Pregnancy‑associated fulminant type 1 diabetes mellitus: Two case reports and literature review

Introduction

Type 1 diabetes mellitus (T1DM) can be divided into two categories, including the autoimmune type (type 1A) and the idiopathic type (type 1B). According to the American Diabetes Association and the World Health Organization, fulminant type 1 diabetes mellitus (FT1DM) is categorized as a subtype of T1DM type 1B in which pancreatic beta cells are destroyed within days or a few weeks, contributing to the sudden occurrence of hyperglycaemia. FT1DM, unlike other forms of T1DM, is distinguished by a rapid onset of diabetic ketoacidosis (DKA), complete annihilation of pancreatic beta cells and a near-normal glycosylated hemoglobin (HbA1c) level (1,2). FT1DM was first identified in Japan and subsequently reported in other East and Southeast Asia countries, including China (3,4). Currently, the diagnosis of FT1DM is based on the 2016 criteria from the Japanese Diabetes Association Committee (5). These criteria rely on serological evidence of very low serum C-peptide and histological findings of almost no pancreatic beta cells. The etiology of FT1DM is uncertain and may be related to genetic susceptibility, autoimmunity and immune regulatory factors, viral infections of the pancreas and pregnancy (6). In recent years, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint antibodies have been widely used as anticancer drugs, and there has been an increase in global reports of PD-1/PD-L1 inhibitor-induced FT1DM (7).

Pregnancy can trigger the development of FT1DM. FT1DM that occurs during pregnancy or within two weeks postpartum is classified as pregnancy-associated FT1DM (PFT1DM). It has been indicated that PFT1DM poses a great threat to the lives of mothers and infants (8). According to statistics from Japan, PFT1DM accounts for ~21% of cases of FT1DM, and intrauterine fetal death has been reported in ~67% of total PFT1DM cases (9). The present study reported two cases with the symptom of hyperglycemia during different gestational weeks and who were subsequently diagnosed with PFT1DM through blood glucose, HbA1c, serum fasting C-peptide and serum glutamic acid decarboxylase antibody (GAD-Ab) tests. The treatment and prognosis of the mothers and the fetuses were outlined and a brief review of the recent literature was provided. These cases highlight the importance of early recognition and prompt treatment to prevent adverse prognosis in mothers and infants with PFT1DM.

Case report

Case 1

A 35-year-old gravida 2, para 1 woman at 17 weeks of gestation was admitted to Jinan Maternity and Child Care Hospital (Jinan, China) in September 2022 due to polyuria and polydipsia, fatigue and chest tightness for 10 days, as well as hyperglycemia for one day. The patient had undergone a cesarean section three years previously for breech position of the fetus and had no history or family history of diabetes. The fasting blood glucose (FBG) at 12 weeks of gestation was normal at 5.4 mmol/l (reference range, 3.89-6.11 mmol/l). On admission, the patient's body temperature was recorded as 36.8˚C (reference range, 36.3-37.2˚C), heart rate at 98 beats per minute (reference range, 60-110 beats per min), respiratory rate at 20 breaths per minute (reference range, 12-20 breaths per minute) and blood pressure at 115/72 mmHg (reference range, ≥90/60 mmHg and <140/90 mmHg). The patient's body mass index (BMI) was calculated as 21.9 kg/m2. All of these parameters were within normal ranges. Physical examination revealed clear bilateral lung sounds and a regular heart rhythm, and no uterine contractions were observed. Fetal heart rate monitoring indicated 146 beats per min.

As shown in Table I, the patient's FBG level was markedly elevated at 21.2 mmol/l. Urinalysis revealed ketonuria (+++) and glycosuria (+++). Blood gas analysis showed metabolic acidosis with a pH of 7.27, accompanied by reduced partial pressure of carbon dioxide (PCO2, 23 mmHg) and normal partial pressure of oxygen (PO2, 95 mmHg). The patient's lactate level was within normal limits at 0.9 mmol/l, while bicarbonate (HCO3-) was decreased at 10.6 mmol/l. HbA1c was mildly elevated at 7.6%, fasting C-peptide was low at 0.13 ng/ml, the serum amylase level was mildly elevated at 167 U/l and serum GAD-Ab was negative. Furthermore, ultrasonography revealed a normal pancreatic structure and dimension, leading to the exclusion of pancreatitis. Based on these findings, the patient was diagnosed with PFT1DM.

Table I Laboratory data for Case 1 and Case 2 on admission.

Table I

Laboratory data for Case 1 and Case 2 on admission.

