Can high-protein diabetes-specific oral nutritional supplements improve postprandial glycemic response in prediabetes? An open-label, cross-over clinical trial

Abstract

Background

Prediabetes is becoming increasingly widespread and often progresses to diabetes, thereby raising the risk of severe complications. High-protein diets, known to improve glucose control and prevent diabetes, can utilize rich-protein oral nutritional supplements. The study aims to evaluate the effectiveness of a diabetes-specific nutritional formula-pro (DSNF-Pro) with high-protein content and evaluate its clinical utility.

Methods

An open-label, cross-over clinical trial was conducted to compare the effects of DSNF-Pro versus Standard nutritional formula (STNF) on postprandial glycemic control. Fifteen subjects with prediabetes were enrolled and consumed DSNF-Pro on the first visit and STNF on the second. Postprandial plasma glucose, serum insulin, and serum c-peptide incremental area under the curve (iAUC), as well as the maximum concentration (C_max) and incremental maximal concentration (iC_max), were measured following the study. Statistical comparisons between DSNF-Pro and STNF were performed using Wilcoxon’s signed-rank test.

Results

DSNF-Pro significantly reduced postprandial glucose iAUC by 73.4% (p = 0.0001) and postprandial c-peptide iAUC by 36.4% (p = 0.0001) compared to STNF. However, there was no significant difference in postprandial insulin iAUC between DSNF-Pro and STNF.

Conclusions

These results demonstrated that DSNF-Pro effectively improved postprandial glucose responses in prediabetes, providing a practical alternative for managing glycemic control without increasing insulin secretion.

Background

Prediabetes is a condition where blood glucose levels are higher than normal but not enough to meet the diagnostic criteria for diabetes, categorized into impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) [1]. The global prevalence of prediabetes is increasing, and 5–10% of prediabetic individuals progressing to diabetes annually [2, 3]. Diabetes is caused by various factors such as age, sex, race, socio-economic, lifestyle, and genetics, thereby leading to serious complications like myocardial infarction, heart failure, renal disease, and cancer, thus increasing the risk of mortality [4, 5]. Consequently, diabetes serves as a significant risk factor for lifestyle diseases and multiple complications, making prevention at the prediabetic stage a necessary health concern in modern society [6, 7].

In individuals without diabetes, postprandial glucose reaches its peak 30–60 min after a meal and is subsequently regulated to normal levels within 2 h through insulin secretion [8]. However, prediabetes and diabetes patients have impaired insulin sensitivity and decreased pancreatic β-cell function, challenging postprandial glucose regulation [9, 10]. Accordingly, in preventing and managing diabetes, medical nutrition therapy (MNT) for blood glucose management is essential, with particular emphasis on postprandial glucose regulation for overall glycemic control [10, 11]. The primary element of MNT involves regulating blood glucose levels through decreasing carbohydrate intake while increasing unsaturated fat and protein [12]. This dietary strategy not only supports blood glucose control but also promotes weight loss, which is beneficial in preventing and treating diabetes [13]. Previous studies have reported that high-protein, low-carbohydrate dietary interventions have more positive effects on body composition, basal metabolic rate, and cardiovascular risk [14]. In addition, increased protein intake promotes insulin secretion, which improves blood glucose regulation, aids in weight loss by maintaining satiety and retaining lean body mass, and helps reduce insulin resistance [15–17]. These advantages suggest that high protein consumption implies preventing diabetes in prediabetes.

To improve protein intake, general strategies include incorporating high-protein foods into daily meals or using protein-rich supplements, both effective for weight loss and retaining muscle mass [18–20]. However, excessive protein intake, while potentially enhancing insulin secretion, aggravates insulin resistance, posing risks for individuals with diabetes or prediabetes [15]. Thus, it is crucial to identify an alternative that retains the advantages of increased protein consumption while ensuring stable glycemic control. A promising approach is using a high-protein diabetes-specific nutritional formula (DSNF) specifically formulated for managing glycemic levels. Several prior studies have explored the role of high-protein DSNF in enhancing glycemic control among individuals with diabetes, emphasizing its potential to support metabolic health through a carefully balanced macronutrient composition tailored to maintain optimal blood glucose levels [21–23]. These DSNFs, characterized by low carbohydrate content, high protein, monounsaturated fatty acids (MUFA), and dietary fiber help maintain muscle mass and overall nutritional status while effectively regulating blood glucose levels [24]. Therefore, this study aims to comprehensively examine the effectiveness of diabetes-specific nutritional formula-pro (DSNF-Pro) with high-protein content for prediabetes and evaluate its clinical utility.

