Table 2.

Immune checkpoint inhibitors associated with pancreatic injury.

Type of pancreatic injury		Characteristics	Possible mechanisms	Treatment	References
						Endocrine (ICIs-DM)	Acute autoimmune insulin-dependent DM	Hyperglycemia; FIDM; DKA; Undetectable C-peptide; Autoantibodies	1. β-cells be destroyed by CD8+ T cells, but α-cells are not affected. 2. The period of onset hyperglycemia may linked to the antibodies.	① New-onset hyperglycemia < 200 mg/dl and a history of T2D with low suspicion for DKA should continue ICIs, monitor serial blood glucose and modify diet and lifestyle; and consider endocrine consultation if patients are symptomatic or glucose levels are persistently uncontrolled. ② New-onset fasting glucose > 200 mg/dl, random blood glucose > 250 mg/dl, history of T2D with fasting/random glucose > 250 mg/dl, and workup negative for DKA should be given similar treatments and management. ③ DKA should hold ICIs, require inpatient care and endocrine consultation. DKA should be managed with institutional guidelines: IV fluids +/– potassium supplementation, IV insulin, and hourly monitoring of laboratory indicators (glucose, serum ketones, blood pH, and anion gap) to correct the anion gap and electrolyte disorder.	(6, 37, 50–52)
Type 2 diabetes-like phenotype	Hyperglycemia; Pre-existing T2DM; Higher BMI; Older age; Hypertension; Detectable C-peptide; Higher HbA1c; CRP; Few with DKA	1. β-cells be destroyed by CD8+ T cells, but α-cells are not affected. 2. T2D-like phenotype can be an insidious side effect on glycemia due to an abnormal chronic subclinical inflammatory state induced by long-term ICIs therapy.	(5, 6, 16, 25, 53, 54)
Diabetes induced by autoimmune pancreatitis	Hyperglycemia; Higher HbA1c; Pancreatitis; Pancreatic atrophy	1. CD8+ T cells infiltrate in and around the pancreatic islets rather than CD4+ T cells. 2. It cause damage to pancreatic cells, including islet β-cells and acinar, thereby destroying exocrine and endocrine pancreatic tissues and resulting in pancreatitis-related diabetes and pancreatic atrophy.	(22, 24, 55)
Diabetes following autoimmune lipoatrophy	Hyperglycemia; AGL; Central obesity; Higher HbA1c	1. The histological analysis revealed CD3+ T cells infiltration and extensive fibroelastosis replacement. 2. The worsening of glycemic control is primarily related to the increased IR and concomitant with the progression of autoimmune lipoatrophy.	(15, 55, 56)
Exocrine	Asymptomatic pancreatic enzyme elevation	A mild increase in amylase and lipase levels	1. The relationship between asymptomatically elevated amylase/lipase levels and pancreatitis is still vague. 2. this increase is likely related to T cell-mediated inflammation present in other organs, a metastatic disease, or renal failure, but it is not linked to pancreatic inflammation.	① Pancreatic enzyme monitoring is not recommended as a routine procedure unless pancreatitis is suspected. ② ICIs can be continued.	(57–61)
	ICIs-P	Requires meeting ≥2 criteria: ① significant symptoms of pancreatitis; ② radiographic evidence; ③ changes in laboratory data.	1. CD3+ T lymphocytes densely infiltrate the pancreatic islets in “healthy” areas, and the ratio of CD8+/CD4+ T lymphocytes in “unhealthy” areas increases. It suggests that immune T cell infiltrates may be the prevalent cytotoxic components of ICIs treatment. 2. Dense CD8+, TIA1+, and granzyme B+ lymphoid infiltrate within a biopsied lesion.	① Once ICIs-P is confirmed with the criteria, hospital admission should be recommended. ② For grade 2, ICIs should be discontinued, and 0.5–1 mg/kg/day prednisone/methylprednisolone should be given instead until symptoms improve to grade ≤1. Then, the dose should be tapered for 4–6 weeks, and IV hydration should be administered. ③ For grades 3–4, ICIs should be permanently discontinued, and treatment with a double daily dose of glucocorticosteroids than moderate grade and IV fluids should be provided.	(57, 62–65)
	ICIs-PEI	Abdominal pain; Good appetite; Irregular stools; Steatorrhea; Fecal pancreatic elastase-1 test	CD8+ T cells infiltrate inside and around the pancreas to damage ductal and acinar cells (exocrine pancreas) and even pancreatic atrophy. This alteration decreases the secretion of pancreatic enzymes and affects the release of bicarbonate, water, and enzymes into the duodenum.	PERT	(66, 67)

ICIs, Immune checkpoint inhibitors; DM, Diabetes mellitus; DKA, Diabetic ketoacidosis; FIDM, Fulminant type 1 diabetes; CRP, C-reactive protein; AGL, Acquired generalized lipodystrophy; ICIs-P, ICIs associated with pancreatitis; ICIs-PEI, ICIs associated with pancreatic exocrine insufficiency; PERT, Pancreatic enzyme replacement therapy.