Diabetic Ketoacidosis Unveiling Severe Hypertriglyceridemia and Acute Mild Pancreatitis: A Rare Initial Manifestation of Type 2 Diabetes Mellitus

Introduction

The combination of diabetic ketoacidosis (DKA), hypertriglyceridemia, and acute pancreatitis, often referred to as the “enigmatic triangle” since its initial description in 1997, affects approximately 4% of individuals with DKA and is exceedingly rare as an initial manifestation of type 2 diabetes mellitus (DM) in adults [1]. Acute pancreatitis is a common acute inflammatory disorder of the pancreas marked by abdominal pain and increased serum pancreatic enzyme levels. Hypertriglyceridemia constitutes the third leading global cause of acute pancreatitis, after gallstone disease and alcohol consumption [2]. Elevated triglyceride levels, often intensified during DKA due to enhanced lipolysis, may lead to fat accumulation within pancreatic cells and contribute to the development of pancreatitis. Hypertriglyceridemia is present as a secondary etiology in about 7% of acute pancreatitis cases. This association is bidirectional; DKA can promote hypertriglyceridemia and pancreatitis, while severe hypertriglyceridemia can impair insulin sensitivity and initiate or aggravate DKA [3]. Diagnosis can be difficult due to overlapping clinical symptoms and nonspecific laboratory findings. However, early identification is essential to ensure timely interventions such as aggressive fluid resuscitation, strict glycemic control, and appropriate management of pancreatitis-associated complications. Standard management typically includes intravenous hydration, continuous insulin infusion, and lipid-lowering therapies. In select cases, plasmapheresis has reportedly been effective [4].

This case report aims to underscore the diagnostic challenges, particularly in individuals without a prior history of DM, and emphasizes the importance of prompt evaluation and timely intervention.

Case Report

A 35-year-old African American man with no known medical history of DM or family history presented to the emergency department with epigastric abdominal pain, which had worsened over the preceding 3 days. He denied associated symptoms such as nausea, vomiting, diarrhea, fever, chest pain, or urinary complaints. His social history revealed chronic tobacco use and a history of daily alcohol consumption, which he discontinued approximately 6 months earlier. He had recently been released from incarceration; his last reported alcohol intake occurred prior to imprisonment. He denied current illicit drug use and was not taking any home medications.

Upon arrival to the emergency department, the patient was hemodynamically stable but tachycardic, with a heart rate of 118 beats/min. His blood pressure was 134/85 mmHg, and he achieved oxygen saturation on room air. Laboratory findings at admission are shown in Table 1.

A computed tomography (CT) scan of the abdomen and pelvis showed mild stranding around the pancreas, suggestive of mild pancreatitis, as shown in Figure 1. Peripancreatic lymphadenopathy was noted and considered reactive. No gallstones were visualized. The pancreas showed an abnormal contour in the head region, but no mass or acute collection was identified. A lipid panel obtained at admission revealed critically elevated triglyceride levels at 2464 mg/dL and a total cholesterol level of 570 mg/dL. These findings, in the context of DKA and abdominal pain, were consistent with hypertriglyceridemia-induced acute pancreatitis precipitating DKA.

The patient was admitted to the intensive care unit and treated with intravenous fluids, an insulin infusion at 0.1 units/kg/h, and electrolyte repletion. He was placed on a fasting regimen (nil per os) and administered a D10–0.45% NaCl infusion with added potassium chloride to prevent hypoglycemia during insulin therapy. Fenofibrate 96.5 mg orally daily and atorvastatin 80 mg nightly were initiated when triglyceride levels began to decline. Triglyceride levels were monitored every 12 h; they steadily decreased to 816 mg/dL by hospital day 3. The insulin infusion was discontinued when triglyceride levels fell below 500 mg/dL and the anion gap closed. A progressive reduction in serum triglyceride levels was observed throughout hospitalization after implementation of insulin therapy, intravenous fluids, and supportive care. This downward trend is illustrated in Figure 2, demonstrating an effective metabolic response to treatment. Subcutaneous insulin therapy was introduced, and the patient was transitioned to a low-fat, low-carbohydrate diabetic diet.

Throughout hospitalization, the patient remained hemodynamically stable without signs of systemic infection. Electrolytes and the metabolic panel were closely monitored; no clinically significant abnormalities were evident beyond transient mild hyponatremia attributed to hyperglycemia. No treatment-related complications occurred. The patient received structured diabetes education and diabetic supplies. He was discharged in stable condition with instructions for outpatient follow-up and lifestyle modifications.

