 % (P = 0.002). These preliminary findings indicate a rapid mobilization of ectopic fat from the liver and pancreas early in the course of the intervention. Fig. 5 provides representative MRI scans from three patients before and after 1.5 months of therapy, illustrating the visible reduction in hepatic and pancreatic fat accumulation. Notably, decreased liver volume and brighter (less fat-dense) pancreatic tissue can be seen post-treatment, consistent with the quantitative fat fraction declines. This reduction in organ fat is important, as it likely underlies the improvements in hepatic insulin sensitivity and beta-cell function contributing to diabetes remission. Overall, the MRI results support the significant metabolic impact of the 2+N system therapy, demonstrating reductions in ectopic fat deposits alongside overall weight loss and improved metabolic outcomes.

Table 3.

Changes in the fat content (%) of the liver and pancreas based on MRI scan.

Variable FCP	Baseline	1.5 months	P-value
Right posterior lobe of the liver	4.95 (3.48–9.15)	3.71 (3.27–4.30)	0.015
Right anterior lobe of the liver	5.05 (3.60–9.23)	3.58 (3.10–4.43)	0.055
Left lobe of the liver	5.60 (4.90–10.05)	4.31 (3.75–4.81)	0.022
Total liver	16.25 (12.70–28.42)	11.55 (10.07–12.33)	0.017
Pancreatic head	5.75 (4.40–7.18)	4.00 (3.65–4.59)	0.009
Pancreatic body	5.70 (4.92–7.30)	4.72 (4.28–5.81)	0.019
Pancreatic tail	6.30 (5.57–8.22)	5.08 (4.63–5.42)	0.002
Total pancreatic	18.75 (15.42–21.77)	14.10 (12.70–15.78)	0.002

Abbreviations: FCP, percentage of fat content. Data are presented as percentage (%) or median (25 -75th) quartiles. Significant P values (P < 0.05) are presented in bold.

Fig. 5.

Representative MRI images of the liver and pancreas demonstrating changes in fat content before and 1.5 months after treatment. The images illustrate the alterations in fat deposition in both organs (liver and pancreas) following the intervention.

4. Discussion

The “2+N system therapy” evaluated in this study represents a comprehensive, multidisciplinary approach to the management of T2DM, integrating pharmacotherapy (both Western medicine and TCM), personalized nutrition, exercise regimens, and psychological support. In a cohort of 1000 patients, this intervention achieved a 70.5 % remission rate at 6 months, defined as HbA1c <6.5 % off all glucose-lowering medications for at least 3 months. Key metabolic improvements included a mean body weight reduction of 9.2 ± 4.3 kg (12.6 % of baseline), a BMI decrease of 3.2 ± 1.4 kg/m², and an HbA1c reduction of 2.1 ± 1.4 %. Indices of β-cell function (HOMA-β) improved by 87.9 ± 66.0, while insulin resistance (HOMA-IR) decreased by 2.4 ± 2.4, indicating enhanced insulin sensitivity. In a subgroup analysis using MRI (n = 26), liver fat content dropped by 28.8 % and pancreatic fat by 25.0 %, highlighting the therapy's impact on visceral adiposity, despite the MRI findings are quite preliminary.

These findings are highly significant in the context of the global T2DM epidemic, which affects over 460 million people and incurs substantial healthcare costs [2]. The high remission rate and metabolic improvements suggest that “2+N system therapy” could offer a scalable, non-surgical alternative to current T2DM management strategies, potentially reducing long-term complications such as cardiovascular disease and improving patient quality of life.

Remission rates achieved in previous trials have varied widely (ranging from 0 % to 100 %), depending on factors like study duration, study design and sample size [18]. Notably, the DiRECT reported a 46 % remission rate at 12 months in 149 participants in a randomized trial of intensive diet in primary care [12]. Our study observed 70.5 % at 6 months in a highly selected cohort; however, due to differences in population (Western population with 12-month follow-up versus Chinese population with 6-month follow-up) and design (randomized trial versus retrospective observational study), no direct comparison can be made. Some early pilot studies reported remission rates as high as 70–100 %, but those trials were of very short duration (5 weeks–6 months) and had very small sample sizes (n = 10) [[19], [20], [21]]. In a very recent trial (n = 72) assessing the efficacy of the intermittent fasting diets, it was found that after 3-month intervention plus 3-month follow-up, 47.2 % of participants (17/36) achieved diabetes remission after a 3-month intervention plus a 3-month follow-up in the Chinese Medical Nutrition Therapy (CMNT) group [22]. Our higher observed high remission rate likely reflects the enrolment of patients with a greater inherent propensity for remission. Accordingly, future controlled studies will be necessary to directly compare the effectiveness of this approach with other therapeutic strategies.

