Clinical characteristics of fulminant type 1 diabetes mellitus following acute pancreatitis

Abstract

Objective

This study aimed to gather clinical data on fulminant type 1 diabetes mellitus (FT1DM) following acute pancreatitis and investigate its clinical characteristics.

Methods

A comprehensive search was conducted in PubMed, Embase, Web of Science, Wanfang Database, and China National Knowledge Infrastructure. This was complemented by manual screening strategies to identify FT1DM cases following acute pancreatitis that met the inclusion and exclusion criteria. Data pertaining to demographic, clinical, and laboratory results were extracted for descriptive analysis.

Results

Fifteen cases met the eligibility criteria, with a male-to-female ratio of 7:8. The average age was 36.27 ± 13.46 years, and the mean BMI was 21.17 ± 3.08 kg/m². Four patients tested positive for glutamic acid decarboxylase antibody. The mean HbA1c level was recorded at 6.19 ± 0.82%. FT1DM occurred 6.53 ± 1.50 days after the onset of symptoms of acute pancreatitis. Four patients had a family history of diabetes. All fifteen patients received intensive insulin regimens.

Conclusion

A temporal association was observed between AP and subsequent FT1DM. Variations in the age of onset, positivity rate of islet-related antibodies, and diabetic family history among FT1DM patients could be attributed to different ethnic backgrounds and preceded factors.

1. Introduction

Acute pancreatitis (AP), frequently encountered in digestive system emergencies, can lead to complications ranging from localized pancreatic necrosis to widespread multi-organ dysfunction. Fulminant Type 1 Diabetes Mellitus (FT1DM), a subtype characterized by rapid destruction of pancreatic β-cells, causes severe hyperglycemia and ketoacidosis. Given its rapid progression, affected individuals are dependent on insulin therapy for life. Alarmingly, the mortality rate for severe cases touches 20%, presenting significant challenges to clinicians. FT1DM is predominantly prevalent in East and Southeast Asia. Its etiology remains elusive, potentially implicating factors such as genetic predisposition, autoimmunity, pregnancy, pharmaceutical agents, viral infections, and vaccination [1]. Numerous case reports have documented FT1DM onset during the recovery phase of AP, however, a definitive causal relationship between AP and FT1DM has not been established. Consequently, investigating the clinical characteristics of FT1DM subsequent to AP holds significant medical importance. This study systematically reviews published cases of FT1DM following AP, examining their clinical features and potential pathophysiological mechanisms, with the objective of establishing a scientific foundation for the early identification of high-risk patient populations.

2. Data and methodology

2.1. Literature search and methodology

A comprehensive literature search was conducted across PubMed, Embase, Web of Science, Wanfang Database, and China National Knowledge Infrastructure (CNKI) databases up to June 30, 2025, employing the keywords “fulminant type 1 diabetes mellitus” and “acute pancreatitis”. This was supplemented by manual screening strategies to identify cases of FT1DM occurring after AP. During the screening process, we carefully checked for duplicate reports of the same patient by comparing author names, institutions, case details, and publication dates; no duplicate cases were identified.

The inclusion of Chinese-language databases in literature searches inevitably introduces selection biases. FT1DM shows significant regional variations with a high prevalence in East and Southeast Asian populations. By incorporating Chinese-language databases, we can enhance both the diversity and quantity of case data. To minimize such biases during subsequent literature screening, we established unified and clearly defined inclusion and exclusion criteria, followed by rigorous document screening processes. Relevant demographic, clinical, and laboratory data were subsequently extracted for integrated analysis.

2.2. Case screening criteria

The inclusion criteria were as follows.

• 1)Acute pancreatitis was diagnosed according to the guidelines established by the Pancreatic Surgery Group, Surgery Branch, Chinese Medical Association [2].
• 2)Patients met the diagnostic criteria for FT1DM proposed by Imagawa et al., in 2012: a) development of diabetic ketosis or ketoacidosis within 7 days after the onset of hyperglycemic symptoms (elevated urine and/or blood ketone bodies at initial diagnosis); b) plasma glucose level ≥16.0 mmol/L (≥288 mg/dL) and HbA1c <8.7% at initial evaluation; c) fasting serum C-peptide level <0.3 ng/mL (<0.10 nmol/L) and postprandial C-peptide level <0.5 ng/mL (<0.17 nmol/L) [3].
• 3)Acute pancreatitis occurred before FT1DM.