Discussion

DKA, while classically associated with type 1 DM, can also occur in individuals with type 2 DM, particularly in those with ketosis-prone type 2 DM. This form is characterized by sudden, temporary reductions in insulin secretion and insulin sensitivity [5]. In the present case, the patient had no prior diagnosis of diabetes, making this an exceptionally rare instance of DKA as the initial manifestation of type 2 DM.

Acute pancreatitis is a sudden inflammatory disorder of the pancreas that typically presents with abdominal pain and increased pancreatic enzyme levels. It results from damage to pancreatic ducts or acinar cells, which may be due to direct or indirect toxic effects. This injury disrupts normal enzyme secretion and can trigger early activation of digestive enzymes within the pancreas, leading to autodigestion and inflammation. Hypertriglyceridemia is recognized as a key contributing factor in the development of acute pancreatitis [2]. Our patient presented with severe hypertriglyceridemia (peak triglyceride levels of 2464 mg/dL), accompanied by CT imaging findings consistent with mild acute pancreatitis. Other causes of acute pancreatitis were excluded through a combination of medical history, laboratory testing, and imaging. The patient had no history of recurrent pancreatitis, early-onset symptoms, or family history suggestive of hereditary pancreatitis. Genetic testing was not pursued because the presentation was clearly attributable to severe hypertriglyceridemia in the setting of new-onset DKA, and no clinical features suggested a hereditary etiology. Imaging showed no structural pancreatic abnormalities. Serum calcium and triglyceride levels, along with the absence of alcohol use and gallstones on ultrasound, supported a diagnosis of hypertriglyceridemia-induced acute pancreatitis as the primary etiology.

The pathophysiology of hypertriglyceridemia-induced acute pancreatitis is multifactorial. Excess triglycerides are hydrolyzed by pancreatic lipase into free fatty acids, which – when exceeding albumin-binding capacity – form cytotoxic micelle-like aggregates. These aggregates damage vascular endothelium, acinar cells, and platelets, causing ischemia and local acidosis that promote premature trypsinogen activation. Concurrently, severe hypertriglyceridemia increases blood viscosity, leading to microvascular obstruction, impaired perfusion, and an amplified inflammatory response [6,7]. During DKA, insulin deficiency triggers increased lipolysis, elevating free fatty acids that stimulate hepatic very low-density lipoprotein (VLDL) production while inhibiting peripheral VLDL clearance, resulting in hypertriglyceridemia, as illustrated in Figure 3. In the present case, similar to previously reported instances, DKA was considered the precipitating factor that exacerbated hypertriglyceridemia and ultimately led to the development of acute pancreatitis, supported by a substantially elevated glycated hemoglobin level.

Such a strongly elevated glycated hemoglobin level indicates chronic poor glycemic control, reinforcing the likelihood that DKA served as the initial trigger in this presentation. A comprehensive assessment of the patient’s diabetes history, lipid profile, and any prior episodes of DKA or pancreatitis is essential to clarify the sequence of events and identify the primary cause. Notably, DKA and hypertriglyceridemia-induced pancreatitis can reciprocally influence each other, forming a challenging cycle that complicates management. In our patient, the clinical picture emphasized DKA as the principal initiating factor within this multifaceted interaction [8].

Currently, no standardized guidelines exist for the treatment of hypertriglyceridemia-induced pancreatitis. Initial management typically follows standard recommendations for acute pancreatitis, including aggressive fluid resuscitation, pain control, and bowel rest. After stabilization, prompt reduction of serum triglyceride levels becomes a key therapeutic objective. Several strategies have been used for this purpose, including intravenous insulin infusions, heparin administration, and plasmapheresis. A 2022 study by Gupta and Safarova demonstrated that severe hypertriglyceridemia is associated with an approximately 2-fold increased risk of venous thrombosis, establishing hypertriglyceridemia as a key contributor to thrombotic events. However, there remains a lack of randomized controlled trials comparing the effectiveness of these interventions. Regarding these approaches, insulin infusion has shown promising results in lowering triglyceride levels among affected patients [9,10]. Insulin lowers serum triglycerides by stimulating lipoprotein lipase, which hydrolyzes chylomicrons and VLDL into glycerol and free fatty acids. In patients with poorly controlled diabetes, insulin is particularly beneficial because it addresses both hyperglycemia and hypertriglyceridemia, often reducing triglyceride levels to less than 496 mg/dL (5.6 mmol/L) within 3 to 4 days [11–13].

