Exogenous insulin-associated autoimmunity and the emergence of double diabetes in type 2 diabetes

Abstract

BACKGROUND

Exogenous insulin may trigger immune-mediated complications, particularly among East Asian populations. Double diabetes, characterized by overlapping features of type 1 diabetes (T1D) and type 2 diabetes (T2D), may arise from insulin-induced autoimmunity. This study aimed to explore the association between high-risk human leukocyte antigen (HLA) class II genotypes and susceptibility to double diabetes in patients initially diagnosed with T2D.

AIM

To investigate clinical and immunogenic features of patients who develop double diabetes following exogenous insulin therapy.

METHODS

We retrospectively analyzed five cases from Peking Union Medical College Hospital and 18 cases identified from published literature. Patients were categorized into two groups: The T2D→T1D group, characterized by autoimmune progression, and the stable T2D (T2D→T2D). Clinical characteristics and HLA class II genotypes were compared descriptively between the two groups.

RESULTS

A total of 23 patients were included in the analysis. Of these, 10 progressed from theT2D→T1D with autoimmune features, while 13 remained in the stable T2D→T2D group. There was no statistically significant difference in age at diagnosis between the two groups (57.10 ± 16.11 years vs 60.31 ± 17.41 years). In the T2D→T1D group, 70% of patients carried the HLA-DRB1 04: 05 allele and 40% carried DRB1 09: 01, both of which are commonly associated with a high risk of T1D. In contrast, the T2D→T2D group showed greater genetic heterogeneity, with a broader distribution of HLA-DRB1 alleles, including DRB1 03: 02 (n = 4), DRB1 09: 01 (n = 4), and several lower frequency alleles such as DRB1*04: 05, *08: 03, *03: 01, *04: 06, *14: 01, *04: 01, *12: 02,*15: 02 and *02: 01.

CONCLUSION

These findings suggest that patients in the T2D→T1D group exhibit a stronger autoimmune genetic predisposition, characterized by an enrichment of high-risk HLA class II alleles. In contrast, individuals with stable T2D demonstrate greater HLA diversity and lack definitive autoimmune-associated markers.

Key Words: Double diabetes; Insulin autoantibodies; Exogenous insulin; β-cell failure; Human leukocyte antigen genotype; Type 1 diabetes; Type 2 diabetes

Core Tip: We report a rare and under-recognized subtype of double diabetes, in which insulin autoantibodies induced by exogenous insulin therapy accelerate β-cell failure in patients with type 2 diabetes. This immune-mediated phenotype-predominantly observed in East Asian populations and associated with high-risk human leukocyte antigen class II alleles highlights a novel immunogenic mechanism underlying diabetes progression.

INTRODUCTION

Advancements in synthesis of recombinant human insulin and its analogues have significantly improved glycemic control in individuals with diabetes. However, several serious immune-mediated adverse responses to insulin therapy have been reported, including insulin allergy, localized lipoatrophy at injection sites, diabetic ketoacidosis (DKA), and acute hypoglycemia[1]. Notably, such immune-related events occur more frequently in Asian populations, particularly among individuals of East Asian descent[2,3]. Both experimental and clinical studies have shown that exogenous insulin can stimulate immune activation, including monocyte/macrophage infiltration into pancreatic islets, reflecting an autoimmune process reminiscent of type 1 diabetes (T1D) pathogenesis[4].

In recent years, the phenomenon of "double diabetes" has received growing clinical attention. Double diabetes is characterized by the coexistence of features from both type 1 and type 2 diabetes (T2D), arising either from autoimmune β-cell destruction in patients with pre-existing T2D or from insulin resistance in individuals with T1D[5]. This hybrid phenotype challenges conventional diagnostic categories and therapeutic strategies[6]. Patients may initially present with insulin resistance and metabolic syndrome features typical of T2D, but later develop autoimmune markers such as glutamic acid decarboxylase antibodies or insulin autoantibodies (IAAs), leading to rapid β-cell decline and insulin dependence[7].

