Remissione del diabete nel diabete mellito di tipo 2 di nuova diagnosi mediante terapia intensiva a breve termine con infusione sottocutanea continua di insulina combinata con un trattamento dietetico a basso contenuto di carboidrati

INTRODUCTION

Diabetes mellitus (DM) has become a major public health concern worldwide, with the incidence of type 2 diabetes mellitus continuing to rise in recent years . Treatment of DM aims to control blood glucose levels and effectively manage the complications and effects of this disease , . However, maintaining consistent optimal glycemic control remains a major challenge in managing patients diagnosed with type 2 diabetes mellitus, the approach to which has undergone a substantial conceptual shift, with treatment objectives focusing on integrated management to achieve remission. According to consensus guidelines from the American Diabetes Association (ADA), diabetes remission is defined as achieving a glycated hemoglobin A1c (HbA1c) <6.5% at least 3 months after withdrawal of antidiabetic drugs at baseline .

The administration of short‐term intensive insulin therapy early in the course of type 2 diabetes mellitus has been an effective strategy for controlling blood glucose levels and reversing pancreatic β‐cell dysfunction by eliminating of glucotoxicity and pancreatic β‐cell overload , . Weng et al . found that early intensive insulin therapy in patients with newly diagnosed type 2 diabetes mellitus yielded favorable outcomes in recovery and maintenance of β‐cell function and protracted glycemic remission. More patients achieved target glycemic control and spent less time in the continuous subcutaneous insulin infusion (CSII) group than those treated with multiple daily injections. Patients with newly diagnosed type 2 diabetes mellitus can be treated with short‐term intensive insulin therapy when HbA1c ≥9% or fasting plasma glucose (FPG) ≥11.1 mmol/L, or accompanied by obvious symptoms of hyperglycemia . Short‐term CSII can effectively control hyperglycemia in patients with type 2 diabetes mellitus and achieve diabetes remission in some cases . However, CSII is influenced by various factors during its implementation, including frequent glucose monitoring, hypoglycemia, and lifestyle management models , . Continuous glucose monitoring (CGM) is increasingly recognized as a method for monitoring blood glucose levels in managing DM. Compared with traditional peripheral blood glucose monitoring methods, CGM can provide detailed information regarding glycemic variability through a standardized ambulatory glucose profile that presents a comprehensive picture of glucose fluctuations throughout the day over an extended period. This enables the quantification of glucose variability and detection of potential episodes of asymptomatic hypoglycemia and hyperglycemia , . Furthermore, the time in range (TIR), standard deviation (SD), and coefficient variation (CV) are important parameters that can be assessed using CGM data . Liu et al .'s study aimed to investigate the role of TIR as a novel glycemic target during short‐term intensive insulin therapy in predicting clinical outcomes. TIR ≥65% has been recommended as a glycemic indicator for short‐term intensive insulin therapy in patients with newly diagnosed type 2 diabetes mellitus for clinical decision making . TIR may be considered the preferred metric for determining the outcomes of clinical studies and assessing of an individual patient's glycemic control levels in individual patients . Therefore, CGM was used for blood glucose monitoring and adjustment of insulin dosage.

An intensive lifestyle intervention approach including adjusting the diet structure, reducing calorie intake, and increasing physical activity levels, contributes to diabetes remission . The Standards of Medical Care in Diabetes from the ADA recognize low‐carbohydrate nutritional therapy as a viable component in the management of type 2 diabetes mellitus . Reducing overall carbohydrate intake for individuals with type 2 diabetes mellitus has provided the most evidence for improving glycemia and may be applied to dietary patterns that meet individual needs and preferences . Furthermore, low‐carbohydrate diet (LCD) patterns have been shown to reduce HbA1c levels and medication burden and contribute to significant weight loss . Therefore, we recommend an LCD eating pattern for patients undergoing intensive therapy to identify those most likely to benefit from type 2 diabetes mellitus therapy.

This study optimized type 2 diabetes mellitus remission therapy during the implementation of CSII. Therefore, we prescribed intensive CSII therapy combined with LCD lifestyle guidance for patients newly diagnosed with type 2 diabetes mellitus and compared it with conventional CSII therapy and traditional lifestyle guidance. CGM was used to monitor blood glucose levels and guide management, and the therapeutic effects and related factors for influencing type 2 diabetes mellitus remission were analyzed.

