Abstract
Background
The classification of early onset (< 30 years old) patients with diabetes mellitus (DM) as either type 1 diabetes (T1D) or type 2 diabetes (T2D) can be a challenge due to their similar overlapping phenotypes. In this study, we attempted to utilize various clinical and laboratory characteristics in combination with immunological factors in the blood to determine whether it would be possible to distinguish and more accurately characterize our patients as T2D.
Methods
Electronic medical records were evaluated to obtain information categorized as either early onset patients with DM (n = 102) and patients with T1D (n = 89). Using the stored serum from these patients, autoantibodies of anti-insulinoma associated 2 (IA2), anti-zinc transporter 8 (ZnT8) and anti-glutamic acid decarboxylase antibody (GAD) were measured.
Results
In the clinical characteristics, early onset patients with DM (n = 102) were younger (31.7 ± 7.0 years old, P < 0.01), more overweight (28.1 ± 5.5 kg/m2, P < 0.05), shorter duration of diabetes (10.4 ± 7.3 years, P < 0.01) and a more prevalent family history of diabetes (81%, P < 0.01) than patients with T1D. The laboratory values from early onset patients with DM exhibited lower glycated hemoglobin A1c (8.0 ± 2.1%, P < 0.01) and glucose levels (165 ± 73 mg/dL, P < 0.01) with conversely higher C-peptide levels (2.2 ± 1.2 ng/mL, P < 0.01). Measurements of immunological factors, demonstrated that the prevalence of anti-ZnT8 (2%) and anti-GAD antibody (2%) in early onset patients with DM was significantly lower (P < 0.01) compared to patients with T1D (13% for anti-ZnT8 and 38% for anti-GAD). The prevalence of anti-IA2 was not significantly different between early onset patients with DM (13%) versus patients with T1D (11%). In the multivariate logistic regression analysis, C-peptide level (B, 4.453; standard error [SE], 0.844; Wald, 27.808; P < 0.001) was the strongest independent factor to distinguish early onset patients with DM as T2D. After adjusting C-peptide level, family history of diabetes (B, 0.830; SE, 0.420; Wald, 3.909; P = 0.048), body mass index (BMI) (B, 0.111; SE, 0.039; Wald, 8.167; P = 0.004) and the relative negative status of anti-GAD (B, −2.041; SE, 0.597; Wald, 11.670; P < 0.001) were determining factors in our analyses.
Conclusion
In this study, our findings suggested that early onset patients with DM may be more accurately diagnosed as T2D if they have a compilation of elevated C-peptide levels, higher BMI, more prevalent history of familial diabetes and the absence of detecting anti-GAD antibodies.
Keywords: Type 2 Diabetes, Early Onset Patients, Family History of Diabetes, Overweight/Obesity, C-Peptide, Anti-GAD Antibody
Graphical Abstract
INTRODUCTION
The global incidence and prevalence of diabetes mellitus (DM) are continuously increasing, with the latter being anticipated to reach 784 million by 2043.1 Type 2 diabetes (T2D) accounts for more than 90% of all types of DM worldwide. Recently the increasing rates of T2D in children, adolescents, and young adults after the 2000s raises the public health concern.2,3,4,5,6,7 Four-decades ago, “juvenile diabetes” referred to type 1 diabetes (T1D) and “adult-onset diabetes” was synonymous with T2D. Today, incidence of T2D in adolescents is twice that of T1D in several ethnic groups.8,9 Accumulating evidence indicates that early onset T2D is associated with a more severe disease phenotype, characterized by faster decline in ß-cell secretory function, leading to necessitation of insulin therapy earlier in the course of disease, alongside with increased lifetime risk of developing unfavorable long-term outcomes.2
DM is a heterogenous disease of metabolic disorders that share hyperglycemia as a common clinical characteristic. T1D is caused by an immune-mediated destruction of ß-cell, resulting in lifelong dependence of exogenous insulin.10 The positivity of pancreatic autoantibodies is helpful to diagnose new-onset T1D.11,12 T2D is characterized by insulin resistance and insufficient insulin secretion.2 Although patients with DM can be classified into T1D or T2D, a considerable proportion of patients do not fit into these classifications, especially challenging the early onset patients with DM correctly to classify into T1D or T2D.