As of 2024, approximately 589 million people are living with diabetes worldwide, including more than 9.5 million individuals affected by T1D (International Diabetes Federation, IDF Diabetes Atlas, 2025). The potential role of exogenous insulin in precipitating autoimmune activation among genetically susceptible individuals adds a novel dimension to the concept of double diabetes[8]. In some genetically predisposed patients-especially those carrying high-risk human leukocyte antigen (HLA) class II alleles-exogenous insulin administration may act as a trigger for autoimmunity. This mechanism may contribute to a unique form of double diabetes that resembles Exogenous Insulin Autoimmune Syndrome (EIAS), where the immune system produces pathogenic IAAs following insulin exposure[9]. The resulting autoimmune attack on pancreatic β-cells may accelerate disease progression and complicate glycemic control, necessitating personalized treatment approaches[2].

Our study aim to explore the potential association between high-risk HLA genotypes and susceptibility to a unique form of exogenous insulin-triggered double diabetes, with the goal of identifying individuals at elevated risk for autoimmune activation during insulin therapy.

MATERIALS AND METHODS

Subjects included in this study were from two sources: (1) Retrospective clinical cases from the Department of Endocrinology at Peking Union Medical College Hospital (PUMCH); and (2) Published case reports identified through a systematic literature review. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of PUMCH (Approval No. K3260). All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Case identification and inclusion criteria

A retrospective review was performed on PUMCH cases up to December 1, 2024. In addition, a comprehensive literature search was conducted using PubMed, Embase, and CNKI databases (up to March 1, 2025), covering both Chinese and English publications. Search terms included: “Insulin autoantibody”, “insulin autoimmune syndrome”, “insulin allergy”, “DKA”, and “β-cell destruction”. Of the 241 records screened, 9 studies met eligibility criteria, yielding 18 Literature-derived cases (Figure 1).

Figure 1 Flowchart illustrating the process of study identification, screening, and inclusion in the analysis. The diagram outlines the number of records identified, screened, excluded, and ultimately included based on predefined eligibility criteria. HLA: Human leukocyte antigen.

Cases from both sources were included if they met all of the following criteria: (1) Initial diagnosis of T2D; (2) Development of IAAs following subcutaneous insulin therapy; and (3) Availability of HLA genotyping data.

Subjects were classified into the T2D→T1D group if they developed undetectable C-peptide levels or DKA within two years of initiating insulin therapy, indicating progression to a type 1-like autoimmune phenotype. Those who retained typical T2D features despite IAA positivity were assigned to the T2D→T2D group.

Summary of included cases

Among the five PUMCH cases, one (Case 1) demonstrated clear autoimmune progression (T2D→T1D), characterized by IAA seroconversion, undetectable C-peptide levels, the onset of DKA, and clinical signs of insulin allergy. Notably, this patient initially responded to insulin therapy with transient glycemic improvement, but experienced rapid deterioration within one month, ultimately developing life-threatening metabolic decompensation. She also exhibited marked glycemic variability and subcutaneous lipoatrophy at injection sites, reinforcing the presence of an immune-mediated process. Given the abrupt β-cell failure shortly after insulin initiation, Case 1 serves as a representative example of exogenous insulin-triggered double diabetes. The remaining four cases (Cases 11-14) tested positive for IAAs following insulin therapy but remained clinically with features consistent with T2D.

In total, 23 cases were included and categorized into two subgroups: T2D→T1D group (n = 10): Autoimmune progression with insulin dependence; (Cases 1-10) T2D→T2D group (n = 13): IAA-positive but stable T2D phenotype (Cases 11-23).

Data collection and analysis

Extracted data included demographic information (age, sex, ethnicity), insulin regimen details (type, duration), duration of diabetes, autoantibody profiles-including GAD-Ab, islet cell antibodies (ICA) and insulinoma-associated antigen 2 antibodies (IA-2Ab), and particularly IAA-insulin-related adverse events (e.g., allergy, lipoatrophy, hypoglycemia, DKA), fasting C-peptide levels before and after insulin therapy, and HLA genotypes.

Due to the limited sample size and heterogeneity of data sources, all analyses were descriptive. Categorical variables were summarized as counts and percentages, while continuous variables were reported as raw values. HLA class II allele distributions were compared qualitatively between subgroups. Clinical characteristics and allele frequencies were visualized using summary tables and figures.

Statistical analysis

Normally distributed quantitative variables were expressed as the mean ± SD, whereas categorical variables were shown as percentages. Parameters that were not normally distributed were transformed or presented as the median (25-75^th percentile). Comparison of variables between groups was performed using Student t-test or non-parametric Mann-Whitney U-test or χ²-test. SPSS (version 22.0) and Excel were used to perform all statistical analyses. P < 0.05 (two-sided) indicated statistical significance.