Methods

Subjects

Twenty-one subjects who were aware of prediabetes were recruited through open announcements. The fifteen subjects were selected to meet the following eligibility criteria in a screening test, including a blood test using hemoglobin A1c (HbA1c) and fasting blood glucose (FBG). Inclusion criteria comprised individuals aged 19–65 with prediabetic status, as defined by the Korea Diabetes Association standards [25], including an HbA1c level of 39 mmol/mol (5.6%) to 46 mmol/mol (6.4%) or an FBG level of 100 mg/dL to 125 mg/dL. Exclusion criteria included individuals diagnosed with type 1 diabetes, an HbA1c level ≥10.2 mmol/mol (8.0%), an FBG level ≥180 mg/dL, and those using antidiabetic medications or insulin except metformin. Other exclusion criteria were body mass index (BMI) ranging from <18.5 kg/m² or >30.0 kg/m², use of medications or health-functional foods that have been known to affect glucose tolerance in the past 1 month; uncontrolled hypertension patients (systolic blood pressure/diastolic blood pressure ≥160/100 mmHg); medical treatments or medical severe histories of cardiovascular, endocrine metabolic, respiratory, hepatobiliary, renal, blood, or tumor disorders; participation in another study in the past 1 month; and those judged by the investigator to be inappropriate for the study.

Study design

An open-label, cross-over clinical trial was conducted to assess the efficacy in fifteen adults with prediabetes. The eligible subjects were assigned to two investigational products: DSNF-Pro on the first visit and Standard nutritional formula (STNF) on the second. Since the interventions were not expected to cause any fixed or random effects, a uniform visit sequence was followed for all subjects. On each visit day, subjects visited the research facility after fasting for 10–12 h. Fasting blood samples were collected via a catheter inserted into an antecubital vein, and subjects consumed the designated investigational product within 5 min of the initial sip. Blood samples were subsequently obtained at 30, 60, 90, 120, and 180-minute post-consumption to assess plasma glucose, serum insulin, and serum c-peptide concentrations. Throughout the study, subjects maintained their regular dietary and physical activity. The subjects had a washout period of 1–14 days between visits.

Investigational products

DSNF-Pro used in this study was Nucare Glucose Plan Pro (Daesang Wellife Corp., Seoul, Republic of Korea), a 230 mL product providing 140 kcal. For comparison, the STNF widely consumed in the general population, was selected to match the isocaloric content. Nucare Glucose Plan Pro contains 12 g of protein, 12 g of carbohydrates, and 6 g of fat per serving. In contrast, the STNF includes 4.9 g of protein, 21 g of carbohydrates, and 4.2 g of fat. Notably, Nucare Glucose Plan Pro has a higher protein and fat content compared to the STNF and also contains monounsaturated fatty acids (MUFA), which are known to help regulate glucose levels, these are comprised 60% of the total fat. Additionally, it includes amounts of low glycemic index (GI) carbohydrates such as xylitol, palatinose, and dietary fiber. The nutritional profiles of the two investigational products are shown in Table 1.

Table 1.

Nutrient composition of the investigational products.

	DSNF-Pro	STNF
Serving size (mL)	230	140
Energy (kcal)	140.00	140.00
Carbohydrate (g)	12.00	21.00
Sugar (g)	2.00	4.90
Dietary fiber (g)	5.00	0.84
Fat (g)	6.00	4.20
Saturated fat (g)	0.60	0.84
Protein (g)	12.00	4.90

DSNF-Pro diabetes-specific nutritional formula, STNF standard nutritional formula.

Measurements

Socio-demographics and anthropometric measurement

During the screening visit, socio-demographic data, including sex, birth, lifestyle, alcohol consumption, smoking status, and medical and family history were collected. Anthropometric measurements (height, weight, body fat mass, body fat percent, skeleton muscle mass) and vital signs (blood pressure, pulse rate) were recorded at each visit. The anthropometric measurements of subjects were measured by a trained clinical trial coordinator while wearing lightweight clothing. Height was assessed using the BSM370 (Biospace Co., Ltd., Seoul, Korea) device, and weight was measured using the Inbody 970 (InBody Co., Ltd., Seoul, Korea). Height and weight measurements were rounded to one decimal place.