A 2024 study in the Journal of Clinical Investigation [14] prospectively evaluated patients with hypertriglyceridemia-induced acute pancreatitis and revealed that elevated nonesterified fatty acids, generated by pancreatic lipase from circulating triglycerides, were strongly linked to more severe disease and organ failure. In animal models, inhibition of pancreatic lipase prevented multiorgan deterioration, highlighting nonesterified fatty acids as a key driver of pancreatic injury. In a prospective longitudinal study published in Medicine [15], continuous intravenous insulin infusion proved to be a safe and effective method for lowering triglyceride levels in patients with hypertriglyceridemia-induced acute pancreatitis of varying severity. Notably, early triglyceride reduction, particularly within the first 24 h, was significantly associated with a lower risk of disease progression, underscoring the therapeutic benefit of insulin-mediated mechanisms, including upregulation of lipoprotein lipase. In a propensity score-matched cohort study, Tan et al [16] demonstrated that among patients with very severe hypertriglyceridemia (>22.6 mmol/L), treatment with insulin and heparin exhibited safety and efficacy comparable to plasma exchange, while incurring substantially lower costs. Their findings support a more cost-efficient alternative for hypertriglyceridemia-induced acute pancreatitis management.

In hypertriglyceridemia-induced acute pancreatitis, standard acute pancreatitis care is initiated with insulin-based triglyceride reduction and intravenous fluids; the target triglyceride level is below 500 mg/dL. Low–molecular-weight heparin is reserved for confirmed thrombosis or high thromboembolic risk, rather than routine triglyceride reduction. Early apheresis – therapeutic plasma exchange or double filtration plasmapheresis – is considered within 24 to 48 h when disease is severe (organ failure or high severity scores), triglyceride levels remain greatly elevated (>1,000–2,000 mg/dL) despite insulin therapy, the patient is pregnant, or the clinical course is refractory or recurrent. In the present case, as well as others previously reported, lipid-lowering agents such as statins and fibrates were initiated to aid in reducing serum triglyceride levels. However, the long-term need for these agents remains uncertain, particularly in the absence of an underlying primary lipid disorder. Considering this context, it is possible that the hypertriglyceridemia was a transient response to DKA and might have resolved with improved glycemic control alone [4,17]. Our patient was successfully transitioned from an intravenous insulin infusion to a subcutaneous insulin regimen when metabolic stability had been achieved. He was subsequently discharged on a structured insulin protocol for outpatient glycemic management. In the 3 cases of DKA with hypertriglyceridemia-induced acute pancreatitis presented by Wang et al [4], the average Ranson score was 5, average Acute Physiology and Chronic Health Evaluation (APACHE) II score was 12, and average CT severity index was 2. Among these scoring systems, the APACHE II score showed the strongest relationship with clinical progression. However, larger cohort studies are warranted to determine the most reliable prognostic model for patients with this condition. In the present case, the patient had a Ranson score of 2 and APACHE II score of 2, both suggesting a relatively mild disease course with a favorable prognosis. These low scores closely corresponded with the patient’s stable clinical status and positive response to standard medical therapy.

Our case highlights the importance of early recognition and targeted management in patients presenting with the rare triad of DKA, hypertriglyceridemia, and acute pancreatitis, particularly when it serves as the initial indication of type 2 DM. Comprehensive evaluation, including CT imaging and lipid profiling, played a pivotal role in timely diagnosis and successful treatment. Although autoimmune marker findings were negative, effectively ruling out type 1 DM, the absence of genetic testing limits insights into potential hereditary predispositions. The case underscores the complex, bidirectional relationship in which DKA may trigger hypertriglyceridemia and subsequent pancreatitis, whereas severe hypertriglyceridemia can worsen insulin resistance and perpetuate DKA. The absence of long-term follow-up data regarding lipid control and diabetes management constituted a limitation, which was related to the acute care setting in which the patient was treated and the lack of documentation concerning subsequent follow-up visits. Future studies and case series could incorporate structured post-discharge follow-up to assess recurrence risk, long-term lipid trends, and glycemic control, which would provide more comprehensive insights into outcomes after hypertriglyceridemia-induced acute pancreatitis. A structured, individualized approach centered on rapid correction of hyperglycemia, ketosis, and triglyceride levels remains essential to optimize outcomes in such multifaceted presentations.

Conclusions

The coexistence of DKA, hypertriglyceridemia, and acute pancreatitis – the “enigmatic triangle” – is a rare but life-threatening presentation of type 2 DM that requires prompt recognition and protocol-driven therapy. Although insulin and aggressive intravenous hydration remain the mainstays of treatment, the role of plasmapheresis in severe or refractory cases requires further clarification through prospective studies. Clinicians should maintain a high index of suspicion in patients with unexplained abdominal pain and metabolic acidosis, even in the absence of classic risk factors.