RESULTS

Clinical characteristics in the T2D→T1D and T2D→T2D groups

Table 1[8,10-17] summarizes the demographics, clinical characteristics, and HLA class II genotyping (DRB1 and DQB1) of the 23 included individuals. All participants were of East Asian descent, including both Chinese and Japanese patients. Based on initial diagnostic classification, 10 patients were assigned to the T2D→T1D group, and 13 patients were classified into the T2D→T2D group. The mean age at diagnosis was 57.10 ± 16.11 years in the T2D→T1D group and 60.31 ± 17.41 years in the T2D→T2D group. Sex distribution was approximately balanced in the T2D→T1D group (male-to-female ratio of 5:5), whereas the T2D→T2D group included more female (male-to-female ratio 5: 8). There were no statistically significant differences in age or sex distribution between the two groups (P > 0.05).

Table 1 Clinical, biochemical, and genotypic characteristics of the 23 cases.

	Ethnicity	Sex/age (year)	Insulin preparation	Duration of insulin use (month)	Duration since initial diagnosis (year)	ICA	IA-2A	GADA	IAA-pre insulin	IAA titer	IAA detection method	Insulin allergy	Lipoatrophy	Hypoglycemia	DKA	C-P (pre) (pmol/L)	C-P (post) (pmol/L)	Treatment	DRB1	DQB1
Case 1	Chinese	F/49	NR, L	1	NA	-	-	-	-	NA	CL	+	+	+	+	329.7	< 30	NA	04:05 15:01	04:01 04:01
Case 2	Japanese	M/70	N	5	30	-	-	+	NA	13	RI	+	NA	+	+	560	< 16.65	NR	04:05 09:01	04:01 03:03
Case 3	Japanese	M/50	A, M30	2	5	+	+	+	NA	12	RI	+	NA	-	-	370	33.3	NU, H	09:01 08:03	03:03 03:01
Case 4	Japanese	M/69	H70/30	2	20	-	-	-	NA	14	RI	-	NA	-	-	900	33.3	H, HN	04:05 04:05	04:01 04:01
Case 5	Japanese	M/63	M30	17	29	-	-	-	NA	2	RI	-	NA	NA	-	NA	< 30	NA	09:01 01:01	03:03 05:01
Case 6	Japanese	F/67	R, H70/30	7	15	-	-	-	NA	9	RI	+	NA	NA	-	NA	< 30	NA	04:05 14:07	04:01 05:02
Case 7	Japanese	F/38	N, NR	13	2	+	NA	+	NA	7	RI	-	NA	NA	-	NA	NA	NA	09:01 09:01	03:03 03:03
Case 8	Chinese	F/25	NR, D	0.5	1	-	-	-	NA	75	RI	+	-	-	+	NA	8	NR, DG	04:05	04:01
Case 9	Japanese	M/75	R, N	12	20	+	+	+	NA	9	RI	-	+	+	-	NA	< 30	Pred	04:05 13:02	04:01 06:04
Case 10	Chinese	F/65	A	6	10	-	-	-	NA	125#	RI	-	NA	-	+	NA	50	Pred	04:03	NA
Case 11	Chinese	M/53	GI	30	8.4	-	-	-	NA	256	CL	NA	+	NA	NA	NA	NA	NA	02:01 03:02	04:03 07:01
Case 12	Chinese	F/24	GI	2	1.4	NA	NA	NA	NA	7.82	CL	NA	NA	NA	NA	NA	NA	NA	03:01 03:02	04:06 11:01
Case 13	Chinese	M/55	H3/7	18	2.2	-	-	-	NA	390	CL	NA	NA	NA	NA	NA	NA	NA	03:01 03:01	12:01 12:02
Case 14	Chinese	F/50	GI	0.5	11.1	-	-	-	NA	691.5	CL	+	NA	NA	NA	NA	NA	NA	03:02 03:02	04:06 04:06
Case 15	Japanese	M/66	H3/7	12	27	NA	-	-	NA	20	RI	+	NA	+	NA	NA	0.47	Liraglutide, voglibose, mitiglinide	04:01 04:06	03:02 05:01
Case 16	Japanese	M/46	NR	12	NA	NA	NA	NA	NA	13.6	RI	NA	NA	+	NA	NA	0.40	Nateglinide	09:01 15:02	03:03 06:01
Case 17	Chinese	M/49	N30R	12	10	NA	NA	NA	NA	NA	RI	NA	NA	+	NA	NA	1.43	Acarbose	04:05	NA
Case 18	Japanese	M/86	NA	20	NA	NA	NA	NA	NA	20.9	RI	NA	NA	+	NA	NA	NA	Cyclophosphamidepulse and Preds	04:06	NA
Case 19	Japanese	M/83	NA	15	NA	NA	NA	NA	NA	22.4	RI	NA	NA	+	NA	NA	NA	DFPP and Preds	08:03 09:01	NA
Case 20	Japanese	F/60	R	21	NA	NA	NA	+	NA	10	RI	NA	NA	+	NA	NA	NA	NA	04:05 09:01	NA
Case 21	Japanese	F/69	M30	20	NA	NA	NA	-	NA	13	RI	NA	NA	+	NA	NA	NA	NA	08:03 09:01	NA
Case 22	Japanese	F/60	M30	2	NA	NA	NA	-	NA	14	RI	NA	NA	+	NA	NA	NA	NA	04:05 14:01	NA
Case 23	Chinese	M/83	N, GI	20	NA	-	-	NA	NA	14	NA	NA	NA	+	NA	NA	1.19	Linagliptin	08:03 12:02	NA