Glycemic profiles

Plasma glucose, serum insulin, and serum c-peptide levels were collected at each visit following a minimum 10-h overnight fast. After allowing the blood to stand at 20–25 °C for 30 min, it was centrifuged at 3000 rpm for 10 min to separate serum and plasma. The separated samples were then refrigerated at 2–8 °C. Blood samples were obtained from venous blood in ethylenediaminetetraacetic acid (EDTA)-treated tubes. Plasma glucose levels were determined using an enzymatic colorimetric glucose oxidase assay (ADAMS glucose GA-1171; Arkray Co, Kyoto, Japan). Serum insulin and c-peptide were collected from venous blood in serum separate tubes (SST) and measured using radioimmunoassay (RK-400CT; Izotop co., Budapest, Hungary, c-peptide IRMA KIT; Beckman Coulter Inc., California, United States, respectively).

Dietary assessment

Nutritional intake with subjects’ regular meals was assessed using a 24-h dietary recall method. Based on previous research indicating that the meal from the previous day affects postprandial glycemic response [26], subjects were instructed to maintain their usual dietary habits throughout the study. At each visit, subjects reported their dietary intake from the previous day, and a registered dietitian conducted interviews to gather information on their dietary choices. Daily nutritional intake analysis was performed using the CAN-Pro program (CAN-Pro 6.0; Korean Nutrition Society, Seoul, Korea).

Physical activity assessment

The physical activity of the subjects was assessed using the International Physical Activity Questionnaire (IPAQ). The IPAQ was recorded weekly for the typical physical activities of the subjects. Physical activity was expressed as the metabolic equivalent task (MET)-min/week (MET level × activity minutes/day × activity days/week). MET scores were calculated based on the intensity of activity as follows: vigorous intensity, 8 METs; moderate intensity, 4 METs; and walking, 3.3 METs (IPAQ Research Committee, 2005).

Ethics

All subjects were provided with detailed information about the experimental procedures and the associated risks, before obtaining their written informed consent. The study was conducted according to the guidelines established in the Declaration of Helsinki, and all procedures involving human subjects were approved by the Institutional Review Board of Kyung Hee University Hospital (KHUH 2023-05-091) and registered at the Clinical Research Information Service (CRIS) of the Korea Disease Control and Prevention Agency (KDCA) (Registration Number KCT0008904).

Statistical analysis

The primary outcome was the changes in postprandial glucose response comparing DSNF-Pro to STNF. Secondary outcomes were changes in postprandial insulin and c-peptide. Sample size calculations were conducted using G^*Power Software for version 3.1.9.7 (Heinrich-Heine-University Düsseldorf, Germany). A sample size of 12 subjects was calculated as adequate for detecting variations in glucose incremental area under the curve (iAUC) with 90% statistical power at a 5% α level, assuming matched pairs based on a prior study [27]. Consequently, a sample size of 15 was calculated, considering a drop-out rate of 20%.

Statistical analyses were executed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Descriptive statistics were presented as means ± standard deviation (SD) for continuous variables, and categorical variables were expressed as n (%). Wilcoxon’s signed rank test was used for variables to compare group differences. The iAUC for postprandial glucose, insulin, and c-peptide were individually calculated using the trapezoid rule [28]. Integrals were determined for each time interval and changed from baseline to the 180-minute endpoint, with the exclusion of the area beneath the baseline concentration. Additionally, the maximum concentration (C_max) and the incremental maximal concentration (iC_max) were determined by subtracting each baseline value from C_max. Statistical significance was defined as a p-value < 0.05.

Results

Socio-demographic and anthropometric characteristics of subjects at baseline

Fifteen subjects who completely participated in the study were analyzed, and their socio-demographic and anthropometric characteristics are shown in Table 2. Subjects had a mean age of 57.1 years and BMI of 26.0 kg/m² with prediabetes. The average of FBG and HbA1c was 101.9 mg/dL and 41.87 mmol/mol (5.82%), respectively. The intervention was well-received, with all subjects in both the DSNF-Pro and STNF entirely consuming their scheduled doses within 5 min.