MATERIALS AND METHODS

### Study population

The present study included hospitalized patients 18–60 years of age who were newly diagnosed with type 2 diabetes mellitus defined as the first diagnosis of type 2 diabetes mellitus in accordance with criteria from the World Health Organization . Patients treated with hypoglycemic or lipid‐lowering drugs, pregnant women, patients with complications of acute or severe chronic diabetes, severe concomitant disease, type 1 diabetes mellitus, latent autoimmune diabetes in adults, and those with secondary diabetes were excluded from the study. Patients included in this study were randomly assigned to either a conventional treatment group or an intensive treatment group. The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and adheres to the principles outlined in the Declaration of Helsinki. Medical Ethics Committee of the First People's Hospital of Nanning granted Approval No. 2022‐055‐01. All participants signed informed consent forms.

### Study procedures

During hospitalization, patients in the conventional and intensive treatment groups underwent an educational program on DM management that included food intake guidance, exercise advice, and lifestyle management. Calories were calculated by a nutritionist. Insulin lispro (Humalog, Eli Lilly and Company, Indianapolis, IN, USA) was administered using an insulin pump (Medtronic Inc., Minneapolis, MN, USA) to control patient blood glucose levels via CSII.

The conventional treatment group received conventional CSII therapy and traditional lifestyle guidance. The initial insulin dose was calculated to be 0.5–0.8 IU/kg, with gradual increases until target blood glucose levels were achieved. The total insulin infusion for the basal dose and pre‐meal dose accounted for 50% each, with the initial total basal dose administered evenly throughout 24 h, and the total pre‐meal dose divided equally before each meal. The target FPG level in the conventional treatment group was <6.1 mmol/L and 2 h plasma glucose (2 h PG) <8.0 mmol/L. Patients in the conventional treatment group were provided with a traditional diet consisting of 55–60% carbohydrate, 10–15% protein, and 25–30% fat, along with exercise guidance that encouraged starting exercise at least 30 min after meals, with a frequency of 3–5 times per week.

Patients in the intensive treatment group received intensive CSII therapy and LCD lifestyle guidance based on an initial insulin amount estimated according to 0.35 × body weight (kg) + 2.05 × FPG (mmol/L) + 4.24 × triglyceride (TG) (mmol/L) + 0.55 × waist circumference (cm) − 49.1. The target goal for FPG level was set between 4.4 and 5.6 mmol/L, and 2 h PG level was set between 4.4 and 7.6 mmol/L. The glycemic target was achieved within 3–4 days . Patients in the intensive group also received intensive lifestyle management, which included following an LCD pattern consisting of 35–40% carbohydrate, 20–30% protein, 30–45% fat. They were provided with suggestions for vegetable recipes, high‐quality protein foods, and nuts to enhance their compliance and vary their daily food intake . They were also encouraged to drink at least 2 L of water each day and engage in combined aerobic resistance training exercises lasting 30–45 min after each meal for 5–6 days per week .

### CGM monitors blood glucose levels

A CGM System (GS1Sb; SIBIONICS, Shenzhen, China) was used to monitor patient blood glucose levels, help adjust the insulin dose, and manage blood glucose levels in the conventional and intensive treatment groups. CGM metrics, including mean glucose (MG), SD, CV, time above range (TAR, blood glucose levels ≥10.0 mmol/L), TIR (blood glucose levels: 3.9–10.0 mmol/L), and time below range (TBR, blood glucose levels ≤3.9 mmol/L), were collected. Patients were made aware of hypoglycemic manifestations, such as palpitations, hand tremors, and cold sweats. CGM set blood glucose level to 3.9–10.0 mmol/L, and when the patient's blood glucose was outside this range, CGM alerted for hypoglycemia or hyperglycemia. Patients completed daily food and exercise records using the CGM system to document dietary intake and physical activity for analysis.

### Clinical and biochemical assessment

Clinical data and biochemical indicators were collected at baseline and 3 months thereafter. General clinical information included age, sex, height, weight, body mass index (BMI), and waist circumference. The primary outcome was HbA1c levels, an indicator of DM remission. FPG, 2 h PG, fasting C‐peptide, fasting serum insulin (FINS), total cholesterol (TC), TG, high‐density lipoprotein cholesterol (HDL‐c), and low‐density lipoprotein cholesterol (LDL‐c) were measured in patients. Homeostasis Model assessment of Insulin Resistance (HOMA‐IR) was assessed with the following formula: FINS (μIU/mL) × FPG (mmol/L)/22.5. Homeostasis Model β‐cell function (HOMA‐β) was assessed with this formula: [20 × FINS (μIU/mL)]/[FPG (mmol/L)‐3.5]. Diabetes remission observed to be an HbA1c level <6.5% after the 3‐month withdrawal from the medication.

