Mulberry Twig Alkaloids Combined With Insulin Infusion: Effects on Blood Glucose Variability in Type 2 Diabetes

Abstract

Background

Glycemic variability is increasingly recognized as an important contributor to the development of diabetes-related complications in patients with type 2 diabetes mellitus (T2DM). Continuous subcutaneous insulin infusion (CSII) is effective in improving glycemic control; however, fluctuations in blood glucose can persist. Mulberry twig alkaloids (MTA), a traditional Chinese medicine component with hypoglycemic properties, have shown potential benefits in regulating glucose metabolism. This study aimed to evaluate whether MTA combined with CSII could further improve glycemic variability and symptoms recognized by traditional Chinese medicine (TCM) in patients with T2DM.

Material/Methods

Sixty hospitalized patients with T2DM were randomly assigned to a control group (CSII alone, n=30) or an MTA group (MTA tablets plus CSII, n=30). Flash glucose monitoring was used to assess glycemic variability indicators, including mean blood glucose (MBG), standard deviation of blood glucose (SDBG), coefficient of variation (CV), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), time in range (TIR, 3.9–10 mmol/L), time above range (TAR), and time below range (TBR) over 14 days. TCM symptom scores were evaluated before and after treatment.

Results

After 14 days, MODD, MAGE, TAR, and TBR were significantly lower in the MTA group compared with the control group (all P<0.05), while TIR was significantly higher (P<0.01). Additionally, the TCM symptom score was markedly reduced in the MTA group compared with the control group (P<0.05).

Conclusions

Our findings suggested that CSII combined with mulberry twig alkaloids can improve blood glucose variability and relive TCM symptoms in T2DM patients.

Chinese Clinical Trail Registry (NO. ChiCTR 2200062688)

Introduction

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronically elevated blood glucose level due to insufficient insulin secretion and/or insulin resistance, the incidence of which has continued to rise in recent years. The International Diabetes Federation (IDF) estimated that the prevalence of diabetes is likely to reach 700 million by 2045, due to the rising incidence of obesity, population aging, and pandemics of infectious diseases such as coronavirus pneumonia [1]. As the disease progresses, most diabetic patients have a gradual decrease in pancreatic β-cell function and reduced ability to regulate blood glucose, resulting in large fluctuations in blood glucose levels [2], which can lead to long-term T2DM complications via activation of oxidative stress, exacerbation of inflammation, and damage to endothelial cells [3]. Therefore, the harm of poor blood variability is worse than that of long-term hyperglycemia. For patients with T2DM, choosing an appropriate anti-hyperglycemia treatment to restore the damaged islet β-cell function and effectively control blood glucose variability is the key to diabetes management.

Mulberry twig alkaloids (MTA) are active polyhydroxy alkaloids extracted from Morus alba L. twigs, a medicinal plant. The total alkaloid content can reach 50% in MTA, and its main active components are 1-deoxynojirimycin (DNJ), trigonelline, and tyrosol [4]. MTA has been reported as a natural α-glucosidase inhibitor and it lowered fasting glucose level and prolonged peak glucose concentration after starch loading [5,6]. Continuous subcutaneous insulin infusion (CSII) is a widely recognized insulin pump-based intensive treatment method. By simulating the physiological secretion of insulin, it delivers basal insulin continuously over 24 hours along with pre-prandial bolus doses, which can rapidly control blood glucose, eliminate the toxic effects of hyperglycemia, and reduce glucose viability. CSII therapy has become a relatively common clinical treatment for diabetic patients [7]. CSII primarily works by supplementing exogenous insulin to mimic physiological insulin secretion. It maintains stable fasting and pre-prandial blood glucose levels through basal insulin infusion, inhibits hepatic glycogenolysis and gluconeogenesis, and prevents excessive fasting blood glucose or nocturnal hypoglycemia. Pre-prandial bolus doses can counteract postprandial blood glucose elevation and reduce postprandial blood glucose peaks. However, it has no direct effect on the intestinal absorption of carbohydrates. If the proportion of carbohydrates in a patient’s diet is too high or digestion is too rapid, CSII alone may require a larger dose of pre-prandial insulin, which easily leads to increased postprandial blood glucose fluctuation or a risk of hypoglycemia in the late phase of the insulin action peak.