Table 2.

Baseline characteristics of the study subjects.

Variables	Subjects
Sex
Male	1 (7)
Female	14 (93)
Age (years)	57.10 ± 6.16
Height (cm)	159.60 ± 5.63
Weight (kg)	66.49 ± 7.42
Body mass index (kg/m²)	26.00 ± 2.09
Body fat mass (kg)	24.82 ± 4.49
Body fat percent (%)	37.40 ± 4.79
Skeletal muscle mass (kg)	22.61 ± 3.84
Fat free mass (kg)	37.35 ± 5.03
SBP (mmHg)	122.73 ± 14.08
DBP (mmHg)	76.27 ± 8.82
PR (beats/minute)	69.40 ± 11.47
HbA1c (mmol/mol)	41.87 ± 3.98
Fasting blood glucose (mg/dL)	101.90 ± 11.87
Drinking Alcohol
Yes	4 (27)
No	11 (73)
Smoking
Yes	0 (0)
No	14 (93)
Ex	1 (7)
Exercise
Yes	7 (47)
No	8 (53)
Average numbers of meals/day	2.81 ± 0.40
Average numbers of snacks/day	1.81 ± 1.21
Average cups of water intake/day	5.57 ± 2.01

Values are expressed as means ± SD or n (%).

For drinking alcohol, answer “yes” if the subject drink’s alcohol more than once a week, otherwise, answer “no”.

Smoking status: “yes” indicates current smokers, “no” indicates non-smokers, and “ex” indicates individuals who have quit smoking.

For regular exercise, answer “yes” if subjects exercise more than once a week, and answer “no” otherwise.

BMI body mass index, HbA1c hemoglobin A1c, SBP systolic blood pressure, DBP diastolic blood pressure, PR pulse rate.

Change in postprandial glucose response

Changes in plasma glucose concentrations at each time point, iAUC, iC_max, and C_max are shown in Fig. 1a and Table 3. Following consumption of the investigational products, DSNF-Pro led to lower postprandial glucose level changes at 30 (10.80 ± 10.14 vs. 33.80 ± 21.90, p = 0.0002), 60 (11.40 ± 11.29 vs. 46.00 ± 23.67, p < 0.0001), and 90 (2.47 ± 8.93 vs. 21.33 ± 16.86, p = 0.0007) minutes compared to STNF, and higher levels at 180 min (−12.80 ± 8.11 vs. −17.87 ± 9.23, p = 0.0364). The plasma glucose iAUC significantly decreased consumption of the DSNF-Pro compared with the STNF (818.04 ± 673.96 vs. 3078.05 ± 1 726.04, p = 0.0001). Additionally, both the iC_max and C_max of glucose exhibited significant decreases after DSNF-Pro consumption compared to STNF (14.73 ± 10.76 vs. 46.80 ± 22.68, p < 0.0001 and 120.27 ± 16.76 vs. 149.93 ± 24.50, p < 0.0001, respectively).

Fig. 1. Postprandial changes in plasma glucose, serum insulin, and serum C-peptide following consumption of DSNF-Pro and STNF.

a Plasma glucose levels. b Serum insulin levels. c Serum C-peptide levels. DSNF-Pro (, green) and STNF (, gray) are shown. Significant differences between DSNF-Pro and STNF were determined by the Wilcoxon signed-rank test ^*p < 0.05, ^**p < 0.01, ^***p < 0.001.

Table 3.

Changes in postprandial plasma glucose, serum insulin, and serum c-peptide at each time point, iAUC, iC_max, and C_max after consumption of the investigational products.

