With the development of the economy and society, the prevalence of diabetes is increasing. The 10th edition of the Global Diabetes Map showed that 537 million people have diabetes worldwide, and the number of adults with diabetes in China ranks first in the world (approximately 140 million), with a prevalence of 12.8% (1). At present, the treatment for diabetes is not optimal. A cross-sectional study in China revealed that 63.5% of diabetic patients received antihyperglycemic treatment, and only 35.1% of diabetic patients achieved glycemic target (2). In recent years, drugs such as glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-dependent glucose transporters-2 inhibitors have been introduced in China and achieved remarkable outcomes. The hypoglycemic efficacy of these medications and their capacity to mitigate the risk of diabetes complications are outstanding. However, due to reasons such as adverse reaction, high price, etc., they still cannot be universally popularized. Long-term failure to effectively control blood glucose in patients with diabetes may lead to serious complications in the heart, brain, kidney and other important organs, seriously worsening quality of life and life expectancy.

Insulin is one of the important means for controlling blood glucose in patients with diabetes. Patients with type 1 diabetes, gestational diabetes, or, in some cases, type 2 diabetes mellitus (T2DM) require insulin to control blood glucose (3). However, insulin could lead to side effects such as weight gain and hypoglycemia. In addition, subcutaneous injection may cause a fear of needles (needle phobia) and even skin damage at the injection site, such as bleeding, ecchymosis, and induration. Some diabetic patients, even medical staff, experience a psychological burden with the use of insulin and may delay or even refuse to use insulin therapy. This psychological state is called psychological insulin resistance (PIR) (4). PIR may delay the optimal time for T2DM patients to start insulin therapy. Patients who are receiving insulin therapy also have difficulty maintaining long-term adherence and satisfaction, and some patients even reduce or stop using insulin on their own. Like insulin, GLP1-RAs also face the challenge of patient reluctance towards subcutaneous injections. PIR is an important cause of the low glycemic control rate in diabetic patients and has a serious negative impact on diabetes management.

Improving diabetes education and innovations in insulin formulation and delivery methods are effective methods for improving PIR. The improvements in insulin dosage include premixed insulin and IDegAsp, which can reduce the injection frequency. Insulin injection devices have also improved, and needle-free injection (NFI) of insulin has been widely used in recent years. The principle of NFI is to shoot drugs through a small hole by instantaneous pressure generated by a mechanical device, create a high-speed jet and send drugs into subcutaneous tissue. NFI causes little damage to the skin. The pore size left by NFI on the skin surface is only 1/4 of that left by needle injection (5). NFI has limited penetration into the skin and less stimulation of nerve endings, so it can reduce pain during injection (6). Based on the above findings, needle-free injections are expected to improve PIR in diabetic patients and maintain good treatment compliance and satisfaction.

The insulin injected by NFI is dispersed in subcutaneous tissue, and its absorption efficiency is improved (7). One study revealed that NFI can accelerate the early absorption rate of rapid-acting insulin (8). Another study revealed that different skin thicknesses did not affect the absorption efficiency of needleless insulin injection (9). The efficiency of insulin absorption affects its hypoglycemic effect. Researches have shown that NFI can enhance the control of postprandial blood glucose via regular insulin and insulin aspart (10) and reduce the dose of insulin glargine needed to achieve the same blood glucose control (11).

At present, data about using premixed insulin administered by NFI in T2DM patients is scarce. Therefore, this study evaluated the effects of NFI on PIR in patients with T2DM through questionnaires and assessed whether NFI could reduce the insulin aspart 30 need of the patient through randomized, cross-controlled prospective research. The aim of this study was to provide new strategies for improving PIR and optimizing blood glucose management in patients with T2DM.

PIR is an important hindrance factor affecting the insulin utilization rate and glycemic target rate in patients with T2DM. The factors contributing to PIR originate from both patients and medical staff. Patient-related causes of PIR encompass insufficient knowledge about insulin, lifestyle inconveniences, fear of adverse reactions such as hypoglycemia, anxiety and fear associated with injections, inadequate self-efficacy in diabetes management, and limited social support (17). Medical staff-related causes involve limited experience in utilizing insulin (especially among non-endocrinologists), apprehension regarding patient rejection, concerns about the risks of hypoglycemia, reluctance to administer insulin to elderly patients,and the need for more time dedicated towards instructing injection techniques and enhancing knowledge related to insulin usage (18).