By inhibiting α-glucosidase, MTA slows the rate of carbohydrate breakdown into glucose, allowing glucose to enter the bloodstream slowly. This mechanism fundamentally reduces the sudden rise in postprandial blood glucose [5]. It precisely compensates for CSII’s inadequacy in regulating carbohydrate absorption, lowers the difference between postprandial blood glucose peaks and pre-prandial blood glucose levels, and reduces postprandial blood glucose variability. Meanwhile, due to the delayed absorption of glucose, the insulin demand curve becomes flatter and more aligned with the insulin action curve of CSII infusion, avoiding blood glucose fluctuation caused by the asynchrony between insulin action and glucose absorption. When used together with MTA, CSII can accurately supplement insulin and regulate the overall balance of blood glucose metabolism, while MTA delays carbohydrate absorption and optimizes the pattern of postprandial blood glucose elevation. CSII combined with MTA can effectively narrow the range of blood glucose fluctuation and brings blood glucose closer to the stable level under physiological conditions.

Xiaoke disease is a classic disease term in traditional Chinese medicine (TCM), which mainly corresponds to diabetes mellitus (DM) in modern Western medicine. The typical symptoms of Xiaoke disease, often summarized as “three polys (polydipsia, polyphagia, polyuria) and one emaciation” in TCM theory, are consistent with the common symptoms of diabetes. As a Chinese original antihyperglycemic drug, MTA tablet was released in 2020 to treat Xiaoke [8], and several studies showed that MTA can reduce blood glucose fluctuation by alleviating insulin resistance, increasing insulin secretion, and regulating the gut microbiota [9–11]. CSII was commonly used to treat poorly controlled diabetes mellitus with obvious blood glucose variability [12,13]. Few studies have assessed the effects of MTA and its combination with CSII in controlling blood glucose variability. The flash glucose monitoring system (FGM) can monitor blood glucose for 24 hours and is widely used to evaluate short-term glucose variability [14]. Therefore, we aimed to investigate the use of FGM in the practice of the combined scheme to treat type 2 diabetes and observe the effects of MTA+CSII on the blood glucose variability.

Material and Methods

This trial was approved by the Ethics Committee of Chu Hisen-I Memorial Hospital of Tianjin Medical University in accordance with the ethics standards of the Declaration of Helsinki and local regulatory requirements. All enrolled patients signed informed consent forms and the consent for publication of any potentially identifiable data or images. All the patients’ personal data was filed in the ethics department of the hospital and patient confidentiality was maintained throughout the study. This study was registered with the Chinese Clinical Trail Registry (NO. ChiCTR 2200062688) and it was a single-center randomized controlled study.

Study design and subjects

We enrolled 60 hospitalized patients with type 2 diabetes in the Department of Integrated Chinese Medicine and Western Medicine of Chu Hisen-I Memorial Hospital of Tianjin Medical University from October 2023 to February 2024.

The a priori power analysis was performed with G*Power 3.1.9.7. by using a two-tailed α=0.05, 1-β=0.80, effect size=0.5, and 2 groups. The analysis yielded a minimum required total sample of N=60 (30 patients per group).

Blinding: (1) Participants were blinded to group allocation; (2) Treating physicians and nurses were not blinded (responsible for insulin administration and insulin titration); (3) Outcome investigators (for TCM scores, glycemic variability indicators) were not blinded; (4) Data analysts were blinded to group allocation during statistical analysis.

Inclusion criteria: type 2 diabetic patients diagnosed by the WHO criteria of 1999, duration of diabetes from 1 month to 10 years, age 18–60 years, baseline hemoglobin A1c (Hb_A1c) level 9.0–15.0%, body mass index (BMI) 24–35 kg/m², and no intention to undergo computed tomography or magnetic resonance imaging during the study.