Variables	DSNF-Pro	STNF	Difference	p-valuea
Plasma glucose
Time point
0 min (mg/dL)	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	–
30 min (mg/dL)	10.80 ± 10.14	33.80 ± 21.90	−23.00 ± 16.48	0.0002
60 min (mg/dL)	11.40 ± 11.29	46.00 ± 23.67	−34.60 ± 19.42	<0.0001
90 min (mg/dL)	2.47 ± 8.93	21.33 ± 16.86	−18.87 ± 16.08	0.0007
120 min (mg/dL)	−5.60 ± 5.10	−3.87 ± 10.23	−1.73 ± 10.92	0.6085
180 min (mg/dL)	−12.80 ± 8.11	−17.87 ± 9.23	−5.07 ± 8.00	0.0364
iAUC (mg∙min/dL)	818.04 ± 673.96	3078.05 ± 1726.04	−2260.01 ± 1329.57	0.0001
iCmax (mg/dL)	14.73 ± 10.76	46.80 ± 22.68	−32.07 ± 14.80	<0.0001
Cmax (mg/dL)	120.27 ± 16.70	149.93 ± 24.50	−29.67 ± 11.74	<0.0001
Serum insulin
Time point
0 min (µIU/mL)	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	–
30 min (µIU/mL)	19.59 ± 15.68	19.99 ± 10.98	−0.40 ± 12.84	0.9780
60 min (µIU/mL)	18.37 ± 13.73	19.59 ± 8.92	−1.22 ± 10.20	0.5245
90 min (µIU/mL)	5.94 ± 4.28	7.70 ± 5.97	−1.76 ± 6.71	0.4212
120 min (µIU/mL)	0.09 ± 3.94	1.30 ± 3.48	−1.21 ± 5.30	0.5995
180 min (µIU/mL)	−1.52 ± 4.75	−0.93 ± 3.72	−0.59 ± 6.05	0.6495
iAUC (µIU∙min/mL)	1415.16 ± 896.11	1534.68 ± 534.18	−119.52 ± 678.42	0.3591
iCmax (µIU/mL)	23.10 ± 15.36	24.03 ± 8.70	−0.93 ± 12.10	0.7197
Cmax (µIU/mL)	31.69 ± 16.42	30.89 ± 10.55	0.80 ± 12.27	0.8904
Serum c-peptide
Time point
0 min (ng/mL)	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	–
30 min (ng/mL)	1.72 ± 0.83	2.14 ± 0.89	−0.42 ± 0.67	0.1828
60 min (ng/mL)	2.23 ± 1.01	3.28 ± 0.96	−1.05 ± 0.72	0.0004
90 min (ng/mL)	1.59 ± 0.63	2.65 ± 0.82	−1.07 ± 0.90	0.0012
120 min (ng/mL)	0.84 ± 0.43	1.52 ± 0.81	−0.68 ± 0.79	0.0067
180 min (ng/mL)	−0.20 ± 0.29	0.12 ± 0.42	−0.32 ± 0.53	0.0805
iAUC (ng∙min/mL)	200.50 ± 82.61	315.34 ± 89.68	−114.85 ± 72.98	0.0001
iCmax (ng/mL)	2.33 ± 0.95	3.50 ± 0.90	−1.18 ± 0.77	0.0003
Cmax (ng/mL)	4.45 ± 1.14	5.52 ± 1.36	−1.07 ± 0.91	0.0020

Values are expressed as means ± SD.

DSNF-Pro diabetes-specific nutritional formula, iAUC incremental area under the curve, C_max maximal value, iC_max incremental maximal value, STNF standard nutritional formula.

^ap-values were obtained using the Wilcoxon signed-rank test.

Change in postprandial insulin response

Changes in serum insulin concentrations at each time point, iAUC, iC_max, and C_max are shown in Fig. 1b and Table 3. Following the DSNF-Pro and STNF consumption, no significant difference was observed in postprandial insulin level changes.

Change in postprandial c-peptide response

Changes in serum c-peptide concentrations at each time point, iAUC, iC_max, and C_max are shown in Fig. 1c and Table 3. After the consumption of the investigational products, DSNF-Pro resulted in lower postprandial c-peptide level changes at 60 (2.23 ± 1.01 vs. 3.28 ± 0.96, p = 0.0004), 90 (1.59 ± 0.63 vs. 2.65 ± 0.82, p = 0.0012), and 120 (0.84 ± 0.43 vs. 1.52 ± 0.81, p = 0.0067) minutes compared to STNF. The serum c-peptide iAUC (200.50 ± 82.61 vs. 315.34 ± 89.68, p = 0.0001), iC_max (2.33 ± 0.95 vs. 3.50 ± 0.90, p = 0.0003), and C_max (4.45 ± 1.14 vs. 5.52 ± 1.36, p = 0.0020) significantly decreased consumption of the DSNF-Pro compared with STNF.