Metabolic surgery, widely regarded as a gold standard for T2DM remission, yields remission in about 23–60 % of cases depending on the procedure and patient characteristics [23]. For instance, Roux-en-Y gastric bypass achieves remission in approximately 40–60 % of cases, but its invasiveness, cost (estimated at $20,000-$30,000 per procedure), and risk of complications (e.g., nutrient deficiencies) limit its scalability [23]. The “2+N″ approach, being non-surgical, circumvents these barriers. The observed weight loss in our cohort (−9.2 kg) aligns with Taylor et al.’s threshold of 10–15 kg for remission [13].Additionally, a small MRI substudy (n = 26) further suggested reductions in hepatic and pancreatic fat, consistent with the twin cycle hypothesis of diabetes remission, but these data should be viewed as hypothesis-generating only [24]. The sample size was too small for definitive conclusions. Future studies with larger imaging sub-cohorts or whole-cohort non-invasive fat measures would be needed to confirm these effects.

Lifestyle-based interventions reveal additional strengths of the “2+N system therapy.” The Look AHEAD trial, a large-scale study of intensive lifestyle intervention (diet and exercise), achieved a modest HbA1c reduction of 0.6 % and weight loss of 8.6 % at 1 year in 5145 participants [14]. In contrast, the DiRECT trial found 46 % remission rate at 1 year with a very low-calorie diet intervention [12]. This context underscores that our observed remission rate is relatively high; however, it's important to note that our patients represented a select group and our follow-up period was relatively shorter (6 months). Systematic reviews indicate that acupuncture improves glycemic control (HbA1c reductions of 0.8–1.5 %) and reduces inflammation via vagal nerve modulation [25]. In our study, some patients (approximately 80 %) received acupuncture (TCM) therapies, though we did not specifically measure their individual impact. The precise contribution of TCM to the observed remission remains unclear. Notably, those who chose TCM therapy tended to be highly motivated, which may have significantly influenced the higher remission rates observed in our research. In addition, sex-specific differences also emerged, with men achieving a higher remission rate (74.6 %) than women (67.4 %), a pattern consistent with DiRECT and other studies linking male responses to higher remission rate, greater visceral fat loss and testosterone-mediated metabolic effects [26,27]. Moreover, a marked reduction in liver and pancreatic fat (28.8 % and 25.0 %, respectively) after 1.5 months of therapy provides preliminary evidence to support the efficacy of this approach, underpinning improvements in insulin sensitivity and glycemic control [28].

Furthermore, the multidisciplinary framework of “2+N,” including online and offline patient supports and close monitoring, likely boosted adherence—a critical determinant of success in lifestyle interventions, as evidenced by qualitative data from DiRECT participants [29]. In addition, unlike strict VLCD programs that carry risks of muscle loss and fatigue, our balanced regimen preserved lean mass, further supporting its practical utility. These practical advantages may have contributed to the overall favorable outcomes of the interventions.

At the physiological level, one factor contributing to the high remission rate may be the profound and rapid metabolic improvements associated with this multimodal approach. The substantial weight loss achieved by the 2+N therapy likely caused marked reductions in ectopic fat in the liver and pancreas, changes that have been shown to restore insulin sensitivity and improve β-cell function [13,28]. Early intensive insulin therapy and calorie restriction would further alleviate glucotoxicity and lipotoxicity, allowing β-cells to recover. In effect, the combined regimen may mimic the metabolic impact of bariatric surgery (which also reduces hepatic steatosis and yields high remission) without surgical intervention [23]. Clinically, the integration of pharmacological therapy, TCM approaches and structured lifestyle interventions may have contributed to the favorable outcomes observed in our cohort. However, the higher remission rate seen here compared with the 46 % reported in the 12-month DiRECT trial [12], should be interpreted cautiously, as differences in patient selection, study design, and program intensity likely account for much of this discrepancy. These observations suggest that addressing multiple pathophysiological factors of T2DM in parallel might support remission in some patients, in line with existing hypotheses of diabetes reversal [13,23].

