Diabetes mellitus is a global pandemic, with the International Diabetes Federation reporting that an estimated 537 million adults were living with diabetes in 2021, a figure projected to rise to 783 million by 2045 [1]. Type II Diabetes Mellitus (T2DM), accounting for approximately 90-95% of all diabetes cases, is characterized by insulin resistance and progressive beta-cell dysfunction, leading to chronic hyperglycemia and associated complications affecting multiple organ systems [2]. The increasing prevalence of diabetes has significant implications for dental practice, as diabetic patients require specialized considerations during oral healthcare delivery, particularly regarding the use of local anesthetics containing vasoconstrictors.

Local anesthesia forms the cornerstone of pain management in dental practice, enabling practitioners to perform procedures with minimal patient discomfort while maintaining hemostatic control [3]. The incorporation of vasoconstrictors, primarily epinephrine (adrenaline), into local anesthetic solutions has been a standard practice for over a century, offering several distinct advantages, including prolonged anesthetic duration, reduced systemic toxicity through delayed absorption, enhanced depth of anesthesia, and improved surgical field visualization through vasoconstriction [4]. Epinephrine, a naturally occurring catecholamine, exerts its effects through activation of both alpha and beta-adrenergic receptors, resulting in vasoconstriction at the injection site and various systemic physiological responses [5].

The physiological effects of epinephrine extend beyond local vasoconstriction to include significant metabolic consequences, particularly those related to glucose homeostasis. Epinephrine stimulates hepatic glycogenolysis and gluconeogenesis through beta-2 adrenergic receptor activation, while simultaneously inhibiting insulin secretion from pancreatic beta cells and promoting insulin resistance in peripheral tissues [6]. These mechanisms collectively contribute to elevated blood glucose levels, a response that may be particularly pronounced in diabetic patients who already exhibit compromised glucose regulatory mechanisms [7]. The clinical significance of these effects has generated considerable debate regarding the safety and appropriateness of epinephrine-containing local anesthetics in diabetic populations.

The existing literature presents a conflicting picture, creating a clinical dilemma for practitioners. For instance, a recent large-scale study by Kumari et al. (2024) reported statistically significant glucose elevations in diabetic patients following the use of lidocaine with 1:80,000 epinephrine [8], aligning with some earlier observations. In contrast, other studies have found minimal to no significant changes. This controversy is further complicated by research into alternative vasoconstrictors. A landmark trial by Milic et al. (2025), for example, found that agents like clonidine may offer comparable anesthetic efficacy with a more favorable safety profile in patients with diabetes [9]. This lack of consensus highlights a critical gap in the evidence and underscores the need for highly standardized studies to clarify the actual acute glycemic effect of the most commonly used anesthetic formulations.

The clinical implications of epinephrine-induced hyperglycemia in diabetic patients extend beyond immediate glucose elevation to potential impacts on wound healing, infection risk, and overall perioperative outcomes. Hyperglycemia has been associated with impaired neutrophil function, delayed wound healing, and increased susceptibility to postoperative infections, particularly relevant in oral surgical procedures where bacterial contamination is inevitable [10]. Furthermore, acute glucose fluctuations may precipitate diabetic complications in poorly controlled patients, necessitating careful consideration of anesthetic choices in this vulnerable population.

Their findings revealed that clonidine provides comparable anesthetic efficacy with a superior cardiovascular safety profile and reduced local side effects compared to epinephrine. Notably, diabetic patients receiving clonidine demonstrated significantly less postoperative paresthesia and more stable hemodynamic parameters, suggesting that alpha-2 agonists may represent a safer alternative for diabetic populations.