Cases 1-10 belong to the T2D→T1D group, while Cases 11-23 comprise the T2D→T2D group. Demographic data, insulin formulations, duration of insulin therapy, time since initial diabetes diagnosis, autoantibody profiles-including changes in insulin autoantibodies and their titers-as well as DRB1 and DQB1 genotypes, are summarized. In addition, key clinical outcomes-including insulin allergy, lipoatrophy, hypoglycemia, and diabetic ketoacidosis-alongside biochemical indicators such as pre- and post-treatment C-peptide levels, are also presented. GADA: Glutamic acid decarboxylase antibodies; IAA: Insulin autoantibodies; ICA: Islet cell antibodies; DKA: Diabetic ketoacidosis.

Prior to insulin initiation, most patients in both groups tested negative for classical T1D–associated autoantibodies, including GAD-Ab, ICA and IA-2Ab. However, within the T2D→T1D group, two patients tested positive for all three autoantibodies, one was positive for both GAD-Ab and ICA, and another tested positive for GAD-Ab alone. In contrast, only one patient in the T2D→T2D group was positive for GAD-Ab. These findings suggest a higher baseline autoimmune burden in a subset of patients who later progressed to insulin-dependent diabetes, despite an initial diagnosis of T2D. In the T2D→T1D group, C-peptide levels were initially detectable but declined significantly following insulin therapy. The median duration from the initiation of to either undetectable C-peptide or the onset of DKA was 6 months (ranging: 0.5 to 17 months) in these originally T2D-diagnosed patients.

The duration of insulin exposure differed significantly between groups. In the T2D→T1D group (n = 10), the median duration was 5.5 months, compared to 15.0 months in the T2D→T2D group (n = 13). This difference was statistically significant (Mann–Whitney U test, P = 0.046), suggesting that longer insulin exposure was associated with a lower likelihood of autoimmune progression. The median duration of diabetes at the time of insulin initiation was 12.5 years in the T2D→T1D group (n = 10) and 8.4 years in the T2D→T2D group (n = 5). However, due to substantial missing data in the T2D→T2D group, statistical comparison was not performed. Insulin allergy was reported in 5 of 10 patients (50.0%) in the T2D→T1D group, while only two patients in the T2D→T2D group experienced local allergic reactions. Lipoatrophy occurred in 2 of 3 patients (66.7%) in the T2D→T1D group and in the only evaluable case in the T2D→T2D group. Hypoglycemia was observed in 3 of 7 evaluable cases (42.9%) in the T2D→T1D group and in all 9 patients (100%) with available data in the T2D→T2D group. DKA occurred in 4 of 10 patients (40.0%) in the T2D→T1D group, whereas no DKA events were reported in the T2D→T2D group.