In this study, we evaluated the clinical and laboratory characteristics and measured the positivity of pancreatic autoantibodies in early onset patients with DM and finally investigated the independent factors to be helpful to diagnose early onset patients with DM into T2D.
METHODS
Study design and participants
In this study, we retrospectively identified medical records of one hundred twelve (n = 112) early onset (age < 30 years old) patients with DM, who were previously diagnosed as T2D by the attending physician in the Endocrinology department at Chungbuk National University Hospital between the years 2014 to 2022 for comparison with clinical information from ninety-five (n = 95) patients diagnosed with T1D. Early onset patients with T2D were identified based not only on age < 30 years, but also on clinical presentation at diagnosis including: absence of diabetic ketoacidosis, no requirement for insulin therapy from onset, preserved C-peptide levels, and negative results for diabetes-related autoantibodies (anti-glutamic acid decarboxylase antibody [GAD], anti-insulinoma associated 2 [IA2], and anti-zinc transporter 8 [ZnT8]). Among these groups of candidates, patients were excluded if they failed to meet one of the following criteria: 1) pancreatitis or pancreatectomy-associated, 2) drug (such as steroid or vacor)-induced, 3) initially diagnosed during the pregnancy, 4) lack of any laboratory data, and 5) lack of any stored serum sample. From those patients that met our criteria, one hundred two (n = 102) early onset patients with DM and eighty-nine (n = 89) patients with T1D were included in our study. Clinical data used for stratification included their current age, diagnosed age, family history of diabetes, sex ratio, duration of diabetes, history of diabetic ketoacidosis (DKA), topographic measurement including height, body weight (Bwt), and current strategy of treatment (including life style modification, oral hypoglycemic agents [OHAs], insulin alone or combined with OHA). The basal laboratory data from their records that were used for analysis included glycated hemoglobin A1c (HbA1c), glucose and fasting C-peptide at their first visit if available.
Pancreatic autoantibodies assay
The reason for measuring three different pancreatic autoantibodies (anti-GAD, anti-IA2, and anti-ZnT8) is to enhance the diagnostic sensitivity for immune-mediated diabetes. While anti-GAD is the most commonly detected in type 1 diabetes, some patients may only be positive for anti-IA2 or anti-ZnT8. Therefore, testing all three allows better differentiation between T1D and T2D in ambiguous cases. This approach is supported by prior studies showing that inclusion of IA2 and ZnT8 can increase diagnostic yield.
The serum samples were stored at −80oC until analysis at the laboratory of the Endocrinology department at Chungbuk National University Hospital. The anti-IA2 (LSBio, Newark, CA, USA) and anti-ZnT8 (Biovendor, Heidelberg, Germany) antibody assays were measured using enzyme-linked immunosorbent assay. The anti-GAD (DIAsource, Springfield, NJ, USA) antibody assay was measured using radioisotope-linked immunosorbent assay. The threshold to determine a positive result (with a 95% specificity) for anti-IA2 antibody was 2.0 ng/mL with a minimal detection limit of 0.31 ng/mL. The threshold for a positive finding for anti-ZnT8 antibody (with a 97% specificity) was 15 U/mL with minimal detection limit of 1.20 U/mL. The threshold for positive detection of anti-GAD antibody (with a 100% specificity) was 2.0 U/mL, including a borderline zone of 1.0–1.9 U/mL, and minimal detection limit of 0.1 U/mL.
Biochemistry
Commercial immunoassays were used to measure C-peptide level (Abbott, Lake Forest, IL, USA), HbA1c (Bio-Rad Laboratories, Hercules, CA, USA) and plasma glucose (TOSHIBA FX-8, Kawasaki, Japan).