Current clinical guidelines regarding local anesthesia in diabetic patients vary considerably, reflecting the limited high-quality evidence available until recently. The American Diabetes Association recommends caution when using epinephrine-containing local anesthetics in diabetic patients, particularly those with poor glycemic control, but does not provide specific contraindications [11]. Similarly, the American Dental Association acknowledges the potential for glucose elevation but emphasizes that the benefits of effective anesthesia generally outweigh the risks in most clinical scenarios [12]. However, these recommendations were formulated before the availability of recent high-quality evidence demonstrating significant glycemic effects.

The concentration of epinephrine in local anesthetic solutions represents a critical factor in determining the magnitude of systemic effects. Standard dental cartridges typically contain epinephrine in concentrations ranging from 1:50,000 to 1:200,000, with 1:80,000 and 1:100,000 being most commonly used for routine procedures [13]. Recent evidence suggests that even these relatively low concentrations can produce measurable glycemic effects, challenging previous assumptions about the safety of standard epinephrine doses in diabetic patients [8, 10].

The timing of glucose measurements following local anesthetic administration has emerged as an important methodological consideration in research studies. While some investigations have focused on immediate post-injection effects, others have extended monitoring periods to capture delayed responses. Kumari et al. demonstrated that peak glucose elevation occurs between 10 and 20 minutes post-injection, suggesting that brief monitoring periods may underestimate the true magnitude of epinephrine effects [8]. This temporal pattern has significant implications for clinical practice, particularly in procedures that require multiple anesthetic administrations or extended treatment times.

Patient-specific factors significantly influence the glycemic response to epinephrine-containing local anesthetics. Age, duration of diabetes, baseline glycemic control, concurrent medications, and presence of diabetic complications all contribute to individual variability in response [14]. Patients receiving antihyperglycemic medications may exhibit blunted responses to epinephrine, whereas those with poor baseline control or insulin deficiency may experience exaggerated glucose elevations [15]. These considerations underscore the importance of individualized risk assessment and monitoring strategies in diabetic patients undergoing dental procedures.

The psychological stress associated with dental procedures represents an additional confounding factor that may influence glucose levels independent of pharmacological effects. Stress-induced catecholamine release can lead to glucose elevation through mechanisms similar to those of exogenous epinephrine administration, potentially amplifying the overall glycemic response [16]. Recent studies have attempted to control for this variable through standardized anxiety management protocols and stress assessment measures, though complete elimination of this confounding factor remains challenging.

Emerging evidence suggests that the route of local anesthetic administration may influence systemic absorption and subsequent glycemic effects. Infiltration techniques, which deposit anesthetic solution in highly vascularized tissues, may result in more rapid systemic absorption compared to nerve block techniques that place an anesthetic in less vascular anatomical locations [17]. This consideration has particular relevance for diabetic patients, who may benefit from anesthetic techniques that minimize systemic drug exposure while maintaining adequate surgical anesthesia.

The development of alternative anesthetic strategies specifically designed for diabetic patients represents an active area of research. Beyond alternative vasoconstrictors like clonidine, investigators have explored modified delivery systems, buffered anesthetic solutions, and combination approaches that may optimize anesthetic efficacy while minimizing metabolic disturbances [18]. These innovations hold promise for improving the safety and predictability of dental anesthesia in diabetic populations.

Quality of life considerations also play a significant role in the risk-benefit analysis of local anesthetic choices for patients with diabetes. Inadequate pain control during dental procedures can result in significant physiological stress, potentially causing glucose elevation through endogenous catecholamine release that may exceed the effects of exogenous epinephrine [19]. This paradox highlights the complexity of clinical decision-making and the need for evidence-based approaches that consider both immediate anesthetic requirements and long-term metabolic consequences.

The present study was designed to address several limitations identified in previous research while providing clinically relevant data to guide evidence-based practice. While recent studies, such as that by Kumari et al., have reported significant glycemic elevations, other research has shown conflicting results, highlighting the need for further investigation with a highly standardized methodology. Given the conflicting evidence, this study was designed to provide clarity on the issue. Our primary objective was to determine if a standard dental cartridge of 2% lidocaine with 1:80,000 epinephrine causes a clinically significant acute change in blood glucose in well-controlled type II diabetic patients compared to healthy controls [8]. A recent meta-analysis has demonstrated that telemedicine can significantly reduce HbA1c levels in patients with Type 2 Diabetes Mellitus (T2DM), underscoring the importance of glycemic control in this population [20].