Daily dietary intake and physical activity level

The results of daily dietary intake and physical activity level are shown in Supplementary Table 1. These variables were assessed at each visit, and no significant differences were observed between them, indicating that dietary intake and physical activity levels remained consistent throughout the study.

Discussion

We demonstrated that DSNF-Pro in prediabetes reduced postprandial glucose responses without increasing insulin secretion in prediabetes. These findings showed that DSNF-Pro resulted in a 73.42% reduction in postprandial blood glucose iAUC in prediabetes. Additionally, postprandial blood c-peptide iAUC decreased by 36.42%. These findings suggest that DSNF-Pro positively affects glycemic control in prediabetes.

The DSNF-Pro included low GI carbohydrates, MUFA, and whey protein, known to mitigate postprandial blood glucose responses effectively. These results are consistent with those of Mongkolsucharitkul et al. [21] who observed that in individuals with type 2 diabetes (T2DM), consumption of a white sesame soymilk smoothie with modified carbohydrate content (SMMC)—containing 10% (−7.8 g) less carbohydrate, and 10% (+7.8 g) and 11% (+3.8 g) more protein and fat, respectively—resulted in significant reductions in postprandial glucose and c-peptide AUC_0-120 compared to Glucerna® [21]. In contrast, a white sesame soymilk smoothie (SM) —containing 11% (+8.2 g) more carbohydrates, and similar protein (−3.2 g) and fat (−2.5 g)—led to higher postprandial glucose, c-peptide, and insulin responses compared to SMMC [21]. These results suggest that while an increase in protein content could have led to an expected increase in insulin secretion, the lower carbohydrate and higher fat content likely offset this effect, resulting in no significant change in insulin secretion. Similarly, the study by Sridonpai et al. [22] reported that in diabetes, consumption of a whey protein-based multi-ingredient nutritional drink led to a significant 63% reduction in postprandial glucose iAUC without altering insulin secretion when compared to the consumption of chicken and white rice. Additionally, they observed a significant 141% increase in postprandial GLP-1 iAUC with the whey protein-based nutritional drink relative to the chicken and white rice group. Unlike our study, their study involved testing and controlling products with similar energy, carbohydrate, protein, and fat content, indicating that not only the macronutrient composition but also the source of these nutrients implies a significant effect on glucose and related metabolic markers.

Consumption of substantial amounts of protein and various amino acids, including arginine, L-alanine, and branched-chain amino acids (BCAAs), within these proteins, are known to promote insulin secretion, and aid in blood glucose regulation [23, 29]. In addition, additional protein intake supports increasing and maintaining lean body mass, strengthening skeletal muscle, and enhancing physical function [30]. Previous research has shown that a high-protein diet significantly reduces postprandial glycemic response in healthy individuals [31]. Similarly, a high-protein diabetes-specific nutritional shake significantly reduces postprandial glycemic response with increased insulin secretion in type 2 diabetes [29]. Furthermore, preloading with protein before a meal decreased postprandial blood glucose levels by 28%, and insulin and c-peptide responses increased by 105% and 43%, respectively [32]. Long-term use of high-protein DSNF in diabetic patients has been shown to reduce HbA1c and fasting glucose and result in significant weight loss [33]. Moreover, several prior studies show that high-protein DSNFs have used a variety of protein sources, with protein proportions typically ranging from approximately 15% to 30% [21, 22, 34–36]. However, these DSNFs still maintained relatively high fat content, sometimes even surpassing the protein content, usually emphasizing unsaturated fat-based strategies, to improve glycemic control. Therefore, these results remain unclear whether the observed glycemic benefits were primarily attributable to the high-protein content or the higher fat content relative to protein. In contrast, DSNF-Pro was designed with equal amounts of protein and fat, enabling a greater carbohydrate replacement ratio, surpassing that of previous high-protein DSNFs. This strategy aimed not only to improve postprandial glycemic control through a high-protein intake but also to address long-term metabolic risk factors such as insulin resistance and weight management. By optimizing the carbohydrate replacement ratio with both protein and fat, this formulation may offer a more effective and balanced nutritional approach for individuals with impaired glucose metabolism. Additionally, a recent systematic review and meta-analysis has provided strong evidence that the amount of protein consumed plays a more significant role in glycemic control than the source of protein [37]. These findings highlight the importance of increasing protein intake, which not only positively impacts both short- and long-term blood glucose management but also improves diabetes risk factors. Therefore, DSNF-Pro, with its higher protein content and reduced carbohydrate proportion, may contribute to better postprandial glycemic control and long-term improvements in diabetes-related outcomes.