Statistical analysis
Statistical analyses were done in SPSS for Windows (version 24.0, IBM Corp., Armonk, NY, USA). The continuous variables are expressed as the mean ± standard deviation and the difference between groups was analyzed with independent Student’s t-test. The expression of median with interquartile range analyzed by Mann-Whitney U test was done for C-peptide due to skewed distribution. A two-sided significance level of 0.05 was used as being significant. The nominal variables are expressed as number (%) and the difference between groups was analyzed with the χ2 test with P < 0.05 of significance. Missing data were excluded case-wise from analysis. Multiple logistic regression test was performed to determine the independent factors to classify early onset patients with DM for T2D.
Ethics statement
The study was carried out in accordance with the principles stated in the Declaration of Helsinki, as revised in 2013 and the International Conference of Harmonization/Good Clinical Practice guidelines.13,14 The Institutional Review Board (IRB) at Chungbuk National University Hospital approved the study (IRB No. 2021-10-001-004), and written informed consent from patients to participate was obtained when serum samples were collected.
RESULTS
Patient characteristics
Table 1 summarized all of the clinical and laboratory characteristics in the early onset patients with DM (n = 102) and the patients with T1D (n = 89). The early onset patients with DM compared to patients with T1D were on average younger (31.7 ± 7.0 vs. 35.9 ± 12.0 years old, respectively; P < 0.01) and had shorter duration of diabetes in years (10.4 ± 7.3 vs. 14.5 ± 10.0 years, respectively; P < 0.01) with a correspondingly higher family history of diabetes (81% vs. 53%, respectively; P < 0.01). In addition, the early onset patients with DM were generally more overweight than patients with T1D (28.1 ± 5.5 kg/m2 vs. 24.3 ± 4.5 kg/m2, respectively; P < 0.05). There was no difference between the two groups with respect to their diagnosed age and sex ratio. In terms of their treatment modality, most patients with T1D (n = 85, 95%) were treated with insulin only except one patient (1%) who was treated with a life style modification and three other patients (3%) were treated with insulin combined with OHA. For early onset patients with DM, their treatments involved various types of modalities, including diet plus exercise (n = 5, 5%), OHAs (n = 61, 60%), insulin only (n = 11, 10%) and insulin plus OHAs (n = 25, 24%). The history of DKA was only observed in patients with T1D (n = 32, 35%). In the laboratory data from their initial visit demonstrated that the early onset patients with DM exhibited lower HbA1c (8.0 ± 2.1%, P < 0.01) and glucose levels (165 ± 73 mg/dL, P < 0.01) with a conversely higher C-peptide level (2.2 ± 1.2 ng/mL, P < 0.01) compared to the HbA1c (9.1 ± 2.7%), blood glucose (216 ± 184 mg/dL) and C-peptide (0.3 ± 0.4 ng/mL) levels in patients with T1D.
Table 1. Clinical and laboratory characteristics of study subjects (n = 191).
| Variables | Early onset DM (n = 102) | T1D (n = 89) | P value | |
|---|---|---|---|---|
| Current age, yr | 31.7 ± 7.0 | 35.9 ± 12.0 | < 0.01 | |
| Diagnosed age, yr | 21.3 ± 4.9 | 21.3 ± 10.2 | NS | |
| Duration of diabetes, yr | 10.4 ± 7.3 | 14.5 ± 10.0 | < 0.01 | |
| FHx of diabetes (+/−) | 80/19 (78.4) | 43/38 (48.3) | < 0.01 | |
| Male | 61 (59.8) | 50 (56.2) | NS | |
| BMI, kg/m2 | 28.1 ± 5.5 | 24.3 ± 4.5 | < 0.05 | |
| Current Tx. modality | < 0.01 | |||
| Diet + exercise | 5 (4.9) | 1 (1.1) | ||
| OHAs | 61 (59.8) | 0 (0.0) | ||
| Insulin alone | 11 (10.8) | 85 (95.5) | ||
| Insulin + OHAs | 25 (24.5) | 3 (3.4) | ||
| HbA1c, % | 8.0 ± 2.1 | 9.1 ± 2.7 | < 0.01 | |
| Glucose, mg/dL | 165 ± 73 | 216 ± 184 | < 0.01 | |
| C-peptide, ng/mL | 2.2 ± 1.2 | 0.3 ± 0.4 | < 0.01 | |
| History of DKA | 0 (0.0) | 32 (36.0) | ||
Continuous variables are expressed as mean ± SD or number (%). Nominal variables are shown as numbers in parentheses indicates the calculated percentage of subjects.