Indicator	Case 1	Case 2	Reference range
Complete blood count
WBC, x109/l	6.14	5.13	4-10
Neutrophils, %	58.2	74.6	40-60
Lymphocytes, %	25.2	17.4	20-40
Monocytes, %	8.3	5.5	2-8
RBC, x1012/l	3.12	3.59	3.5-5.5
Hb, g/l	97	125	110-150
HCT, %	27.5	35.3	37-48
PLT, x109/l	221	162	100-300
Liver function
AST, U/l	6	13	5-35
ALT, U/l	7	67	0-40
γ-GTP, U/l	10	12	7-30
TBIL, µmol/l	10.5	5.7	1.7-17.1
ALP, U/l	44	67	50-135
TP, g/l	57.6	68.2	60-80
ALB, g/l	33	34.7	35-55
Renal function
Cr, µmol/l	37	55	44-97
BUN, mmol/l	2.3	2.4	1.7-8.3
Enzyme and inflammation
CK-MB, ng/ml	0.5	0.58	0-5
Amylase, U/l	167	229	30-110
CRP, mg/l	6.4	36.7	0-10
Blood glucose
GLU, mmol/l	21.2	9.8	3.89-6.11
HbA1c, %	7.6	5.5	4-6
C-peptide, ng/ml	0.13	0.01	0.62-2.74
GAD-Ab, U/ml	<5	<5	0-5
Thyroid hormones
TSH, µIU/ml	2.85	1.06	0.27-4.20
FT4, pmol/l	9.47	9.61	9.6-17.0
Electrolytes
Na+, mmol/l	136	141.8	135-145
K+, mmol/l	3.31	3.82	3.5-5.5
Cl-, mmol/l	114	98.7	96-106
Coagulation
PT, sec	11.3	12.9	10-14
APTT, sec	19.8	32.1	20-40
FDP, µg/ml	2.66	5.71	<5
D-dimer, mg/l	0.41	0.51	<0.5
Blood gas
pH	7.27	7.43	7.35-7.45
PCO2, mmHg	23	38	35-45
PO2, mmHg	95	95	80-100
HCO3, mmol/l	10.6	19.2	22-27
LAC, mmol/l	0.9	0.8	0.5-1.7
Urinalysis
pH	5.5	6.5	4.5-8.0
Protein	-	-	-
Glucose	+++	+++	-
Blood	-	-	-
Ketone	+++	+++	-

[i] WBC, white blood cells; RBC, red blood cells; Hb, hemoglobin; HCT, hematocrit; PLT, platelet; AST, aspartate transaminase; ALT, alanine transaminase; γ-GTP, γ-glutamyl transpeptidase; TBIL, total bilirubin; ALP, alkaline phosphatase; TP, total protein; ALB, albumin; Cr, creatinine; BUN, blood urea nitrogen; CK-MB, creatine kinase-MB; CRP, C-reactive protein; GLU, glucose; HbA1c, glycosylated hemoglobin; GAD-Ab; glutamic acid decarboxylase antibody; TSH, thyroid-stimulating hormone; FT4, free thyroxine level 4; PT, thromboplastin time; APTT, activated partial thromboplastin time; FDP, fibrin degradation products; PCO₂, partial pressure of carbon dioxide; PO₂, partial pressure of oxygen; HCO₃^-, bicarbonate; LAC, lactate.

Following rehydration therapy and continuous intravenous insulin infusion, the patient's ketonuria and blood electrolytes normalized within 24 h. Subcutaneous insulin therapy was then initiated, with doses adjusted based on blood glucose monitoring. The insulin regimen was gradually optimized to Aspart insulin at 40 U/day and Detemir insulin at 36 U/day. After blood glucose was stable, the patient was discharged with guidance on weekly outpatient follow-up and insulin dose adjustments. Subsequent blood glucose levels remained within the target range and serum amylase levels returned to normal. At 37 weeks of gestation, the patient delivered a healthy male baby via a cesarean section, weighing 3,350 grams with an Apgar score of 10 at 1 min. The postpartum C-peptide release test showed significantly low fasting C-peptide levels at <0.1 ng/ml, indicating impaired pancreatic beta cell function. Thus, insulin therapy was continued to manage blood glucose levels without further adjustments, administered as Aspart insulin at 24 U/day (8 units before each meal) and Detemir insulin at 20 U/day. Follow-up was performed every three months through telephone communication for 1 year and the patient reported well-managed blood glucose levels through finger-prick blood glucose monitoring and no plans for another pregnancy.