The exclusion criteria included the following.

• 1)Patients were under 18 years old or pregnant women.
• 2)Patients had severe comorbidities such as severe hepatic or renal dysfunction.
• 3)Patients were diagnosed with malignant tumors.
• 4)Patients could not confirm the chronological order of acute pancreatitis and FT1DM.
• 5)FT1DM was temporally associated with other causes.

2.2.1. Statistical methods

Descriptive statistics were used in this study. Only available data were used for descriptive analysis, and missing values were not imputed. Descriptive data are expressed as counts and percentages, and continuous data are expressed as mean ± standard deviation.

3. Results

3.1. Demographic data

Fifteen cases of FT1DM following acute pancreatitis were included in this study. All patients met the diagnostic criteria for FT1DM proposed by Imagawa et al., in 2012 and the diagnostic criteria for acute pancreatitis. Among them, 13 patients had normal blood glucose levels recorded during acute pancreatitis, and the other two cases were confirmed to have developed acute pancreatitis prior to the onset of FT1DM. All 15 patients were from East Asia, including seven males and eight females.

The average age was 36.27 ± 13.46 years and the median age was 33 years. The body mass index (BMI) of seven patients was recorded, with a mean value of 21.17 ± 3.08 kg/m². Details are shown in Table 1.

Table 1.

Clinical data of 15 cases of FTIDM following acute pancreatitis.

No	Year	author	age	sex	BMI(kg/m2)	trigger	Amylase(U/L)	Lipase(U/L)	severity of AP	time(d)	Any islet-related antibody	HbA1c(%)	FHD	HLA typing
1	2001	Inoue G,et al. [13]	24	F	-	-	316(60-200)	-	-	6	GADA+	6.8	N	A 24/-, B 52/-, 4/- C −/−; DR 2/-, -/I, DQ 1/-
2	2002	Fukui K,et al. [6]	18	F	-	-	331(37-130)	-	moderate	7	N	6.8	2	-
3	2002	Sakurai M,et al. [14]	24	F	16.8	-	285(10-35)	1594(9-55)	mild	9	N	4.5	N	DRB1∗0401
4	2005	Kiriya Tomomi et al. [15]	38	F	18.9	-	434(38-125)	740(8-25)	mild	9	N	5.4	IGT	DR4、DR6
5	2007	Ishizuka N,et al. [16]	55	M	25.1	-	1071(40-125)	-	mild	6	N	7.3	N	DRB1∗0403-DQB1∗0302,DRB1∗0901- DQB1∗0303
6	2011	Wang Rui et al. [17]	22	F	-	High in fat	560	-	-	4	-	6.1	N	-
7	2014	Yuan Yanping et al. [18]	41	M	-	High in fat	150	-	-	6	N	6.1	-	-
8	2019	Miyagahara T,et al. [19]	30	M	-	-	79	271	mild	6	GADA+	5.7	U	DRB1∗0405-DQB1∗0401
9	2020	Egashira F,et al. [20]	31	F	-	-	370	-	mild	8	N	5.7	U	DRB1∗0401-DQB1∗0301 DRB1∗1302-DQB1∗0604
10	2020	Hu, Yanyan et al. [21]	49	F	19.63	-	242	-	-	5	P	6.4	N	-
11	2020	Xing Shimei et al. [22]	50	F	-	-	318	-	-	5	N	6.6	N	-
12	2021	Chen YN,et al. [23]	23	M	22.46	diet	280	771	-	8	N	7.9	N	DRB1∗0701-DQB1∗0202
13	2021	Chen YN,et al. [23]	40	M	20.59	Jump from a height	201	-	mild	6	GADA+	5.69	N	DRB1∗0401-DQB1∗0301 DRB1∗1302-DQB1∗0604
14	2021	Li Wang et al. [24]	33	M	24.74	A drink	354(16-220)	392(1-60)	mild	5	GADA+	5.8	-	-
15	2024	Zhang Peiheng et al. [25]	66	M	-	-	427	大于300	mild	8	N	6	N	-

Note: All cases showed typical imaging features of AP (e.g. pancreatic edema and/or peripancreatic fluid) by pancreatic computed tomography or ultrasound. "-" means “not reported”; Year: Year of publication; F: female; M:Male; Y: yes; N: no; ID: Imageological diagnosis; Time: the time from acute pancreatitis to diabetes mellitus; FHD:Family history of diabetes; N:Negative for any islet-relative antibody; P: Positive for any islet-relative antibody; U: Unspecified type of diabetes.