### Measurement of fat area

The visceral fat area (VFA) and subcutaneous fat area (SFA) were assessed using a direct segmental multifrequency bioelectrical impedance analysis method (Inbody 770; Biospace Co. Ltd., Seoul, South Korea). Following an overnight fast, all patients underwent anthropometric evaluations, including height, weight, and waist circumference. Each patient was instructed to maintain a supine posture for at least 10–15 min before the measurements began. Eight tetrapolar adhesive electrodes (two for each hand and foot) were then attached to the participant to obtain 30 impedance measurements across 6 frequencies (1, 5, 50, 250, 500, and 1,000 kHz), as well as 15 reactance and phase angle measurements across three frequencies (5, 50, and 250 kHz) at each of 5 body segments (left arm, right arm, trunk, left leg, and right leg).

### Statistical analysis

Statistical analyses were performed using SPSS version 23.0 (IBM Corporation, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables were expressed as percentages (%), and the normality of the data was verified. Differences in variables between the two groups were compared using the t ‐test (normally distributed data) or Mann–Whitney test (non‐normally distributed data). The chi‐square test was used to compare the diabetes remission rate between the two groups. Pearson correlation (normally distributed data) or Spearman correlation coefficients (non‐normally distributed data) were calculated for correlation analysis. Differences with two‐sided P < 0.05 were considered to be statistically significant.

RESULTS

### Participant characteristics at baseline

A total of 120 hospitalized patients with newly diagnosed type 2 diabetes mellitus were recruited for this study and randomly divided into either a conventional or intensive treatment group ( n = 60 each). The baseline characteristics of patients at the beginning of treatment are summarized in Table . The patients had a mean (±SD) age of 40.44 ± 9.77 years, weight of 73.30 ± 10.78 kg, BMI of 26.65 ± 3.31 kg/m 2 , and waist circumference of 92.14 ± 10.73 cm. The patients exhibited high blood glucose levels: HbA1c 11.89 ± 2.31%; and FPG 12.71 ± 2.82 mmol/L. Most patients had insulin resistance: HOMA‐IR 5.07 ± 3.56; impaired β‐cell function, HOMA‐β 21.47 ± 16.07%; lipid metabolism disorders, TC 6.41 ± 1.29 mmol/L, TG 4.09 ± 2.40 mmol/L, HDL‐c 1.00 ± 0.28 mmol/L, LDL‐c 3.26 ± 1.10 mmol/L; VFA 120.07 ± 35.28 cm 2 ; and SFA 203.22 ± 62.64 cm 2 . There were no significant differences in anthropometric, glucose, or lipid metabolism data between the two groups ( P > 0.05).

### CGM monitors blood glucose levels

The characteristics of CGM metrics were analyzed. Hyperglycemia was observed at the beginning of hospitalization in the conventional treatment and intensive treatment groups. The CSII controlled blood glucose levels for 2 weeks, and the CGM blood glucose data adjusted the insulin dosage. The conventional treatment group controlled blood glucose at the predetermined target for 1 week, whereas the intensive treatment group controlled blood glucose at the predetermined target for 3–4 days.

During hospitalization, MG was 8.41 ± 1.38 mmol/L in the conventional treatment group and 6.19 ± 0.76 mmol/L in the intensive treatment group. The MG, SD, and CV values in the intensive treatment group were lower than those in the conventional treatment group ( P < 0.05). The mean TIR of the conventional and intensive treatment groups were 81.75 ± 9.18% and 93.72 ± 2.52%, respectively. The TIR in the intensive treatment group was higher than that in the conventional treatment group ( P < 0.05). In addition, the mean TBR of the conventional and intensive treatment groups were 1.93 ± 1.58% and 1.97 ± 1.41%, respectively. There was no difference in the incidence of hypoglycemia between the two groups ( P > 0.05), and no serious hypoglycemia occurred (TBR <3.0 mmol/L (%)). Patients in the intensive treatment group experienced 3–4 episodes of mild hypoglycemia after daytime exercise during the insulin reduction period, which was rapidly corrected by reducing the insulin infusion dosage and eating food (Table ).