Accordingly, the null hypothesis of this study was that there would be no significant change in blood glucose levels after the administration of local anesthesia with epinephrine in either group. The alternative hypothesis was that there would be a significant change in blood glucose levels in at least one of the groups.

The findings of this prospective comparative study provide important evidence regarding the safety of epinephrine-containing local anesthetics in diabetic patients undergoing routine dental procedures. The study demonstrates that lidocaine 2% with epinephrine 1:80,000 does not produce clinically significant acute glucose elevations in either healthy individuals or patients with type 2 diabetes mellitus. These results align with recent high-quality evidence, addressing several methodological limitations present in earlier investigations and thereby contributing to the evolving understanding of anesthetic safety in diabetic populations. The observed modest glucose increases of 2.85 ± 6.92 mg/dL in healthy controls and 3.15 ± 8.47 mg/dL in diabetic patients, while numerically consistent with epinephrine's known glycemic effects, failed to reach statistical significance (p = 0.066 and p = 0.082, respectively) and fall well within clinically acceptable ranges for both populations. To put this in perspective, normal daily glucose fluctuations in patients with diabetes can be much larger, often exceeding 50-100 mg/dL, making a change of approximately 3 mg/dL clinically insignificant [22, 23]. These findings contrast with the recent study by Kumari et al. (2024), which reported statistically significant glucose elevations at 10 and 20 minutes post-injection in both healthy and diabetic patients using similar epinephrine concentrations [8]. However, several methodological differences may explain this discrepancy, including their crossover design with plain lidocaine as the control, an extended monitoring period of 20 minutes, and a larger sample size of 120 participants, which may have provided greater statistical power to detect smaller effect sizes. The clinical significance of the observed glucose increases (approximately 10-23 mg/dL in healthy patients and 23-37 mg/dL in diabetic patients) remains debatable, as these elevations, although statistically significant, may not translate to meaningful clinical consequences in patients with adequate baseline glycemic control [24, 25]. Our findings are more consistent with the emerging evidence from Milic et al. (2025), who conducted a double-blind randomized trial demonstrating that while epinephrine-containing local anesthetics may produce measurable physiological effects, alternative vasoconstrictors, such as clonidine, offer comparable anesthetic efficacy with potentially superior safety profiles in diabetic patients [9].

