The International Diabetes Federation estimates that the prevalence of diabetes in the global adult population will be 10.5% in 2021 and 12.2% in 2045 [1]; 90%-95% of cases are type 2 diabetes mellitus (T2DM) [2]. Worldwide, approximately 50% of adults with diabetes have not been diagnosed, which can lead to serious vascular complications and premature death [1]. Intermediate hyperglycemia (IH) is a condition in which blood glucose levels do not meet the criteria for diabetes but have abnormal carbohydrate metabolism [3] and impaired glucose regulation [4]. IH prevalence is increasing worldwide [3], if left untreated, 37% of people with IH will develop T2DM within 4 years [5]. Both IH and T2DM are diagnosed based on glucose criteria that measure fasting blood glucose (FBS) and hemoglobin A1c (HbA1c) [6]. As the prevalence of diabetes continues to increase, more sensitive and practical methods to detect IH are needed [1]. As an adverse effect of IH, the risk of developing DM increases due to poor blood sugar control and continuous exposure to hyperglycemia [1,3,5]. IH also has a higher risk of developing cardiovascular disease due to unstable glycemic control and potential changes in blood pressure and lipid levels [7,8].

Obesity is positively correlated with IH and is a major risk factor for exacerbating IH [9]. Obesity is a risk factor that exacerbates inflammatory conditions and increases the incidence of impaired fasting glucose [10,11]. Obesity status is generally assessed using body mass index (BMI); however, the BMI scale has limitations such as its inability to account for variations in body composition [2]. As an indicator of abdominal obesity (AO), waist-to-hip ratio (WHR) may be appropriate for comparisons between different races and genders [7,12,13]. Waist circumference (WC) is a direct measure of the amount of abdominal fat and is useful in assessing AO. It is also a simple and reliable alternative measure of body composition [12]. Based on WC, AO is 90 cm or more for men and 85 cm or more for women, which is particularly useful for measuring the AO of normal or overweight individuals based on BMI [14,15]. AO may occur because of the accumulation of abdominal visceral fat when the BMI is normal [12]. Our study was conducted on Koreans, a single race, and AO was classified based on WC.

AO is also positively associated with IH, and is a major risk factor for IH exacerbation [3]. AO increases IH prevalence because fat tissue induces insulin resistance (IR) and decreases the function of Langerhans cells, which secrete insulin in people with obesity [16]. IR and elevated blood sugar levels are more closely associated with visceral fat than with fat in other areas [14]. Asians accumulate more visceral fat than Westerners, despite having lower BMIs, which leads to a higher risk of IH [17].

Individuals with obesity exhibit a greater abundance of macrophages in their adipose tissues, indicating that both adipocytes and macrophages play significant roles in inflammation during obesity [18]. Even though Asians may be classified as normal weight based on BMI, C-reactive protein (CRP) levels are increased in those with AO as measured by WC [13]. CRP is an inflammatory marker, elevated CRP levels are associated with IH and T2DM [19] Inflammation reduces vascular permeability and alters peripheral hemodynamics, blocking the transport of insulin across tissues and cells and promoting IR [18]. It is a key factor in the pathogenesis and development of diabetes [18,19].

Leptin, which is primarily responsible for regulating body weight by achieving a balance between food intake and energy expenditure, also helps regulate glucose homeostasis and insulin sensitivity [2]. Leptin levels are increased in IH. Additionally, obesity and leptin levels are positively correlated [20]. Secretion of both leptin and insulin is affected by the total amount of fat deposits, including short-term changes in energy balance [21]. Leptin and insulin signaling are important for the regulation of brain energy homeostasis [20]. Individuals with obesity have elevated leptin concentrations and insulin and appear to be resistant to appetite loss [12].