At the 3‐month follow‐up, the MG level in the conventional and intensive treatment groups were 7.22 ± 1.02 and 5.61 ± 0.55 mmol/L, respectively ( P < 0.05). The CV of the conventional and intensive treatment groups were 29.79 ± 5.41% and 17.66 ± 3.34%, respectively. The TIR of the conventional and intensive treatment groups were 78.58 ± 7.11% and 98.42 ± 0.76%, respectively ( P < 0.05). Blood glucose levels in the intensive treatment group were stable, whereas those in the conventional treatment group fluctuated greatly. TIR in the intensive treatment group was significantly higher than that in the conventional treatment group ( P < 0.05), and there was no occurrence of severe hyperglycemia in the intensive treatment group (TAR >13.9 mmol/L (%)) (Table ).

### Remission of type 2 diabetes mellitus

After withdrawal of CSII treatment, 97% of the 57 patients in the conventional treatment group were treated with various antidiabetic drugs, whereas only 32% of the 19 patients in the intensive treatment group required one antiglucose drug (metformin, SGLT‐2, or GLP‐1). At the 3‐month follow‐up, HbA1c levels in the conventional and intensive treatment groups were 7.35 ± 0.71% and 6.03 ± 0.56%, respectively. In the conventional treatment group, only 2 (3%) patients achieved type 2 diabetes mellitus remission, while in the intensive treatment group, a remarkable 41 (68%) patients achieved remission. The diabetes remission rate was significantly higher in the intensive treatment group that in the conventional treatment group ( P < 0.05).

Changes of glucose and lipid metabolism indices of patients in the two groups before and after treatment, and the factors influencing diabetes remission were analyzed. There was a decrease of 4.03 ± 1.59 kg in body weight, 1.44 ± 0.56 (kg/m 2 ) in BMI, 6.40 ± 6.07 (cm) in waist circumference, 28.10 ± 16.90 (cm 2 ) in VFA, and 43.75 ± 52.12 (cm 2 ) in SFA from baseline to 3‐month follow‐up in the intensive treatment group compared with before treatment. These changes were significantly greater in the intensive treatment group than in the conventional treatment group ( P < 0.05). Compared with the conventional treatment group, FPG, HbA1c, HOMA‐IR, TG, and LDL‐c decreased significantly in the intensive treatment group ( P < 0.05). Additionally, there were no significant differences in HDL‐c levels, HOMA‐β, and SFA values between the two groups ( P > 0.05). (Table ). Results of correlation analysis indicated that HbA1c was significantly correlated with FPG, HOMA‐IR, TG, LDL‐c, and changes in body weight, BMI, waist circumference, and VFA ( P < 0.05) (Table ).

DISCUSSION

Insulin dose adjustments, glucose monitoring, and hypoglycemic events affect the implementation of type 2 diabetes mellitus remission therapy. We used CGM to monitor blood glucose levels and adjust the insulin dose in patients receiving CSII during hospitalization. In this study, the intensive treatment group controlled their blood glucose levels at a predetermined target for 3–4 days. The mean values of MG, SD, and CV in the intensive treatment group were lower than those in the conventional treatment group ( P < 0.05), and the TIR in the intensive treatment group was higher than that in the conventional treatment group ( P < 0.05). During follow‐up, blood glucose levels in the intensive treatment group were stable, whereas those in the conventional treatment group fluctuated greatly. Compared with traditional monitoring using blood glucose meters, CGM provides glucose measurements, low‐ and high‐glucose alerts, and trend information . Lind et al . found that, in patients with inadequately controlled insulin‐treated type 2 diabetes mellitus, CGM had an impact superior to peripheral blood glucose monitoring in improving overall blood glucose control and other important health parameters. A high percentage of patients with type 2 diabetes mellitus receiving insulin injections who used CGM experienced improved blood glucose control, suggesting the potential benefits of this additional management approach . Furthermore, CGM demonstrated higher sensitivity and specificity for detecting hypoglycemia. CGM is capable of identifying episodes of hypoglycemia at a higher percentage , . In this study, hypoglycemia mainly occurred after postprandial exercise and was accompanied by symptomatic cold sweats, mild palpitations or asymptomatic hypoglycemia. No serious hypoglycemia occurred in the conventional and intensive treatment groups. CGM can detect mild or asymptomatic hypoglycemia and promptly adjust insulin dose. The use of CGM guidance to adjust insulin therapy was safe and effective, significantly reducing the incidence of hypoglycemic events . Bergenstal et al . reported that CGM was more effective than traditional peripheral blood glucose monitoring in reducing hypoglycemia, particularly in patients undergoing higher‐risk therapies for hypoglycemia. Therefore, CGM may be helpful for insulin regulation and blood glucose management during diabetes remission therapy in patients with type 2 diabetes mellitus.