DM = diabetes mellitus, T1D = type 1 diabetes, NS = not significant, FHx = family history, BMI = body mass index, Tx. = treatment, OHA = oral hypoglycemic agent, HbA1c = glycated hemoglobin A1c, DKA = diabetic ketoacidosis.
Prevalence of pancreatic autoantibodies
To investigate the immunogenic profile in the early onset patients with DM (n = 102) and patients with T1D (n = 89), three different types of anti-IA2, anti-ZnT8 and anti-GAD antibody assay were performed. As shown in Table 2, each of the pancreatic autoantibodies were detected at a relatively less prevalent number of patients in the early onset with DM compared to those patients with T1D. Anti-IA2 autoantibody was detected in ~13% of the early onset patients with DM (n = 14 out of 102 patients), but this was not significantly different from patients with T1D (11%; n = 10 out of 89 patients). On the contrary, a significantly higher number of positive patients with T1D (P < 0.01 for both antibodies) for plasma anti-ZnT8 antibodies (~13%, n = 12 out of 89) and anti-GAD antibodies (~38%, n = 34 out of 89) were determined in comparison to the low number of early onset patients with DM (~2%, n = 2 for both antibodies in this group).
Table 2. Prevalence of pancreatic autoantibodies in study subjects (n = 191).
| Antibody | Results | Early onset DM (n = 102) | T1D (n = 89) | P value |
|---|---|---|---|---|
| Anti-IA2 | Negative | 88 (86.0) | 79 (88.0) | |
| Positive | 14 (13.0) | 10 (11.0) | NS | |
| Anti-ZnT8 | Negative | 100 (98.0) | 77 (86.0) | |
| Positive | 2 (2.0) | 12 (13.0) | < 0.01 | |
| Anti-GAD | Negative | 100 (98.0) | 55 (61.0) | |
| Borderline | 1 (1.0) | 6 (7.0) | ||
| Positive | 1 (1.0) | 28 (31.0) | < 0.01 |
All data are shown as numbers in parentheses indicates the calculated percentage of subjects. The χ2 test was performed for comparison between two groups.
Anti-IA2 = anti-insulinoma associated 2 antibody, positive > 2.0 ng/mL, NS = not significant, Anti-ZnT8 = anti-zinc transporter 8 antibody, positive > 15 U/mL, Anti-GAD = anti-glutamic acid decarboxylase antibody, positive > 2.0 U/mL, Borderline 1.0–1.9 u/mL.
Subgroup analysis according to the autoantibody-positivity
Subgroup analysis in early onset patients with DM (n = 102) was performed to further investigate whether there may be a distinguishing factor from the number of patients being positive for one of the autoantibodies being detected in their banked blood. Among the antibody positive patients (n = 18), in whom no one had duplicate positive antibody, and the antibody negative patients (n = 84), none of the following parameters (diagnosed age, family history of diabetes, duration of diabetes, body mass index (BMI), glycemic profile or C-peptide level) were significantly different between the two groups.
In the subgroup analysis of the patients with T1D (n = 89), there were forty-seven patients (n = 47) with positive antibody, among whom seven patients had double and one patient had triple positive antibody, and forty-two patients (n = 42) with negative antibody. The patients detected with a positive antibody result (n = 47) exhibited a shorter duration of diabetes (P < 0.01) compared to those without any antibody (n = 42) (Table 3). Other parameters were not different between both groups.