The DSNF-Pro also contained low GI carbohydrates and MUFAs, which are known to effectively moderate fluctuations in postprandial glucose and insulin levels. In the previous study, the intake of DSNF-containing isomaltulose reduced the postprandial blood glucose iAUC by 41% and postprandial insulin iAUC by 29% in prediabetes compared to the intake of standard oral nutritional supplement (ONS) [23]. Additionally, previous meta-analyses have shown that using DSNF containing high MUFA in patients with diabetes or hyperglycemia can improve postprandial blood glucose, insulin, and HbA1c levels compared to standard ONS [38]. Therefore, in this study, the postprandial insulin responses to DSNF-Pro and STNF were similar, which could be attributed to low GI carbohydrates and MUFA supplements offsetting the insulin secretion promoted by the protein in DSNF-Pro.

Although high-protein consumption provides many potential benefits for individuals with prediabetes, there are important precautions to consider. First, while high dietary protein intake tends to stimulate insulin secretion, and short-term high-protein intake can be beneficial in managing diabetes, long-term high-protein consumption may lead to excessive insulin secretion and potentially worsen insulin resistance [15]. Insulin resistance can hinder blood glucose control and increase the risk of long-term weight gain and progression to diabetes [39]. Second, high protein intake can strain the kidneys, potentially increasing the risk of kidney function decline [40]. Therefore, when considering DSNF-Pro, prediabetes should assess their health status thoroughly, seek expert advice, and plan an optimal dietary strategy with continuous health monitoring and consultation with healthcare professionals for effective blood glucose control.

This study has several strengths. First, we adopted a cross-over design, which ensured that each participant received both the experimental and control interventions, thereby minimizing inter-individual variability and ensuring consistent intervention effects. Second, we recruited individuals with prediabetes due to their mild glucose dysregulation and stable glycemic control, which enabled precise evaluation of intervention effects. Normal individuals were excluded as they do not require diabetes prevention, and those with diabetes were excluded due to excessive glucose variability and potential medication effects, making prediabetes the ideal focus for this study. However, there are a few limitations to this study. One limitation is the difference in volume between the DSNF-Pro and the STNF. The DSNF-Pro was 230 mL, whereas the STNF was 140 mL. While the volume difference could potentially influence other physiological responses, we aimed to mitigate this by ensuring both investigational products were isocaloric. Additionally, this study was an administration trial, making it difficult to generalize to long-term effects. Future research with longer follow-up periods has to confirm and better understand the long-term effects of diabetes management and prevention. Incorporating indicators such as insulin resistance and pancreatic insulin secretion in long-term studies would offer deeper insights into the mechanisms underlying diabetes prevention, helping to assess the lasting effects of the intervention. Despite these limitations, our study provides insights into the impacts of DSNF-Pro on glycemic control in prediabetes, highlighting the significance of the study focused on identifying the role of protein-rich DSNF in diabetes management and prevention compared to general STNF.

This study demonstrated that DSNF-Pro effectively improved postprandial glucose without increasing insulin secretion in prediabetes. These results emphasize the potential of high-protein DSNF as a tool for managing and preventing the progression of prediabetic conditions.

Author contributions

YH, MB, SC, and HL conceived the research. YH, MB, SC, and HL designed the research. YH and MB recruited and monitored trial participants during screening and follow-up visits. MB and YH collected data. YH performed the statistical analysis, prepared the figures, and wrote the manuscript. BM, SC and HL revised the manuscript. All the authors provided scientific interpretation and approved the manuscript.

Funding

This research was supported by grants from Daesang Wellife Corp., Seoul, Republic of Korea.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Kyung Hee University Hospital’s Institutional Review Board approved this study (IRB number: KHUH 2023-05-091). All the subjects provided written informed consent to participate in the study.

Consent for publication

Written informed consent was obtained from the subjects for the publication of their data.

Supplementary information

The online version contains supplementary material available at 10.1038/s41387-025-00399-2.