HLA-DR and DQ genotypes

Our study revealed a distinct distribution of HLA class II alleles between the T2D→T1D group and the T2D→T2D groups. In the T2D→T1D group, DRB1*04:05 was the most frequently observed allele, present in 7 individuals, followed by DRB1*09: 01 in 5 individuals. Less common alleles included DRB1*08:03, DRB1*13:02, DRB1*14:07, DRB1*15:01, and DRB1*01:01, each detected in one patient. Consistent with these DRB1 findings, the corresponding DQB1 alleles-DQB1*04:01 (typically paired with DRB1*04:05) and DQB1*03:03 (associated with DRB1*09:01)-were the most common in this group, with frequencies of 8 and 5, respectively (Figure 2).

Figure 2 Distribution of human leukocyte antigen-DRB1 and human leukocyte antigen-DQB1 alleles in the type 2 diabetes→ type 1 diabetes and type 2 diabetes→ type 1 diabetes groups. The upper panels display high-risk human leukocyte antigen (HLA)-DRB1 allele frequencies in each group, while the lower panels show HLA-DQB1 distributions. In the type 2 diabetes (T2D)→type 1 diabetes (T1D) group, DRB104:05 and DRB109:01, as well as DQB104:01 and DQB103:03, were predominant, consistent with classical T1D susceptibility haplotypes. In contrast, the T2D→T2D group exhibited a broader and more heterogeneous distribution of both DRB1 and DQB1 alleles, with no dominant autoimmune-associated patterns. T1D: Type 1 diabetes; T2D: Type 2 diabetes; HLA: Human leukocyte antigen.

In contrast, the T2D→T2D group exhibited a more heterogeneous HLA profile. DRB1 alleles such as DRB1*03:02 (in 4 individuals), DRB1*09:01 (in 4 individuals), and a variety of others including DRB1*02:01, 15:02, 12:02, 04:01, 14:01 and 04:06 appeared less frequently and did not form dominant cluster as observed in the T2D→T1D group. The DQB1 alleles in this group were similarly diverse, including DQB1*04:06 (3 individuals), and several other lower-frequency variants such as DQB1*05:01, 06:01, 03:03, 07:01, 03:02, 12:02, 11:01, 04:03 and 12:01 (Figure 2). Importantly, the T2D→T2D group lacked the enrichment of classical T1D high-risk haplotypes seen in the T2D→T1D group, supporting the hypothesis that these patients have a more metabolically driven disease course with limited autoimmune involvement.

These findings support the hypothesis that individuals who progress from T2D→T1D may carry a genetic predisposition associated with classical T1D-linked HLA class II haplotypes, particularly DRB104:05-DQB104:01 and DRB109:01–DQB103:03.

DISCUSSION

The emergence of IAAs in all cases following insulin therapy—contrasted with the predominantly negative status of other T1D-associated autoantibodies prior to insulin initiation-suggests that exogenous insulin may act as a trigger for autoimmune β-cell destruction in genetically susceptible individuals[18]. This concern is particularly relevant for East Asian populations, where unique immunogenetic factors may exacerbate the risk of such immune-mediated responses. The high incidence of insulin allergy followed by subsequent β-cell failure highlights the importance of monitoring autoimmune markers in patients receiving insulin therapy, especially those who develop local allergic reactions to injection sites[19]. Recent evidence suggests that insulin-derived fibrils formed at subcutaneous injection sites may contribute to these complications by inducing macrophage cytotoxicity, promoting inflammation, and leading to localized tissue damage and poor glycemic control[20].

The immune response to exogenous insulin may arise through several mechanisms that disrupt immune tolerance. As an antigen, insulin can be presented by antigen-presenting cells (APCs) and activate both CD4+ and CD8+ T cells[21], triggering immune cascades that promote the development of IAAs[22]. Exogenous insulin-particularly formulations that differ in purity or molecular structure from endogenous insulin-may breach immune tolerance, even in insulin-naïve individuals[23].

At the injection site, dendritic cells and other APCs process the insulin and present it to T-helper cells, initiating a response that stimulates B cells to produce insulin-specific IgG antibodies[24]. Several factors influence susceptibility to this response, including the site and route of insulin administration, insulin formulation, and host genetic predisposition-especially HLA class II genotypes[18]. Variations in these factors, along with structural modifications of insulin analogs, can also increase immunogenicity and the likelihood of breaking immune tolerance. The resulting antibodies may form immune complexes that contribute to β-cell damage, reduced insulin secretion, and clinical manifestations such as insulin allergy and hypersensitivity reactions.