Table 3. Clinical and laboratory characteristics according to the autoantibody-positivity in patients with T1D (n = 89).
| Variables | Positive antibody (n = 47) | Negative antibody (n = 42) | P value | |
|---|---|---|---|---|
| Current age, yr | 34.2 ± 13.0 | 37.8 ± 10.7 | NS | |
| Diagnosed age, yr | 23.0 ± 11.6 | 19.5 ± 8.0 | NS | |
| Duration of diabetes, yr | 11.1 ± 9.2 | 18.3 ± 9.6 | < 0.001 | |
| Male | 26 (55.3) | 24 (57.1) | NS | |
| BMI, kg/m2 | 23.6 ± 4.2 | 24.9 ± 4.8 | NS | |
| Current Tx. modality | ||||
| Diet + exercise | 1 (2.1) | 0 (0.0) | ||
| OHAs | 0 (0.0) | 0 (0.0) | ||
| Insulin alone | 44 (93.6) | 41 (97.6) | NS | |
| Insulin + OHAs | 2 (4.3) | 1 (2.4) | ||
| HbA1c, % | 9.4 ± 2.4 | 8.7 ± 2.9 | NS | |
| Glucose, mg/dL | 237 ± 186 | 193 ± 182 | NS | |
| C-peptide, ng/mL | 0.3 ± 0.5 | 0.2 ± 0.3 | NS | |
| History of DKA | 13 (27.7) | 19 (45.2) | NS | |
Continuous variables are expressed as mean ± SD or number (%). Nominal variables are shown as numbers in parentheses indicates the calculated percentage of subjects.
T1D = type 1 diabetes, NS = not significant, BMI = body mass index, Tx. = treatment, OHA = oral hypoglycemic agent, HbA1c = glycated hemoglobin A1c, DKA = diabetic ketoacidosis.
Quantitative analysis to classify the early onset patients with DM into T2D
To determine the independent factor to classify the early onset patients with DM into T2D, multiple logistic regression analysis with the clinical, laboratory and immunological parameters was performed. Among those factors, C-peptide level (B, 4.453; standard error [SE], 0.844; Wald, 27.808; P < 0.001) was the strongest factor to classify the early onset patients with DM into T2D (Table 4). After adjusting C-peptide, family history of diabetes (B, 0.830; SE, 0.420; Wald, 3.909; P = 0.048), BMI (B, 0.111; SE, 0.039; Wald, 8.167; P = 0.004) and anti-GAD positivity (B, −2.041; SE, 0.597; Wald, 11.670; P < 0.001) were the independent factors to categorize the early onset patients with DM into T2D (Table 4).
Table 4. Multivariate logistic regression analysis to classify the early onset patients with DM into T2D.
| Variables | B | SE | Wald | P value | |
|---|---|---|---|---|---|
| Without adjusting | |||||
| Diagnosed age | 0.055 | 0.063 | 0.760 | 0.383 | |
| FHx of diabetes | 0.971 | 1.054 | 0.848 | 0.357 | |
| BMI | 0.008 | 0.075 | 0.012 | 0.913 | |
| HbA1c | −0.105 | 0.175 | 0.363 | 0.547 | |
| Glucose | 0.001 | 0.003 | 0.037 | 0.847 | |
| C-peptide | 4.453 | 0.844 | 27.808 | < 0.001 | |
| Anti-IA2 | −1.102 | 1.283 | 0.738 | 0.390 | |
| Anti-ZnT8 | −0.309 | 2.476 | 0.016 | 0.901 | |
| Anti-GAD | −3.913 | 6.655 | 0.346 | 0.557 | |
| With adjusting C-peptide | |||||
| Diagnosed age | 0.020 | 0.030 | 0.417 | 0.518 | |
| FHx of diabetes | 0.830 | 0.420 | 3.909 | 0.048 | |
| BMI | 0.111 | 0.039 | 8.167 | 0.004 | |
| HbA1c | −0.156 | 0.096 | 2.670 | 0.102 | |
| Glucose | 0.000 | 0.002 | 0.003 | 0.955 | |
| Anti-IA2 | −0.087 | 0.567 | 0.023 | 0.878 | |
| Anti-ZnT8 | −1.008 | 0.930 | 1.174 | 0.279 | |
| Anti-GAD | −2.041 | 0.597 | 11.670 | < 0.001 | |
DM = diabetes mellitus, T2D = type 2 diabetes, FHx = family history, BMI = body mass index, HbA1c = glycated hemoglobin A1c, Anti-IA2 = anti-insulinoma associated 2 antibody, Anti-ZnT8 = anti-zinc transporter 8 antibody, Anti-GAD = anti-glutamic acid decarboxylase antibody, B = correlation coefficient, SE = standard error, Wald = Wald statistics for logistic regression analysis.