The favorable remission rate observed in our study may also be attributable to several other factors. Firstly, the close connections between participants and healthcare providers enabled timely, personalized interventions. The use of an AI-enabled mobile app facilitated multiple components of the program, ensuring delivery of appropriate advice and prompt responses to participant feedback. Secondly, the multidisciplinary nature of the intervention—combining medication, TCM, diet, physical activity, and counselling support—was important. A study by Ried-Larsen et al. showed that lifestyle intervention alone, even with improved fitness, did not lead to an increased remission rate [27], emphasising the need for combined approaches. Thirdly, the relatively short duration of diabetes in our cohort may have contributed to the high remission rate. Remission of T2DM has been shown to depend on the underlying disease pathogenesis, particularly the extent of β-cell dysfunction. Steven et al. found that after an 8-week very low-calorie regimen (VLCR), patients who remained in remission at 6 months had a significantly shorter disease duration than those who did not achieve remission [30].

We did not conduct a formal cost-effectiveness analysis, and no quantitative data were collected for the 2+N system therapy. The approach is resource-intensive, involving a multidisciplinary team, app usage, and frequent clinic visits—about 15 per patient over 6 months, plus remote monitoring, costing around US$1500 per patient (estimated costs in Guangzhou, China), excluding research expenses. Although the initial cost is relatively high, achieving remission could result in significant long-term savings. However, scalability and reimbursement may be difficult without proven cost-effectiveness.

Despite these promising results, several limitations temper our conclusions. The real-word and single-arm study design lacked a concurrent control group, precluding definitive causal attribution of outcomes to the “2+N system therapy.” We cannot ascertain how much of the observed improvement was due to the intervention itself versus general trends (e.g., regression to the mean, increased medical attention) or other factors. The results must therefore be interpreted as descriptive outcomes in a motivated patient cohort rather than proof of efficacy Selection bias is a concern, as participants were motivated volunteers with preserved β-cell function (fasting C-peptide ≥1.1 ng/mL), a known predictor of remission success [31]. This may overestimate efficacy compared to broader T2DM populations with advanced β-cell decline. Our remission rate of 70.5 % was achieved in a best-case scenario group: relatively young (mean ∼58 years), recently diagnosed, not severely hyperglycemic, and highly motivated individuals. The 6-month follow-up period, while sufficient to establish short-term remission, cannot address durability; relapse rates in dietary interventions can exceed 50 % within 2 years [32]. The MRI subgroup (n = 26) was small and the data is rather preliminary, limiting the generalizability of visceral fat findings, though statistical significance (p < 0.01) was achieved. Resource intensity—requiring multidisciplinary teams, TCM expertise, and MRI access—may hinder implementation in low-resource settings, where T2DM prevalence is rising fastest [2]. Finally, variability in TCM formulations and practitioner skill could also affect reproducibility, a challenge noted in prior TCM trials [25].

5. Conclusions

In conclusion, the “2+N system therapy” offers a potent, non-surgical strategy for T2DM remission, achieving a 70.5 % remission rate through a holistic approach integrating pharmacotherapy, TCM, and lifestyle support to simultaneously address both metabolic and behavioral drivers of T2DM.These findings align with emerging paradigms of diabetes reversal [24] and highlight the potential of multidisciplinary care. However, due to the lack of a control group and the select nature of our cohort, these results should be interpreted with caution. Thus, prospective randomized controlled trials are essential to confirm efficacy and assess long-term remission in broader populations.

CRediT authorship contribution statement

Kejing Zeng: Writing – review & editing, Writing – original draft, Validation, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. Bo Chen: Writing – review & editing, Validation, Software, Resources, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation. Hejun Li: Writing – review & editing, Visualization, Validation, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation. Nina Ren: Writing – review & editing, Visualization, Validation, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation. Yingying Song: Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation. Minlin Liang: Writing – review & editing, Visualization, Software, Methodology, Investigation, Formal analysis, Data curation. Yin Yang: Writing – review & editing, Validation, Resources, Methodology, Investigation, Formal analysis, Data curation. Yali Huang: Writing – review & editing, Validation, Software, Methodology, Investigation, Formal analysis, Data curation. Ting Liu: Writing – review & editing, Validation, Resources, Methodology, Investigation, Formal analysis, Data curation. Yiguang Lin: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Conceptualization. Gugen Xu: Writing – review & editing, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Conceptualization.

Funding

This work was supported by multiple research grants from: the National Natural Science Foundation of China (81902004), Distinguished Young Scientists projects(also called Siqing Talent project) by Guangdong Second Provincial General Hospital (#2024E005), the Basic and Applied Basic Research Foundation of Guangdong Province (#2023A1515012575), Guangzhou Municipal Bureau of Science and Technology Municipal Schools (Institutes) Joint Funding (Dengfeng Hospital) Basic Research Project (#202201020567).

Conflict of interest statement

There is no conflict of interest.

Appendix A. Supplementary data

The following is the supplementary data to this article:

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.