3.2. Clinical characteristics

Triggers for acute pancreatitis were identified in five case reports. Fourteen patients presented with gastrointestinal symptoms and abdominal CT or ultrasound revealed pancreatic edema in all 15 patients. Eight patients were documented as having mild acute pancreatitis and one patient had moderate AP. In the other six patients, the severity of acute pancreatitis was not explicitly graded; however, based on the authors’ descriptions, none constituted severe acute pancreatitis. In all cases, FT1DM occurred during the recovery phase of AP, with normal glucose levels documented during the acute phase of AP. FT1DM occurred at 6.53 ± 1.50 days after the onset of symptoms of acute pancreatitis, all during the recovery phase of acute pancreatitis. Five patients (5/14, 35.71%) tested positive for any islet-related antibody [glutamic acid decarboxylase antibody (GADA), islet cell antibody (ICA) or insulin autoantibody (IAA)] among whom four (4/14, 28.57%) were GADA-positive. The mean HbA1c level was 6.19% ± 0.82%, and all patients exhibited extremely low fasting C-peptide levels. Among them, four patients (4/13, 30.77%) had a family history of diabetes mellitus, nine patients had no confirmed family history, and two patients did not mention their family history. Human leukocyte antigen (HLA) typing was performed in eight patients. All 15 patients received intensive insulin therapy using an insulin pump or basal-bolus insulin regimen.

4. Discussion

FT1DM was first proposed by Japanese scholar Imagawa in 2000 as a special subtype of type 1 diabetes [4]. This study included 15 clinically confirmed cases of FT1DM following acute pancreatitis, which is a group of patients who had not received enough attention before.

Acute pancreatitis can cause type 3c diabetes, but this is rare. Approximately 3% of cases develop hyperglycaemia after severe acute pancreatitis and 2% after moderate acute pancreatitis [5,6]. For many years, diabetes mellitus following acute pancreatitis has been considered a transient phenomenon (“stress hyperglycaemia”). However, observational studies have shown that up to 25% of patients with acute pancreatitis developed new-onset diabetes within 3 years [7,8]. The pathophysiology of secondary diabetes due to acute pancreatitis is not fully understood. Most patients may be heterogeneous, and the risk of diabetes increases significantly even after mild acute pancreatitis. This suggests that the pathogenesis of diabetes following acute pancreatitis may involve mechanisms beyond pancreatic necrosis and loss of islet cells [7,8]. All 15 cases included in this study occurred during the recovery phase of acute pancreatitis, with severe conditions and rapid progression. Therefore, type 3c diabetes secondary to acute pancreatitis cannot explain the condition of these 15 patients, and they were diagnosed as FT1DM following acute pancreatitis.