DISCUSSION
The present study provides a new assessment to help clinicians to distinguish and more accurately classify patients as having T2D from a population of early onset patients (age < 30 years old) diagnosed generically with DM. Our analyses demonstrated that using prior patient information (family history of diabetes, Bwt and C-peptide levels) with new laboratory measurements of pancreatic autoantibodies may provide a more accurate clinical signature that can differentiate patients with T2D from T1D diagnosed at a similar age.
It is known that the over-weight/obesity status can be a major risk factor to develop the T2D in adolescents and young adults. In this study, 72% (n = 73) of early onset patients with DM (n = 102) were over-weight (BMI > 25 kg/m2)/obesity at their initial visit to the hospital. In a previous study aiming to assess the phenotype characteristics and risk factors leading to early onset T2D (< 40 years old), 95% of the participants were found to be either over-weight or obese.15 Consistent with these findings, severe obesity (BMI > 35 kg/m2) was shown to increase the risk for T2D in early adulthood in both sexes.16 Although the pathophysiology and precise mechanisms involved in the development of T2D for these young people were not fully described, the overall etiology is similar to those patients exhibiting later-onset T2D, including insulin resistance and ß-cell dysfunction.17 Obesity, which is major determinant of insulin resistance, is more common in early onset patients with T2D (95%) compared to later-onset (> 40 years old) T2D (50%).17 Moreover, it is considered to be one of the key drivers in developing the early onset phenotype of the disease. On the other hand, BMI and age of T2D onset are shown to have a strong inverse correlation.18 More important than obesity per se seems to be the unfavorable distribution of adipose tissue and intramyocellular and intrahepatic lipid content, which is also more prominent in early onset patients with T2D. In fact, intrahepatic fat, which is emerging as the most important marker of insulin resistance, is threefold higher compared to later-onset T2D and BMI-matched peers without diabetes.19
The substantial difference between early- and later-onset T2D is that the impairment of ß-cell function progresses more rapidly, highlighting that impaired insulin secretion is the key operating pathophysiologic mechanism. The yearly ß-cell function deterioration in early onset T2D was reported to be 20–35% by the Multi-Ethnic treatment Options for T2DM in Adolescent and Youth (TODAY) study of 699 youth and adolescents with T2D, much higher compared to 7% per year in later-onset T2D.20 The exact mechanism underlying the accelerated loss of ß-cell function in early onset T2D remains to be fully characterized. However, a widely accepted hypothesis to explain this phenomenon is that insulin hypersecretion occurs more prominently in children and adolescents compared to older adults at the initial stage of impaired glucose tolerance or newly diagnosed T2D. If this is accurate, there may be accelerated ß-cell exhaustion.21 With that said, a median C-peptide level, which is a diagnostic marker for insulin activity, in early onset patients with T2D of this study was very high (2.2 ± 1.2 ng/mL), ranged from 1.03 ng/mL to 5.09 ng/mL.
In addition, several studies describe that genetic predisposition and family history of T2D seem to be strong predictors of early presentation of the disease with 60% of patients having one parent affected by T2D17 and 74–100% of children presenting with T2D are estimated to have a 1st or 2nd-degree relative with T2D.22 These results are comparable to this study where 81% (n = 80) of early onset patients with T2D (n = 99) had family history of T2D.