Exclusion criteria: type 1 diabetes, severe diabetic complications such as diabetic ketoacidosis, coronary artery disease, severe liver or kidney diseases, infectious or gastrointestinal diseases, intolerance to α-glucosidase inhibitor, pregnancy or breast-feeding, receiving other α-glucosidase inhibitor, and other reasons making them unsuitable for this trial.

The diagnostic criteria for Xiaoke referred to the 2007 edition of “Guide to the Prevention and Treatment of Diabetes Mellitus by TCM (Chinese)”. The primary symptoms (dry mouth and pharynx, tiredness, and fatigue) and secondary symptoms (thirst, shortness of breath, lethargy, spontaneous sweating, night sweating, palpitations, and insomnia) were combined for diagnosis.

Randomization and Treatment

Once enrolled, sealed numbers were generated consecutively for subjects and they were randomly assigned to the MTA group and control group according to the number at a 1: 1 ratio. After enrollment, all subjects received insulin aspartate (NoVo Rapid, 3 ml: 300 u, Novo Nordisk China Pharmaceutical Co., Ltd.) by continuous subcutaneous insulin infusion with an insulin pump (MiniMed 722, Medtronic, USA). The MTA group was treated with MTA (Beijing WuheBoao Pharmaceutical Co., Ltd.) 50 mg, 3 times per day based on the CSII. The initial insulin dosage was 0.5 IU/kg/day and the basal infusion was 50% of the total daily dosage. The other 50% was distributed as bolus dosage at each meal.

During the treatment, all subjects wore a FGM device (Abbott, USA) to monitor blood glucose fluctuation. The probe of FGM device was implanted by a single nurse who was specialized in diabetes care. The target of fasting blood glucose (FPG) was <7.0 mmol/L and postprandial blood glucose <10.0 mmol/L. Blood glucose is considered to normal at 7 to 10 mmol/L. A team of 2 dedicated endocrinologists, who strictly followed a standardized insulin titration protocol, adjusted the basal and bolus doses of insulin infusion by 2 to 8 units daily to maintain blood glucose within the target range throughout the study. The insulin dosage was adjusted according to the FGM results, which needed no calibration for analysis.

Throughout the trial, all subjects were provided with education on diabetic diet and exercise guidance. The daily diabetic diet was 50% of carbohydrate (300 g rice or noodle),15% fat, and 35% protein. For daily physical exercise, the diabetes education nurse led all subjects in performing traditional Chinese tai chi for 30 min after each meal.

Adverse events (AEs) were identified in the following methods: 1) Daily structured inquiries by nursing staff; 2) Spontaneous reporting by patients; 3)Clinical observation during routine assessments and recorded by using a standardized AE reporting form, including details on onset time, duration, symptoms, and interventions.

General Information

We collected information on age, sex, duration of diabetes mellitus, blood pressure, BMI, insulin dosage, and FGM indicators on the first day of enrollment. The fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, glomerular filtration rate, and urine albumin were measured.

Flashing glucose Monitoring (FGM) Indicators

Intra-day blood glucose variability indicators were mean blood glucose level (MBG), standard deviation (SDBG), average blood glucose fluctuation range (MAGE), coefficient of variation (CV), mean of daily difference (MODD), percentage of time in the target range between 3.9 and 10.0 mmol/L (TIR), percentage of time below the target range <3.9 mmol/L (TBR), and percentage of time above the target range >10.0 mmol/L (TAR).

TCM Syndrome Score

The TCM syndrome score was collected at enrollment and after 14 days of treatment.

The main symptoms (tiredness and fatigue, dry mouth and throat, thirst, shortness of breath, palpitations, insomnia, spontaneous sweating, and night sweating) were scored as mild (2 points), moderate (4 points), or severe (6 points). The total points were calculated for each group.