The absence of significant glucose changes in our study population, despite the inclusion of patients with varying degrees of glycemic control (HbA1c range 6.1-8.4%), suggests that standard epinephrine concentrations pose minimal acute glycemic risk for most diabetic patients encountered in routine dental practice. The subgroup analysis, revealing a statistically significant glucose increase only in male participants (p = 0.043), warrants further investigation, as gender-based differences in epinephrine sensitivity have been reported in other clinical contexts and may reflect variations in adrenergic receptor distribution, metabolic rate, or stress response patterns [26, 27]. However, this finding should be interpreted with caution, as it may represent a false positive (Type I error) due to multiple subgroup analyses and requires further confirmation. The lack of association between glucose changes and diabetes duration, baseline glycemic control, or antidiabetic medication regimens suggests that the acute effects of epinephrine are relatively consistent across different diabetic phenotypes, supporting the generalizability of these findings to diverse diabetic populations. From a pathophysiological perspective, the minimal glucose changes observed may reflect the relatively low epinephrine dose delivered through standard dental cartridges (approximately 36 μg in a 1.8 mL cartridge at 1:80,000 concentration) compared to doses required to produce significant metabolic effects in experimental settings [28, 29]. Additionally, the rapid clearance of epinephrine from the systemic circulation, combined with the local vasoconstriction that limits systemic absorption, may further attenuate the magnitude and duration of glycemic effects [30]. The clinical implications of these findings extend beyond immediate glucose management to broader considerations of anesthetic selection and patient monitoring in diabetic populations. While our results support the safety of standard epinephrine concentrations, they do not negate the importance of individualized risk assessment, particularly for patients with poor glycemic control, significant diabetic complications, or concurrent cardiovascular disease [31, 32]. The emerging evidence for alternative vasoconstrictors, particularly clonidine, offers promising options for practitioners seeking to minimize even theoretical glycemic risks while maintaining optimal anesthetic efficacy [10, 33]. However, the widespread adoption of alternative vasoconstrictors must be balanced against considerations of cost, availability, practitioner familiarity, and the extensive safety database established for epinephrine-containing formulations over decades of clinical use [34, 35]. The absence of stress biomarker measurements prevents a definitive separation of epinephrine-induced effects from procedure-related stress responses, which could contribute to glucose elevation through endogenous catecholamine release [36, 37]. Future research directions should include larger multicenter studies with extended monitoring periods, investigation of dose-response relationships across different epinephrine concentrations, evaluation of alternative vasoconstrictor formulations in head-to-head comparisons, and assessment of long-term glycemic outcomes in diabetic patients receiving repeated epinephrine exposures during comprehensive dental treatment [38, 39]. The development of point-of-care continuous glucose monitoring technologies may enable a more precise characterization of glucose response patterns and the identification of individual risk factors that predispose individuals to epinephrine sensitivity [40]. From a clinical practice perspective, these findings support current evidence-based recommendations that standard epinephrine-containing local anesthetics can be safely used in diabetic patients with adequate glycemic control, while emphasizing the continued importance of comprehensive medical history assessment, baseline glucose monitoring when indicated, and maintenance of emergency protocols for managing potential adverse events [41, 42]. The integration of these findings with emerging evidence regarding alternative vasoconstrictors and personalized anesthetic approaches will ultimately enhance the safety and effectiveness of dental care for the growing population of diabetic patients worldwide.

This study has several limitations, including a small sample size (n = 40), a single time-point measurement at 10 minutes post-injection, the exclusion of poorly controlled diabetic patients (HbA1c > 8.5%), and a focus on mandibular extractions only. The single-time-point measurement at 10 minutes post-injection, although based on previous research indicating peak epinephrine effects, may have missed a later glycemic peak (e.g., at 20 minutes), as reported by other studies. The minimum 2-hour fasting period is shorter than the standard for many glucose studies. The single-center design and absence of stress biomarker measurements may limit generalizability and prevent separation of epinephrine effects from procedure-related stress responses.

This study robustly demonstrates that the use of a standard dental anesthetic, 2% lidocaine with 1:80,000 epinephrine, does not cause a clinically or statistically significant acute increase in blood glucose levels in either healthy or well-controlled type II diabetic patients. For dental practitioners, this provides strong evidence to support the continued use of this anesthetic formulation, confirming that its benefits in achieving effective pain control, thereby reducing patient stress, far outweigh the negligible risk of glycemic disturbance. These findings should reassure clinicians and contribute to more confident and standardized care for the growing diabetic population. Looking forward, future research should build on these findings by exploring a wider range of anesthetic formulations in larger, multicenter trials. The use of continuous glucose monitoring in such studies could provide a more granular understanding of glycemic dynamics. At the same time, head-to-head comparisons of different vasoconstrictors would help to definitively establish the safest and most effective options for all patient populations.

The authors confirm contribution to the paper as follows: M.A.S. was responsible for conceptualization and resources; S.M.I. contributed to methodology, investigation, data curation, and writing of the original draft; M.E.M. performed validation and supervision; and both M.A.S. and S.M.I. participated in writing, review, and editing. All authors have read and agreed to the published version of the manuscript.