Most previous studies on DM have included patients with diabetes [2,7,15,19], obesity [4,7,9], CRP [13,19], leptin [2,20,21], conversion from IH to T2DM [6], and diabetes prevalence [1,3,11]. IH increases the risk of developing DM [3,5]. IH is also associated with a higher risk of developing unstable cardiovascular disease [8]. Therefore, early detection of IH is important. Asians, such as Koreans, often have AO with a normal BMI [17]. Therefore, it is necessary to determine whether IH significantly increases in AO. Moreover, Asians with IH are more susceptible to developing T2DM than Westerners [3]. Leptin is involved in the regulation of insulin sensitivity, so measuring leptin in IH may help elucidate the mechanisms leading to diabetes. Also, because leptin plays a role in regulating appetite and energy balance, checking leptin levels in IH may predict appetite dysregulation and weight management problems [2]. Therefore, it is important to determine the relationship between leptin and IH. To our knowledge, these studies have not confirmed the relationship between obesity and inflammatory markers, which are factors influencing IH in Asian Korean adults, who have a higher conversion rate to T2DM than Westerners [3].

This study investigated the associations among IH, increased BMI, AO, hs-CRP, and leptin biomarkers in Korean adults. In particular, our study targeted adult patients with IH. Identifying the predictive factors for IH may contribute to the early detection of T2DM.

This study investigated the association between IH and increased levels of AO, hs-CRP, and leptin in Korean adults. WC was positively correlated with hs-CRP and leptin levels, and hs-CRP levels were also significantly correlated with leptin. As WC, an AO indicator, increased CRP [19], and leptin levels increased [20].

Our study revealed that WC was notably higher in the IH group, a factor that significantly influenced the IH incidence. This is particularly significant as the pathogenesis of obesity and diabetes involves common pathways with increased IR and proinflammatory patterns [2]. Furthermore, the distribution of adipose tissue, as an independent factor in IR increase regardless of BMI [17], leads to pancreatic beta cells secreting insulin inappropriately to overcome this resistance, which in turn leads to T2DM [11].

In particular, excessive visceral fat accumulation without general obesity may be accompanied by enhanced IR and inflammation [3]. AO increases inflammatory cytokines secreted from adipocytes in abdominal fat, inhibits the action of insulin receptors, increases blood insulin concentration, and worsens IR [12,14,15]. On the other hand, in general obesity, more fat is distributed in tissues such as muscles than abdominal fat. Because abdominal fat secretes relatively less inflammatory cytokines, IR may be lower compared to AO [3,12,14]. Therefore, the authors considered AO to be associated with IH. At similar BMI levels, Asians have higher abdominal and visceral fat levels than Caucasian Europeans [3]. AO is also associated with IH [9,11]. Central obesity, including a large WC or WHR , is a predictor of IH and has been shown to increase IH risk of IH 1.50 times [24]. Increased visceral fat increases CRP levels and IH risk [3], and causes the secretion of adipokines (such as tumor necrosis factor and interleukin-6), that interfere with insulin receptor function, in turn increasing IR and exacerbating IH progression [24]

AO is more strongly associated with IH than general obesity indices, such as BMI, which supports our findings that WC had a greater influence on IH. Higher WC increases c conversion from IH to T2DM [17], Therefore, reducing WC improves glycemic control and prevents IH from progressing to T2DM [25].

In this research, the hs-CRP levels were higher in the IH group, which affected IH incidence. Obesity is associated with increased hs-CRP levels, which correlate with WC in middle-aged Korean adults [26]. The effect of hs-CRP (1-3 mg/L) was higher in the AO group than in the group with obesity [23]. AO is an indicator for the relationship between hs-CRP and AO, leading to a higher IH risk [3].

Visceral fat is associated with an increase in hs-CRP, even if the BMI index is normal, hs-CRP increases in individuals with only AO [26]. AO measures are more closely associated with the risk of IH and T2DM than BMI, and AO is associated with hs-CRP independent of BMI [26]. CRP is the most widely measured marker of inflammation, and inter-individual differences are primarily due to genetic factors. However, adiposity is another major determinant of CRP synthesis in the liver through the production of proinflammatory cytokines [19].

After classifying hs-CRP levels into three grades, there was a relationship between the inflammatory factor hs-CRP and IH [27]. Elevated serum CRP levels in middle-aged Asians are associated with increased IH risk factors, especially high HbA1c levels [19]. CRP is associated with IR [23], in addition, when the CRP concentration is high, the risk of progression to diabetes increases [27].