Case 2

A 28-year-old gravida 1, para 0 woman at 26 weeks of gestation was admitted to Jinan Maternity and Child Care Hospital (Jinan, China) in August 2024 due to hyperglycemia and ketonuria for one day. The patient had no history or family history of diabetes. At 24 weeks of gestation, the patient was diagnosed with GDM via an Oral Glucose Tolerance Test at a local hospital. Subsequently, through dietary management and exercise, the patient successfully maintained satisfactory blood glucose levels. At 25 weeks of gestation, the patient developed a fever peaking at 38.5˚C, accompanied by fatigue and muscle aches, without sore throat or cough. No viral serological tests were conducted and outpatient treatment with acetaminophen resulted in symptom resolution. On admission, the patient's physical examination revealed the following vital signs: Temperature of 36.9˚C, heart rate at 110 beats per minute, respiratory rate at 20 breaths per minute and blood pressure of 118/78 mmHg. The patient's BMI was calculated as 30.4 kg/m2. All of these parameters were within normal ranges. Auscultation of the lungs revealed normal breath sounds bilaterally and the heart rhythm was regular.

Obstetric examination showed a uterine height of 26 cm, abdominal circumference of 95 cm, fetal heart rate at 154 beats per minute and no uterine contractions. The patient's laboratory tests revealed an elevated FBG at 9.8 mmol/l, an elevated postprandial 2-h blood glucose at 17.7 mmol/l, ketonuria (+++) and an elevated serum amylase level at 229 U/l. Blood gas analysis showed a normal pH at 7.43, a normal PCO2 at 38 mmHg and PO2 at 95 mmHg, a normal lactate level at 0.8 mmol/l and a decreased HCO3- levels at 19.2 mmol/l. Additional testing results found a normal level of HbA1c at 5.5% and a decreased serum fasting C-peptide level at 0.01 ng/ml, and serum GAD-Ab was negative. The detailed data of the patient are shown in Table I. Ultrasonography of the pancreas showed no significant abnormalities. Therefore, the patient was diagnosed with PFT1DM.

Prompt rehydration was initiated alongside continuous intravenous insulin therapy. After resolving ketonuria, subcutaneous insulin therapy was initiated with multiple daily injections and doses were titrated based on blood glucose monitoring. The insulin regimen was gradually adjusted to Aspart insulin at 62 U/day and Glargine insulin at 40 U/day. After blood glucose was stable, the patient was discharged. In the following three months, blood glucose remained within the target range and serum amylase levels normalized. At 38 weeks of gestation, the patient delivered a healthy male baby via a cesarean section, weighing 3,410 grams, with an Apgar score of 10 at 1 min. After childbirth, the C-peptide release test showed that fasting C-peptide levels remained low at 0.01 ng/ml, suggesting impaired pancreatic beta cell function. To achieve effective glycemic control, the patient continued insulin therapy with Aspart insulin at 30 U/day and Glargine insulin at 20 U/day without further adjustments. Over the subsequent 12 months, telephone follow-up indicated effective blood glucose management through finger-prick blood glucose monitoring. Additionally, the patient has no plans for future pregnancy.

Discussion

FT1DM was first reported in Japan in 1987, with subsequent reports emerging in East and Southeast Asian countries, such as South Korea, China and Malaysia. FT1DM, as a distinct subtype of T1DM, is predominantly observed in Asian populations, with only a small number of cases reported in European populations (10). Unlike other subtypes of T1DM, >90% of FT1DM cases occur in adults. The exact etiology of FT1DM remains elusive, though it is potentially linked to genetic factors, viral infections, autoimmune reactions and pregnancy. The DRB1*04:05-DQB1*04:01 haplotype of the human leukocyte antigen class II gene plays a critical role in the development of FT1DM (11). A recent study reported that several viral infections are associated with the development of FT1DM, including Coxsackievirus (B1, B3, B4, A4, A5, A6), Cytomegalovirus, Epstein-Barr Virus, Mumps virus and B19 parvoviruses (12). Viral infections trigger autoimmune responses through exposure to viral antigens, which can cause rapid and widespread damage to pancreatic beta cells in patients (13). Additionally, it was reported that roughly 20% of patients with FT1DM experienced virus infections 1-2 weeks before the disease onset (14). In the current study, Case 2 presented with upper respiratory tract infection symptoms before the onset of FT1DM, which is consistent with a previous case report (15). Thus, increasing efforts in viral serological testing among pregnant women with FT1DM can aid in elucidating the etiology of this disease.