In this study, the ITAS created by a Chinese researcher was used to assess PIR of the subjects. The results showed that the incidence of PIR decreased from 45.3% to 23.4% after the use of NFI. NFI can significantly reduce the degree of PIR. The incidence of PIR investigated by the original author of the scale was 41.5%. Other studies have shown that the incidence of PIR in Chinese T2DM patients was 44.9% (19), and the incidence of PIR in other countries was 28.2-82.6% (20–22). Although the results of different studies differ greatly, the overall PIR situation is not optimistic, and NFI is expected to become an important means to improve PIR. Dimension 3, “fears and limitations related to insulin injection”, had the highest score, among which the proportion of subjects who agreed with question 18 “I am afraid that insulin injection will hurt very much” and question 19 “Even if insulin injection does not hurt much, I am still afraid to give myself injections” was the highest. This finding shows that the fear of injection itself is the main reason for patients to resist insulin. This fear may stem from pain during injection and from injection-related adverse reactions. In addition, some patients with needle phobia, while tolerating the pain of injection, are still afraid to inject themselves. The score in Dimension 3 decreased the most after NFI was used, and the results of the self-edited questionnaire also showed that most subjects believed that NFI could improve their fear of injection, which was one of the main reasons why NFI could improve PIR.

This study revealed that 50% of the participants had poor insulin compliance, which improved somewhat after the study. The adherence to Dimension 1, “medication”; Dimension 4, “self-monitoring”; and Dimension 5, “periodic review”, improved, probably due to the supervision and reinforcement of subjects in regular medication, blood glucose monitoring, and periodic review during the study period. However, the lifestyles of the subjects were solidified during the study, so there was little change in Dimension 2, “diet”, or Dimension 3, “exercise”.

In this study, the overall satisfaction of subjects receiving insulin therapy improved after NFI was administered. The satisfaction scores in Dimension 5, “satisfaction with insulin injection method and its efficacy”, Dimension 1, “limitations and obstacles caused by insulin injection”, and Dimension 3, “confidence in avoiding symptoms caused by abnormal blood glucose”, increased significantly, indicating that the subjects were more satisfied with the NFI method itself and its hypoglycemic effect. There was little change in satisfaction with Dimension 2, “flexibility of lifestyle after insulin injection”, or Dimension 4, “influence of hypoglycemia caused by insulin on patients”. It is possible that insulin treatment requires a more rigorous lifestyle and results in increased difficulty in study, work and travel, but NFI does not improve these situations. Moreover, due to the higher absorption efficiency of NFI, blood glucose levels drop relatively quickly, so additional attention is needed to prevent the occurrence of hypoglycemia.

The first-phase insulin secretion is delayed in most T2DM patients. During meals, patients need exogenous insulin to act more quickly to stabilize postprandial blood glucose. NFI can quickly stabilize early postprandial blood glucose levels due to its greater absorption efficiency (10). Previous studies on the pharmacokinetics and pharmacokinetics of NFI have mostly focused on rapid-acting insulin and insulin analogs. Premixed insulin analogs, which maintain both basal and postprandial insulin levels, have a relatively high usage rate in T2DM patients and are expected to benefit from NFI. A study revealed that, compared with that of needle-free insulin, the dosage of short-acting insulin was lower in hospitalized T2DM patients receiving intensive insulin therapy than in those receiving needle injection, but no difference was observed in long-acting insulin (23). Another study showed that NFI can reduce the dosage of insulin glargine by an average of 3.11 U/d (11). In this study, the blood glucose levels of the subjects were controlled at the same level, and the dose of insulin aspart 30 in the NFI was significantly less than that in the NP by an average of 3.2 U/d (10% of the original dose). In addition, as the insulin dosage increased, the reduction in NFI was more pronounced. In the high-dose subgroup, NFI reduced the insulin dosage by an average of approximately 4.0 U/d. A reduction in insulin dosage could alleviate injection-related adverse reactions; reduce the degree of weight gain, hypoglycemia, and hyperinsulinemia; and thus improve PIR. In addition, dosage reduction could also ease the economic burden of patients, save medical resources, and contribute to environmental protection. It can be seen that NFI has very broad development prospects.