Statistical Methods

SPSS 23.0 software was used to perform statistical analysis. For normally distributed variables, a paired t test was used to compare intra-group differences and the independent t test was used to compare differences between groups. Wilcoxon’s rank test was used for non normally distributed continuous variables. The chi-square test was used to analyze the differences in proportions. Differences were considered statistically significant at P<0. 05. We calculated 95% confidence intervals (CI) for the TCM symptom score mean change from baseline.

Results

Comparison of General Information Between Groups

There were no dropouts and no missing data throughout the trial. The general information and clinical characteristics of groups are summarized in Table 1. The groups were similar in sex, age, duration of diabetes mellitus, blood pressure, body mass index, glomerular filtration rate, fasting blood glucose, postprandial 2-hour blood glucose, glycosylated hemoglobin, proportion of diabetic retinopathy and neuropathy, microalbuminuria, and blood glucose fluctuation indexes (MBG, SDBG, CV) on the first day of enrollment (all P>0.05) (Table 1).

Table 1.

Demographic and baseline characteristics.

	Control group (n=30)	MTA group (n=30)	P value
Sex (M/F)	18/12	17/13	0.789
Age (years)	51.12±11.09	50.44±9.89	0.878
Duration of diabetes (year)	5.99±4.23	6.54±4.09	0.611
BMI (kg/m2)	26.66±3.12	27.12±2.98	0.879
HbA1c (%)	9.29±1.04	10.06±1.52	0.617
eGFR (mL/min/1.73 m2)	96.61±9.44	101.11±8.41	0.406
FPG (mmol/L)	11.44±3.26	10.87±3.07	0.354
2hPG (mmol/L)	15.24±5.22	16.41±4.98	0.118
MBG (mmol/L)	9.89±1.11	10.21±1.09	0.643
SDBG (mmol/L)	1.86±0.59	1.79±0.68	0.831
CV (%)	31.46±6.21	30.23±6.41	0.256
SBP (mmHg)	136.66±14.32	137.52±15.36	0.549
DBP (mmHg)	82.86±10.14	83.69±9.87	0.895
Diabetic retinopathy (%)	8.91	11.23	0.325
Diabetic neuropathy (%)	14.21	8.48	0.528
Microalbuminuria (%)	12.36	15.14	0.893

BMI – body mass index; Hb_A1c – glycosylated hemoglobin; FPG – fasting blood glucose; 2hPG – 2-hour postprandial blood glucose; SBP – systolic blood pressure; DBP – diastolic blood pressure; eGFR – glomerular filtration rate.

Comparison of Flashing Blood Glucose Monitoring Parameters Between Groups

After 14 days of treatment, MBG, SDBG, CV, MODD, MAGE, TAR, and TBR were all decreased in both groups, but compared to the control group, the decrease of MODD, MAGE, TAR, and TBR was statistically significant in the MTA group (all P<0.05). There was no significant difference between the 2 groups in MBG, SDBG, and CV (all P>0.05). TIR (3.9–10.0 mmol/L) was significantly higher in the MTA group compared with the control group (P<0.01) (Table 2, Figure 1).

Table 2.

Comparison of continuous blood glucose monitoring parameters between groups.

	Control group (n=30)	MTA group (n=30)	P value
MBG (mmol/L)	7.13±1.22	6.71±1.06	0.286
SDBG (mmol/L)	2.33±0.54	1.86±0.59	0.202
CV (%)	26.87±5.69	23.61±6.98	0.229
MAGE (mmol/L)	4.55±1.28	3.67±0.86	0.029*
MODD (mmol/L)	1.78±0.61	1.51±0.43	0.022*
TAR (≥10.0 mmol/L) (%)	11.22±8.23	7.54±5.55	0.021*
TIR (3.9–10.0 mmol/L) (%)	85.2±7.19	90.14±6.08	0.007*
TBR (≤3.9 mmol/L) (%)	5.68±4.26	3.91±2.08	0.016*

^*Comparison between groups, P<0.05.

Figure 1.