The diagnostic criteria for FT1DM primarily encompass four key aspects (5): i) Symptoms of hyperglycemia may occur, such as dry mouth, polydipsia and polyuria, which progress rapidly to ketosis or DKA within a week, or patients may present with ketosis as the initial symptom. ii) Random blood glucose ≥16 mmol/l at the time of diagnosis, with HbA1C <8.7%, indicating the need for insulin therapy. iii) Pancreatic auto-antibodies are negative in most cases. iv) Urinary C-peptide level <10 µg/d in the early stages of onset, or serum fasting C-peptide level <0.3 ng/ml, or serum fasting C-peptide level <0.5 ng/ml after glucagon stimulation at 2 h postprandial. In Case 1 and Case 2, patients exhibited a shorter duration of hyperglycemic symptoms, lower levels of serum fasting C-peptide and nearly normal HbA1c levels, all of which met the FT1DM diagnostic criteria. As a key serological biomarker for T1DM, GAD-Ab exhibits high specificity and sensitivity (16). GAD-Ab testing in Case 1 and Case 2 were negative, confirming the diagnosis of PFT1DM in both patients. The results suggested GAD-Ab testing can aid in confirming the diagnosis when PFT1DM is clinically suspected. In addition, ultrasound imaging showed no evidence of pancreatitis; the elevated serum amylase levels in Case 1 and Case 2 may have been due to the infiltration of pancreatic exocrine lymphocytes.

HbA1C is widely regarded as the gold standard for assessing glycemic control and diabetes severity (17). However, during acute episodes of FT1DM, HbA1C levels tend to remain normal and are therefore insufficient to assess the condition. Qiu et al (18) reported that a plasma glucose (PG)/HbA1C ratio of ≥4.389 could be used as a threshold for distinguishing patients with FT1DM from those with DKA, with a sensitivity of 75% and a specificity of 81.6%. Another study by Liu et al (19) also demonstrated that a PG/HbA1C ratio threshold of ≥4.2 could identify patients with DKA at high risk of FT1DM, with a sensitivity of 94% and a specificity of 98%. In the present cases, the PG/HbA1C ratio was 4.20 in Case 1 and 3.22 in Case 2, aligning with values reported in a previous study (20). These findings demonstrated that the PG/HbA1C ratio could serve as a tool to assess the likelihood of FT1DM in pregnant women with DKA.

PFT1DM is characterized by poor maternal and infant outcomes and high perinatal mortality (21,22). Early identification and treatments are crucial for preventing adverse pregnancy outcomes in PFT1DM (23). DKA management includes aggressive fluid resuscitation and early insulin administration, maintenance of the fluid and electrolyte balance, infection control and fetal heart rate monitoring (24,25). After correcting DKA, intensive insulin therapy is administered to maintain blood glucose within the target range. Here, although early diagnosis and insulin therapy were unable to prevent Cases 1 and Cases 2 from progressing to T1DM, both patients successfully delivered. Therefore, prompt administration of fluids and timely initiation of insulin treatments led to favorable neonatal outcomes.

However, given the limited number of cases and the absence of supporting viral serological test results, the present case report is merely preliminary and serves as a basis for future research. Due to the lack of long-term follow-up after delivery, it is not feasible to determine the long-term function of pancreatic beta cells and the progression of PFT1DM. Regarding the PG/HbA1C ratio as a diagnostic biomarker, further large-scale multicenter studies are needed to determine whether it is clinically applicable.

In conclusion, PFT1DM is often mistaken for acute pancreatitis or gastroenteritis, resulting in delayed treatment. Pregnant women should be encouraged to seek immediate medical attention at the onset of any of symptoms, including polyuria, polydipsia and weight loss, or gastrointestinal symptoms, such as nausea and vomiting, or reduced fetal movement, or signs of preterm labor. In pregnant women experiencing viral infections, systematic blood glucose monitoring is essential to prevent delayed PFT1DM diagnosis and adverse perinatal consequences. When PFT1DM is suspected, blood glucose, HbA1c, C-peptide and GAD-Ab tests should be performed for diagnostic purposes. Focusing on the PG/HbA1C ratio can further enhance diagnostic accuracy. Timely correction of DKA and prompt insulin administration can enhance pregnancy outcomes of PFT1DM. Due to irreversible pancreatic beta cell dysfunction, postpartum lifelong insulin therapy is required for patients with PFT1DM.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The datasets generated in the present study may be requested from the corresponding author.

Authors' contributions

JL conceived the study and wrote the manuscript. JL, LZ, XW and NL were responsible for collecting and analyzing the patient data and the literature search. JL, KF and DC were involved in project administration and confirm the authenticity of all the raw data. KF and DC analyzed the patient data, and made critical revisions to the manuscript. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The patients provided written consent for the publication of their anonymized data/case information.

Competing interests

The authors declare that they have no competing interests.

References