Recently, LCD patterns have been advocated as valid and effective therapeutic options for both type 2 diabetes mellitus and obesity. Compared with conventional CSII treatment and lifestyle guidance, we evaluated the benefits of LCD patterns for diabetes remission in patients newly diagnosed with type 2 diabetes mellitus who received intensive CSII therapy. Our results revealed that patients in the intensive treatment group exhibited significantly higher type 2 diabetes mellitus remission rates than those in the conventional treatment group and exhibited significant improvements in weight, blood glucose, HOMA‐IR, TG, LDL‐c, and VFA. In a clinical trial, involving patients newly diagnosed with type 2 diabetes mellitus who consumed <30 g of carbohydrates per day for 90 days, a significant decrease in HbA1c levels was observed . Saslow et al . suggested that patients with type 2 diabetes mellitus may be able to improve their blood glucose control with less medication through a moderate reduction in carbohydrate intake over a 12‐month period. Unwin et al . demonstrated that choosing an LCD pattern for an average of 23 months led to a 46% drug‐free type 2 diabetes mellitus remission rate in primary care settings in the United Kingdom as well as significant improvements in weight, blood pressure, and lipid profiles. A systematic review of the effect of LCD on type 2 diabetes mellitus remission indicated that LCD was associated with an increase in diabetes remission rates . Therefore, we recommend intensive CSII therapy and LCD lifestyle guidance to increase diabetes remission rates and improve glucose and lipid metabolism in patients with type 2 diabetes mellitus.

This study investigated the primary factors influencing HbA1c levels. Our correlation analysis revealed a significant positive correlation between FPG, HOMA‐IR, and HbA1c levels. Zou et al . demonstrated that a reduction in FPG levels following lifestyle medicine intervention was primarily responsible for a decrease in HbA1c levels. A prospective study of patients with type 2 diabetes mellitus who underwent metabolic surgery reported significant improvements in FPG and HOMA‐IR levels in those who achieved type 2 diabetes mellitus remission post‐surgery . Our correlation analysis also indicated a significant association between diabetes remission and changes in weight, waist circumference or BMI loss, which is consistent with the findings of another study, in which diabetes remission may be achieved through changes in weight or BMI . Intensive CSII and LCD lifestyle management also had health benefits for lipid metabolism, as indicated by improvements in several parameters including TG, LDL‐c, and VFA. The reductions in TG, LDL‐c, and VFA levels in the intensive treatment group were significantly greater than those in the conventional treatment group. Sun et al . reported a positive association between TG, VFA, and blood glucose control patients with type 2 diabetes mellitus . Additionally, Liu et al . demonstrated that TG was the main factor influencing blood glucose levels, whereas VFA was not a reliable predictor of insulin resistance among individuals with newly diagnosed type 2 diabetes mellitus . Therefore, FPG, HOMA‐IR, TG, LDL‐c, and changes in body weight, BMI, waist circumference, and VFA may be influencing factors for diabetes remission.

In summary, results of the present study demonstrated that intensive CSII therapy combined with an LCD lifestyle induced remission of new‐onset type 2 diabetes mellitus, with FPG, HOMA‐IR, TG, LDL‐c, and changes in body weight, BMI, waist circumference, and VFA representing influential factors. However, this study had some limitations, the first of which was its single‐center design; as such, the generalizability of the results to different regions requires further validation. Moreover, longer‐term follow‐up studies are warranted.

DISCLOSURE

The authors declare no conflict of interest.

Approval of the research protocol: This study was approved by the Medical Ethics Committee of the First People's Hospital of Nanning (Approval No. 2022‐055‐01). The study was carried out following the Declaration of Helsinki, including written informed consent from all participants.

Informed consent: Informed consent was obtained from all patients before the commencement of the study.

Registry and the registration no. of the study/trial: The study was registered on 30 May 2024 at the Chinese Clinical Trial Registry (ChiCTR) (Registered no. ChiCTR2400084765).

Animal studies: N/A.