Analysis of the clinical data from 15 cases showed no sex difference in FT1DM following acute pancreatitis. The mean age of patients was (36.27 ± 13.46) years, which is higher than that of onset for FT1DM caused by other preceded factors in China (29.2 ± 12.1 years) [9] but lower than the mean diagnostic age of FT1DM in a cross-sectional study in Korea [10]. Their BMI values were similar to those reported for FT1DM in other East Asian countries such as Japan [11] and Korea [10], as well as for Chinese patients with FT1DM of other etiologies, indicating that this type of diabetes tends to occur in non-obese and non-overweight individuals. Previous studies have reported variability in the GADA positive rate among patients with FT1DM across different populations. In Japanese cohorts, the reported rates ranged from 4.8% to 7.62% [9,11], while a Korean cross-sectional study documented a rate of 23.1% [10]. In China, Luo et al. analyzed 53 patients with FT1DM from 24 hospitals and found that nearly 34.0% tested positive for low titers of autoantibodies against GAD, IA-2, zinc transporter 8 (ZnT8), or a combination of GAD and ZnT8 [12]. Similarly, Liu et al. reported a GADA positive rate of 30.7% among Chinese patients [9]. In the present study, the GADA positive rate in patients with FT1DM following acute pancreatitis fell within the range reported for Chinese patients with other preceded factors, while appearing somewhat higher than the rates observed in Japanese and Korean populations. The observed differences in GADA positive rate may be influenced by variations in study populations, and sample sizes, and that larger multinational studies are needed to confirm these trends. In a Korean study of FT1DM, 3 out of 12 patients (25%) had a family history of diabetes, whereas a Japanese cross-sectional study revealed that 43.11% of patients with FT1DM had a family history of type 2 diabetes mellitus [11]. However, only one case (0.6%) among 161 Japanese patients with FT1DM had a family history of diabetes, and none of the 26 Chinese patients with FT1DM (0%) did in the study by Liu et al. [9].In the present study, 4 patients (30.77%) had a family history of diabetes mellitus. Notably, among the four patients with a family history of diabetes, one had a family history of type 2 diabetes, one of imparied glucose tolerance, and two was unspecified. These comparisons should be interpreted with caution because of the limited number of cases and potential heterogeneity across studies.This aligns with emerging evidence that FT1DM may co-aggregate with type 2 diabetes in families, suggesting shared genetic or enviromental risk factors beyond classic autoimmune susceptibility.

In conclusion, FT1DM after acute pancreatitis mostly occurs in East Asians, but there are differences among countries in terms of age at onset, positive rate of diabetes-related antibodies, and family history of diabetes mellitus. These differences are also associated with predisposing factors.

At present, there is little research on the pathogenesis of FT1DM following acute pancreatitis. Based on previous studies and literature reports on the mechanism of FT1DM, the possible factors include genetic susceptibility and immune mechanisms.Studies show certain HLA genes raise the risk of FT1DM. Japanese research has linked specific gene types to the disease. T cells play a key role in FT1DM after mild pancreatitis. In some patients, CD8⁺ T cells were found near the pancreas but not inside it months after the attack, suggesting they may be involved in the disease [6].Antibodies against insulin cells were found in 35% of patients in this study, showing that the body's immune attack on itself contributes in some cases.

Our study has limitations. First, All included cases were from East Asia, which may reflect both the known higher prevalence of FT1DM in East Asian populations and the inclusion of Chinese-language databases (Wanfang, CNKI) in our search strategy. Our findings may not be generalizable to other ethnic groups. Future multinational case registries are needed to better understand the global epidemiology of FT1DM following AP. Second, because our study is based on published case reports, it is subject to publication bias, as cases with negative findings or those not reported in the literature may not be represented. Third, the absence of a denominator population precludes estimation of the incidence of FT1DM following acute pancreatitis.

4.1. Clinical implications

Our findings highlight that FT1DM can develop during the recovery phase of acute pancreatitis, even in patients with mild pancreatitis and without prior glucose abnormalities. Clinicians should maintain a high index of suspicion for new-onset hyperglycemia or ketoacidosis in patients recovering from AP, as early recognition of FT1DM allows prompt insulin therapy and may prevent life-threatening complications. Given the rarity of this association, any case of unexplained diabetic ketoacidosis following AP warrants consideration of FT1DM and measurement of C-peptide and HbA1c to confirm the diagnosis.

5. Conclusion

Our findings suggest a temporal sequence between AP and FT1DM, though causality cannot be inferred from this descriptive review. FT1DM following AP is a critical metabolic emergency characterized by rapid β cell destruction. This reminds clinicians to be alert to the sudden onset of diabetic ketoacidosis in patients recovering from AP and closely observe the occurrence of FT1DM, which would enable early diagnosis and intervention.

CRediT authorship contribution statement

Yaning Chen: Writing – review & editing, Writing – original draft, Conceptualization. Yingying Chen: Resources, Data curation, Conceptualization. Jia Cui: Visualization, Software. Xingchen Lu: Methodology, Data curation.

Conflicts of interest

The authors declare that there is no conflict of interest.