Comparison of TAR, TIR, and TBR between groups. After 14 days, compared to the Control group, TAR (11.22±8.23 vs 7.54±5.55) and TBR (5.68±4.26 vs 3.91±2.08) in the MTA group were significantly lower (all P<0.05) and the TIR was higher (85.2±7.19 vs 90.14±6.08) (P<0.01).* Comparison between groups, P<0.05.

Comparison of TCM Symptom Score Between Groups

In both groups, the total score of TCM symptoms (thirst, dry mouth and throat, tiredness and fatigue, shortness of breath, palpitations, insomnia, spontaneous sweating, and night sweating decreased after 14 days of treatment (all P<0.05). After treatment, the TCM score of the MTA group was significantly lower than in the control group (P<0.05), with a between-group difference (mean change from baseline (MTA group vs control group) of −8.23, 95% CI (−6.87, −12.72), which indicated that the TCM symptoms were significantly alleviated compared with the control group (Table 3).

Table 3.

Comparison of TCM symptom score of patients between groups.

Group	N	Baseline	14th day	t	P
Control	30	28.64±4.51	22.47±3.98*	4.711	0.000
MTA	30	29.35±65.41	12.37±2.31*#	9.732	0.000
t	–	−.546	7.210	–	–
P	–	0.527	0.000	–	–

^#Comparison between groups, P<0.05;

^*comparison before and after treatment within groups, P<0.05.

Hypoglycemia Incidence, Body Weight Change, and Insulin Dosage After Treatment

All AEs were systematically graded for severity by using the Common Terminology Criteria for Adverse Events, CTCAE v5.0. No severe hypoglycemia (<2.6 mmol/L) occurred throughout the study. The incidence of hyperglycemia or hypoglycemia showed no significant difference between groups. The body weight loss of the MTA group was (−1.26±0.30), which is greater than in the control group (−0.38±0.22) (P<0.05) (Table 4), and the daily insulin dosage in the MTA group was significantly lower than in the control group (0.32±0.14 vs 0.61±0.11 IU/kg/day; P<0.05). Two cases of abdominal distension in the MTA group were recorded and no other gastrointestinal symptoms were reported. Time needed to reach the normal blood glucose range (3.9–10.0 mmol/L) was also compared, and the MTA group needed significantly fewer days than the control group (2.16±0.68 vs 4.16±1.16). Several hyperglycemic episodes were recorded in the control group and no severe hypoglycemia was recorded in either group.

Table 4.

Patients’ characteristics after treatment between groups.

Item	Control group	MTA group	P value
Hypoglycemia incidence (%)	0.4	0.0	0.241
Hyperglycemia incidence (%)	1.8	0.4	0.002
Gastrointestinal symptoms (%)	–	2.4%	–
Body weight (kg)	−0.38±0.22	−1.26±0.30	0.000
Time to reach normal blood glucose (days)	4.16±1.16	2.16±0.68	0.001
Daily insulin dosage (IU/kg/day)	0.61±0.11	0.32±0.14	0.000

Discussion

In patients with T2DM, good glycemic management is a therapeutic priority for effective intervention for diabetes and its complications. Glucose variability, as an important indicator of glycemic management, can provide more information about blood glucose and is closely related to the development of chronic complications of diabetes [15]. Hypoglycemia and poor blood glucose variability are major challenges in optimizing glycemic control [16]. The greater the magnitude of blood glucose variability, the higher the incidence of hypoglycemia. Thus, lowering glucose to the normal range, preventing hypoglycemia, and reducing blood glucose variability are currently emerging strategies in diabetes management. In previous blood glucose management, Hb_A1c was the standard method for assessing glycemic control and therapeutic effects, but it cannot reflect the fluctuation of blood glucose and the risk of hypoglycemia in the short term [17]. The TIR, as a new indicator for glycemic control assessment, is an important complement to Hb_A1c in clinical diabetes management, and can predict the risk of long-term diabetic complications [18]. Since TIR is mainly determined by the degree of hyperglycemia, it is relatively insensitive to hypoglycemia [19]. To better reflect the overall glycemic change, time above the target range (TAR) and time below the target range (TBR) should be considered. Our study showed that mulberry twig alkaloids significantly increased TIR and decreased the percentage of TBR and TAR in the MTA group. As reported, reductions in TAR and TBR reduce the risk of acute glycemic events (hyperglycemic symptoms, hypoglycemia) and long-term microvascular damage [15]. Our results indicated that mulberry twig alkaloids can better improve the overall blood glucose variability in terms of reducing both postprandial hyperglycemia as well as hypoglycemia induced by CSII therapy alone.

