Insulin Resistance Spawns Hypertriglyceridemia-induced Acute Pancreatitis and Diabetic Ketoacidosis: Unboxing a New Metabolic Crisis

Background Insulin resistance (IR) in adipose tissue (Adipo-IR) is linked to uncontrolled lipolysis with free fatty acids (FFAs) dissipation, ectopic fat deposition and hypertriglyceridemia (HTG). As a valuable component in the metabolic syndrome, HTG increases the likelihood of atherosclerotic cardiovascular disease (ASCVD). By analyzing two cases with severe HTG in poorly controlled T2DM which provoked hypertriglyceridemic acute pancreatitis (HTGAP) and diabetic ketoacidosis (DKA), we suggest an Adipo-IR-induced new metabolic crisis of lipid and glucose metabolism underlying HTGAP and DKA. Case Presentation In this case series, case 1 involves a 48-year-old female with triglyceride of 3841 mg/dL and HbA1c 10.1%, while case 2 describes a 32-year-old male with triglyceride of 650 mg/dL initially which was up to 5359 mg/dL 9 months later with HbA1c 12%. Both had increased anion gap, positive ketones and elevated c-peptide with significant IR. Both developed significantly increased lipase with abdomen CT scan showing edematous pancreatitis. Both patients were admitted to the intensive care unit receiving continuous insulin and Lactated Ringer’s solution infusion. The DKAs were resolved in 24 hours and triglycerides gradually decreased to < 1000 mg/dL on days 5 to 6. Both were discharged with Fenofibrate, Atorvastatin and insulin therapy. 3-month follow-up showed well controlled triglyceride and HbA1c levels. Insulin injection was switched to oral hypoglycemic medications. Discussion This scenario represents an acute crisis of lipid and glucose metabolism induced by Adipo-IR and its consequent over-activated lipolysis. Adipo-IR and over-activated lipolysis create a two-way feedback between white adipose tissue and liver (Hep-IR), which further damages pancreases with pancreatic self-hydrolysis leading to HTGAP. HTGAP further triggers counter-regulatory hormone worsening hyperglycemia and lipolysis and ultimately causing downward spiral of HTGAP-DKA. Acute management involves fluid resuscitation, insulin infusion, and nutrition management and complications prevention. Chronic management includes non-pharmacological measures and medications including Fibrates, Statin, Omega-3 fatty acids, Metformin and Sodium-glucose cotransporter-2 inhibitors. Further investigation is needed for clinically applicable assessment and stratification of Adipo-IR/Hep-IR axis.