In our study, the term “double diabetes” refers primarily to individuals initially diagnosed with T2D who later transitioned to an insulin-dependent state[25]. In this context, this transformation is largely driven by immune responses to exogenous insulin, which appears to play a pivotal role in the progression toward insulin dependence[23]. Compared to patients with EIAS who do not develop features of T1D, this emerging subtype is more frequently associated with high-risk HLA class I alleles. These findings suggest a genetic predisposition that may contribute to a more complex clinical course and present additional challenges for therapeutic decision-making.

Our findings reveal a clear divergence in HLA class Il allele distribution between patients with stable T2D and those who progressed to double diabetes following insulin therapy. The overrepresentation of DQB1*04: 01, DQB1*03: 03, DRB1*04: 05, and DRB1*09: 01 in the T2D-T1D group is consistent with alleles known to be associated with T1D and autoimmune β-cell destruction. These genotypes are believed to enhance antigen presentation and T-cell activation. thereby facilitating autoimmune responses in genetically predisposed individuals[26].

The predominant haplotypes-DRB1 04: 05-DQB1 04: 01 and DRB1 09: 01- DQB1 03: 03-are well-established high-risk markers for T1D. Their presence in the T2D→T1D group supports the notion that these individuals harbor classical T1D-susceptibility HLA haplotypes. This aligns with previously reported genetic patterns in autoimmune diabetes. Notably, among East Asian populations, these haplotypes represent major susceptibility markers and differ significantly from those observed in Caucasian populations[27,28]. These findings underscore a population-specific genetic predisposition influencing progression to T1D in East Asians.

These observations support the hypothesis that exogenous insulin may act as an environmental trigger in individuals carrying high-risk HLA genotypes, promoting the development of IAAs, progressive β-cell dysfunction, and eventual clinical transition from T2D to a double diabetes phenotype[29]. In contrast, the broader and more heterogeneous HLA profile observed in the T2D→T2D group may indicate a lower genetic predisposition to autoimmunity and a pathophysiology more strongly driven by metabolic factors[30].

From a clinical perspective, these findings underscore the potential utility of HLA class II genotyping as a predictive biomarker for insulin-induced autoimmune progression in patients with T2D. Early identification of genetically susceptible individuals prior to insulin initiation could support closer monitoring of islet autoantibodies and enable timely implementation of immunomodulatory interventions to preserve residual β-cell function.

This study has several limitations that should be acknowledged to support the accurate interpretation and credibility of our findings. First, the retrospective design and small sample size limit the generalizability of the results and preclude definitive conclusions regarding causality. Second, although we focused on immunogenetic characteristics, particularly HLA class II alleles, other potential causes of pancreatic β-cell destruction were not comprehensively assessed due to data limitations. Detailed clinical information on factors such as alcohol consumption, prior pancreatitis, or recent viral infections-known contributors to β-cell dysfunction-was unavailable for many literature-derived cases and partially in the institutional records. Third, concomitant autoimmune conditions, such as Hashimoto’s thyroiditis or polyglandular autoimmune syndromes, were not systematically evaluated, which may have influenced disease progression and immune activation. Lastly, as an observational study, it is not possible to establish exogenous insulin as a definitive environmental trigger for autoimmune diabetes in genetically susceptible individuals. Despite these limitations, our findings offer a plausible hypothesis that warrants further investigation in larger, prospective studies incorporating genetic screening and longitudinal monitoring of autoimmune markers.

CONCLUSION

In summary, our findings support the existence of a distinct subset of patients with T2D who, following exposure to exogenous insulin, develop autoimmune features and progress to a “double diabetes” phenotype. This transition is closely associated with the development of IAAs and a high frequency of HLA class II alleles known to confer susceptibility to T1D. These results suggest that genetic predisposition—particularly specific HLA-DR and DQ variants-may play a pivotal role in disrupting immune tolerance to insulin and accelerating β-cell failure.

Given the potential for immune-mediated complications, HLA class II genotyping may serve as a valuable tool for identifying individuals at increased risk prior to initiating insulin therapy. Early identification could enable personalized monitoring strategies and timely immunomodulatory interventions aimed at preserving endogenous insulin secretion and improving long-term metabolic outcomes.