Most studies on glucose variability have been based on continuous glucose monitoring (CGM) [20], and there are few published clinical trials based on the FGM device to explore the effects of MTA add-on therapy in T2DM. In this study, FGM was used to observe the effect of mulberry twig alkaloids on 14-day blood glucose variability in patients with T2DM. The MTA group was treated with mulberry twig alkaloids based on the same CSII treatment program as the control group. The results of this study showed that MBG, SDBG, CV, MODD, and MAGE were lower in the MTA group than in the control group after the trial, among which MODD and MAGE were significantly decreased in the MTA group. Our results suggest that the addition of mulberry twig alkaloids to CSII can improve the blood glucose variability and reduce the incidence of hypoglycemia in patients with T2DM. The comparison between groups at the end of the trial also showed that the hypoglycemic effect of CSII + mulberry twig alkaloids was much more rapid than with CSII alone, based on the time needed to reach the normal blood glucose range. The MTA add-on therapy also reduced the required dosage of daily insulin of CSII. The reductions in MAGE and MODD of the magnitude observed were associated with decreased oxidative stress and inflammation in diabetic patients [18], which might explain the protective effects of MTA on chronic diabetic complications [9].

Western antihyperglycemic drugs have the advantage of lowering blood glucose rapidly and effectively, but also have drawbacks like hypoglycemia and poor blood glucose variability. Traditional Chinese medicine (TCM) treats Xiaoke from the overall perspective by correcting the internal environmental disorders and balancing Yin and Yang to a stable state [21]. Mulberry twig (Ramulus mori) is the dry branch of mulberry, which is a commonly used TCM herbs for treating Xiaokebi syndrome manifesting as numbness and pain of the limbs [22]. The MTAs are nitrogen-containing organic compounds with a variety of biological activities, and can exert different pharmacological effects at different concentrations and combinations. At low doses, MTA mainly exerts an α-glucosidase-inhibitory effect, which moderately regulates postprandial blood glucose. At medium doses, it enhances insulin sensitivity and improves peripheral glucose utilization. At high doses, the alkaloid combination can activate the adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway, and simultaneously exert multiple effects of lowering blood glucose, regulating lipid metabolism, and reducing inflammation [4,5,23]. Our study showed that the effect of MTA was remarkable in relieving the symptoms of diabetes mellitus in TCM, such as dry mouth and throat, fatigue, shortness of breath, spontaneous sweating, and night sweating, which suggests that CSII combined with mulberry twig alkaloids therapy had obvious advantages in improving clinical symptoms of Xiaoke compared with CSII alone.

Animal studies have also demonstrated that MTA can reduce fasting and postprandial blood glucose, alleviate insulin resistance, and improve glucose-stimulated insulin secretion in diabetic rodents [24]. A multicenter clinical study showed that Hb_A1c, FPG, 1h-PBG, 2h-PBG, and AUC0–2h in the MTA group were significantly lower than those in the placebo group, and no adverse effects reported [25]. Therefore, it was hypothesized that MTA can reduce blood glucose variability and synergize with insulin to help patients with T2DM to reach a normal blood glucose level rapidly and steadily. The results of our trial verified the glucose-lowering effect of MTA. The time needed to reach normal blood glucose levels showed that the combination of MTA and insulin pump could rapidly and effectively control blood glucose and might shorten the hospitalization time, and MTA also reduced the daily insulin dosage required.