It is also important to consider latent autoimmune diabetes in adults (LADA), a slowly progressive form of autoimmune diabetes that shares features with both T1D and T2D. Patients with LADA may initially present without insulin dependence and may even respond to OHAs, but eventually require insulin therapy. They are often positive for anti-GAD antibodies but may be misclassified as T2D if antibody testing is not performed. In our study, patients with early onset DM who were anti-GAD positive were considered separately, and their autoantibody status was a key factor in the classification. Nonetheless, we acknowledge that without genetic testing and longitudinal follow-up, it may be difficult to completely exclude LADA or maturity-onset diabetes of the young (MODY).
The classification of different forms of diabetes in young populations presents significant challenges, as differential diagnosis spectrums is wider than in older populations. Early onset patients with T2D overlaps with clinical patterns commonly seen in T1D, LADA and MODY. The more aggressive phenotype of the disease, accompanied by early insulinopenia and initiation of insulin therapy, overlaps with clinical characteristics of T1D or LADA. Unlike T2D, immune-mediated diabetes (T1D, LADA) is identified by the presence of autoimmune markers. The presence of two or more autoantibodies such as anti-GAD, anti-ZnT and anti-IA2 has been shown to be indicative of either T1D or LADA.23 In this study, the prevalence of positive anti-GAD or anti-ZnT8 antibody in early onset patients with DM was considerably lower than the patients with patients with T1D. No difference in the positive detection of anti-IA2 autoantibodies was determined in both stratified groups. In our analyses, the significantly higher difference between anti-GAD antibodies between T1D versus the early onset patients with DM was a crucial parameter in distinguishing these two patient populations. The patients with T1D in this study were included with patients referred from pediatric department of our or other hospital and some of patients with T1D were LADA patients who diagnosed at age over 30 years old (n = 15) (ranged from 31 to 53 years old). Because of these reasons, patients with T1D in this study showed relatively to be older and had longer duration of diabetes compared to early onset patients with DM. It is not clear that MODY patients could be included in this study, which is the limitation of this study. MODY, the most common type of monogenic diabetes, is caused by a single-gene mutation resulting in impaired ß-cell function and decreased insulin secretion. Similarly to T1D and early onset T2D, MODY also typically presents during adolescent or early adult period. At least, 14 subtypes have been identified to date and clinical features, onset age and management differ depending on affected specific gene.24 Importantly, the autosomal dominant inheritance in most forms of MODY overlaps with strong association between early onset T2D and positive family history. In addition, not all affected relatives are obese and autosomal dominant inheritance is present. Accordingly, these overlapping features and inadequate genetic testing, 50–90% of MODY cases are reported to be misdiagnosed as T1D or T2D.25
In conclusion, the present study provides a detailed characteristics of early onset patients with DM and differential patient history in combination with biological measurements to more accurately classify these patients as either T1D or T2D. More specifically, our results may provide an analytical method that includes the comparison of C-peptide levels, the positive nature of anti-GAD antibody detection, the degree of obesity, and a detailed family history of diabetes to better stratify early onset patients with DM as T2D instead of T1D.
ACKNOWLEDGMENTS
This work was conducted during research year of Chungbuk National University in 2023.
Medical Writing and/or Editorial Assistance: We would like to express our sincere thanks to Dr. Frank Park (University of Tennessee Health Science Center in Memphis) for his editing of the manuscript.
Footnotes
Funding: This work was supported by the research grant from Chungcheongbuk-do, the Chungbuk-type Biohealth Industry's Big Data Platform project (2021). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Jeon HJ, Oh TG.
- Data curation: Lee DH.
- Formal analysis: Lee DH.
- Software: Jeon HJ.
- Writing - original draft: Jeon HJ.
- Writing - review & editing: Jeon HJ, Lee DH, Oh TG.
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