In contrast, lower CRP levels increase the likelihood of blood sugar levels returning to normal. In adult participants, 65.9% returned to normal blood sugar levels during a 4-year follow-up study [27]. These results suggest that hs-CRP level may be a common indicator for verifying IH progression.

Throughout this study, leptin levels, which is a factor that affects IH, were higher in the IH group. Leptin is a hormone secreted by the adipose tissue [21]. The inflammatory response caused by AO causes leptin resistance by interfering with the operation of leptin receptors. Leptin resistance indicates changes in lipid metabolism, which reduces the function of insulin receptors and interferes with the insulin signaling pathway, resulting in IR [2,21]. Leptin increases FBS and HbA1c [21], and is associated with IH [20]. Since leptin affects the development of IH by suppressing insulin secretion [2], individuals with elevated leptin levels had a higher IH rate (20%) than those in the normal group (2%) [20]. Our multiple logistic regression analysis showed that leptin levels increased with IH [20]. An association has been reported between leptin and IR [28]. IR is a key factor in the pathogenesis of IH and T2DM [21].

In the hypothalamus, leptin interacts with leptin receptors to stimulate satiety. Insulin is responsible for maintaining proper energy storage and utilization, whereas leptin reduces the ongoing energy intake. Therefore, both are necessary for the regulation of energy expenditure and glucose homeostasis [29]. Hyperleptinemia has been linked to the presence of IR, however, leptin levels have been negatively correlated with insulin sensitivity [21]. Our study also found that increased leptin levels were associated with IH risk factors.

In our current study, the IH group had older participants, which was a factor affecting IH incidence. In one study, IH increased by 1.30 times in those aged ≥ 65 years than in those aged 50-59 years [11]. The American Diabetes Association that the prevalence of IH in older adults is more than 50% [3], which is similar to that in the Korean adult in this study. As aging progresses, AO increases, and insulin sensitivity decreases owing to a decrease in skeletal muscle mass [12]. Additionally, T2DM prevalence in Korea is higher for those in their 30s (16.7%) and for those aged ≥ 65 years (30.1%), and increases with age [15]. Physiological changes due to aging make blood sugar control difficult, and complications are more likely to occur in older than in younger adults [11]. Since IH is closely related to T2DM, factors associated with IH in older adults must be identified to prevent T2DM [3].

Pathological dysregulation that eventually leads to diabetes is preceded by IH [3]. We believe this is an initial step and opportunity for preventive interventions. Approximately 25% of patients with IH progress to T2DM within 3-5 years, and up to 70% of patients with IH develop diabetes during their lifetime [3].

Our study provides insights for the early detection and prevention of diabetes progression in patients with IH. Reducing AO in patients with IH can prevent the progression to diabetes. AO management is an important intervention for preventing the transition from IH to T2DM [25]. In particular, aerobic exercises, such as walking, running, and cycling, should be implemented to reduce AO [30].

A limitation of this study is that patients could not be excluded who had with liver failure, a factor that interferes with CRP production [19]. Additionally, unmeasured factors such as the amount of exercise, eating habits, and body fat percentage may have influenced the study results. In future studies, it is necessary to identify a more accurate indicator of the amount of abdominal fat by including not only WC in the measurement of AO, but also WHR, which reflects hip circumference.

The results of this study indicated WC, hs-CRP, leptin, and age were factors that affected IH incidence. IH prevention and management programs for Korean adults should include management of AO, hs-CRP, and leptin. This can prevent the conversion to diabetes.

In the present study, patients with IH were able to control their blood sugar levels by monitoring their inflammation levels. This suggests that hs-CRP and leptin may be additional biomarkers for identifying individuals at a high risk of IH. This has clinical significance for the treatment and prevention of IH [27]. Patients should be educated about the potential consequences of poorly managed IH and obesity. Lifestyle modifications that influence leptin levels should be encouraged as proactive measures.