CSII mimics physiological insulin secretion in vivo, which can reduce the effects of high glucose toxicity on β-cells by lowering blood glucose rapidly, alleviate insulin resistance, restore pancreatic β-cell function of T2DM to the maximum extent and reduce glucose fluctuations [26]. MTA improves blood glucose variability by inhibiting α-glucosidase activity, slowing the hydrolysis of carbohydrates to glucose to lower the postprandial blood glucose, and reducing hypoglycemia caused by excessive insulin secretion. The Chinese diet consists of a large proportion of carbohydrate, and most T2DM patients have distinct postprandial blood glucose elevation. Therefore, glycosidase inhibitors are more suitable for Chinese diabetic population. As a selective dual enzyme inhibitor, MTA has strong inhibitory activity on sucrase and maltase, but almost no effect on amylase, thus avoiding intestinal flatulence caused by starch hydrolysis [27]. Our trial showed that MTA had fewer associated gastrointestinal symptoms.

This study had a single-blinded design, with treating clinicians responsible for insulin dose adjustments and outcome investigators responsible for evaluating TCM scores and other outcomes being aware of group allocation. This lack of blinding might have led clinicians to adjust insulin doses more aggressively in one group or investigators to interpret TCM symptoms with subtle bias, which could have inflated or otherwise altered the reported treatment benefits.

Study Limitation and Future Direction

Due to the lack of funding, the sample size was relatively small and the duration of this trial was short. This trial had a small-sample, short-term design, with its core advantage lying in maximizing subject adherence. The small sample size facilitates refined management of each subject by the research team, including full-process guidance on FGM device wear, real-time responses to usage queries, and regular follow-up monitoring. This effectively reduces the risk of decreased adherence caused by complex operations and heavy follow-up burdens. Ultimately, no patients dropped out, ensuring the completeness and continuity of research data, and avoiding sample bias due to loss to follow-up. The conventional wearing period for FGM devices is 14 days, a duration determined based on device technical characteristics, such as sensor lifespan and data storage capacity. Our findings were limited to short-term outcomes (eg, MAGE, MODD) and insulin dose changes over the 14-day study period. No conclusions can be drawn regarding long-term glycemic control, the durability of the observed effects, or the risk of diabetes-related complications (eg, microvascular or macrovascular complications), and long-term follow-up studies are needed to address these questions.

MTA can lower blood glucose through mechanisms such as inhibiting α-glucosidase and protecting pancreatic islet β-cells [9], while CSII can simulate the physiological insulin secretion pattern and precisely control basal and prandial blood glucose [7]. The combined regimen can reduce blood glucose variability and the risk of hypoglycemia, and is particularly suitable for patients with excessive blood glucose variability. For patients with insulin-dependent diabetes, MTA can reduce the insulin dosage and alleviate insulin resistance, and long-term use might help delay the decline of pancreatic islet function. In the future, it is necessary to further explore the molecular mechanisms underlying the synergistic effect between MTA and insulin – such as how these two jointly regulate insulin signaling pathways and the association between intestinal flora and glucose metabolism – to provide a theoretical basis for optimizing the combined therapy. Additionally, studies on the impact of MTA on insulin pharmacokinetics could be conducted to clarify whether they alter the absorption, distribution, and metabolism of insulin, thereby guiding the precise adjustment of clinical medication dosages. It is also essential to develop new formulations of MTA (eg, sustained-release formulation) and combine them with the closed-loop system of intelligent insulin pumps to achieve real-time regulation of blood glucose-lowering effects and improve the convenience and precision of the combined therapy. Furthermore, the application of the combination of MTA and CSII in special populations such as patients with gestational diabetes or elderly patients should be explored to develop personalized treatment plans.

Conclusions

The combined application of mulberry twig alkaloids and CSII in patients with type 2 diabetes mellitus can improve blood glucose variability and alleviate the clinical symptoms of diabetes in TCM. This study suggests that natural plant extracts like MTA can effectively improve blood glucose variability in diabetic patients, providing new treatment options for clinicians. Longer, multicenter studies with larger sample sizes are needed to further assess the effects of mulberry twig alkaloids in regulating glucose variability.