Patients with diabetes have poor self-regulation of blood glucose. When the lifestyle is irregular or insulin is applied, the degree of glycemic variability increases significantly. SMBG is not the method to measure glycemic variability leading to potential worsening of the diabetes. In this study, FGM was used to collect blood glucose data. During each treatment period, FGM was worn for 14 days, and relatively stable blood glucose data were analyzed in the middle 10 days (days 3-12). The results showed that there was no significant difference in blood glucose levels (TAR, TIR, TBR, or AG) between the two injection methods, which confirmed that the blood glucose control level was the same between the two injection methods. No significant difference was found in the indices of glycemic variability (SD, MAGE, or CV) between the two injection methods. Other studies also did not find an effect of NFI on glycemic variability (11, 24). Although NFI could stabilize early postprandial blood glucose, it has little effect on glycemic variability.

Hypoglycemia is one of the main adverse reactions to insulin, and severe hypoglycemia is life-threatening. When insulin is absorbed relatively quickly by NFI, patients need to be more vigilant about hypoglycemia. A meta-analysis showed no difference in hypoglycemia rates between the two injections (25). The results of this study showed that the incidence and severity of hypoglycemia in NFI-treated patients were greater than those in NP-treated patients, but the difference was not significant. To avoid hypoglycemia, patients with diabetes are advised to appropriately reduce the original dosage when using needle-free syringes for the first time.

Traditional needle injection may cause pain, induration, bleeding, ecchymosis and other injection-related adverse reactions, which are also among the main causes of PIR. Improper use habits, such as reusing needles, could increase the incidence of these adverse reactions. NFI results in less damage to the skin, limited depth into the subcutaneous tissue and less stimulation to nerve endings, which could reduce these adverse reactions. A meta-analysis showed that the incidence of redness, swelling and induration after NFI was less than that after insulin injection, and there was no significant difference in the incidence of pain, bleeding or ecchymosis (25). In this study, compared with those after the use of NP, the incidence of induration and leakage after the use of NFI was significantly lower. The incidence of bleeding and ecchymosis decreased, but the difference was not significant. The pain VAS score can transform pain, a subjective experience that is difficult to quantify, into a measurable form. This study revealed that the pain VAS score was lower in NFI-treated patients than in NP-treated patients. The results of the self-edited questionnaire also showed that most subjects believed that NFI could reduce the occurrence of pain, redness, induration, bleeding and ecchymosis. In general, NFI is safer than needle injection and can alleviate resistance to insulin therapy in patients.

In terms of acceptance, the results of our self-edited questionnaire showed that most subjects were satisfied with NFI, believed that NFI could increase the convenience and regularity of treatment and increase their confidence in controlling blood glucose, and were willing to continue using NFI in the future. However, only a small number of subjects believe that NFI is more economical than NP. With NFI as an emerging technology, the price of injection devices is still not affordable for most patients, and challenges still exist in terms of popularization.

The highlights of this study are to introduce needle-free insulin injection into PIR of T2DM patients, explore the effect of NFI in improving PIR, and provide a new solution strategy for enhancing blood glucose management in T2DM patients. However, there are some limitations in this study. First of all, the sample size is not large enough, and further verification is needed to determine if the results can be applied to all T2DM patients. Additionally, this is a short-term study, and it remains unknown whether long-term use of NFI can maintain its current advantages without causing more injection-related adverse reactions.

NFI improved PIR in T2DM patients and increased insulin therapy adherence and satisfaction. NFI can reduce the dosage of premixed insulin analogs while achieving the same hypoglycemic effect as needle injection. NFI does not affect glycemic variability, does not significantly increase the risk of hypoglycemia, and reduces pain and injection-related adverse reactions. Therefore, the application and popularization of NFI may lead to new strategies for optimizing blood glucose management.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of First Affiliated Hospital of Dalian Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

WW: Writing – original draft, Data curation, Formal analysis, Investigation, Visualization, Validation. LM: Data curation, Formal analysis, Resources, Writing – review & editing. YW: Resources, Writing – review & editing. CS: Resources, Writing – review & editing. HY: Investigation, Writing – review & editing. HL: Investigation, Writing – review & editing. HZ: Conceptualization, Investigation, Methodology, Project administration, Writing – review & editing. JD: Conceptualization, Funding acquisition, Methodology, Supervision, Writing – review & editing.