Diabetes Mellitus Type 1 vs Pancreatogenic Diabetes Mellitus after Total Pancreatectomy: Who is at higher risk for Diabetic Ketoacidosis?

Both type 1 diabetes mellitus (T1DM) and pancreatogenic diabetes mellitus (PDM) following total pancreatectomy are characterized by an absolute deficiency of endogenous insulin, making regular insulin administration essential to prevent hyperglycemia and diabetic ketoacidosis (DKA).

However, the risk of developing DKA in case of missed insulin doses differs between these two forms of insulin-deficient diabetes. Do you know who is at higher risk?

Patients with type 1 diabetes have a higher risk of DKA than those with pancreatogenic diabetes after total pancreatectomy. Do you know why?

To understand why, it is helpful to recall how DKA develops. DKA results from an excessive accumulation of ketone bodies due to altered fatty acid metabolism in the setting of insulin deficiency. Insulin normally inhibits ketogenesis by regulating key enzymes in lipid metabolism. When insulin levels fall:

• Free fatty acid (FFA) release increases — due to reduced inhibition of hormone-sensitive lipase (HSL).

• FFA uptake into mitochondria increases — due to decreased activity of acetyl-CoA carboxylase (ACC), lowering malonyl-CoA and disinhibiting carnitine palmitoyltransferase 1 (CPT1).

• Ketone body production increases — due to increased activity of HMG-CoA synthase.

Ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) are water-soluble organic acids. Their accumulation lowers blood pH, resulting in metabolic acidosis — the hallmark of DKA.

Ketogenesis is further stimulated by counterregulatory hormones such as glucagon, cortisol, catecholamines, and thyroid hormones, which enhance lipolysis and FFA availability.

Glucagon increases ketogenesis through:

• Increased hepatic FFA production

• Increased mitochondrial FFA uptake

• Increased ketogenic enzyme activity

In pancreatogenic diabetes after total pancreatectomy, both insulin and glucagon secretion are absent. In contrast, in type 1 diabetes, only β-cells are targeted by the immune system, while α-cells (the source of glucagon) remain intact. Consequently, the strong glucagon-mediated drive for ketogenesis is preserved in type 1 diabetes, explaining the greater DKA risk compared to pancreatogenic diabetes after total pancreatectomy.

Note: Cell distribution in pancreas is illustrative and does not represent real histology accurately