What is 3c (pancreatogenic) diabetes?

What is Type 3c (Pancreatogenic) Diabetes?

Type 3c diabetes is a secondary form of diabetes caused by structural and functional damage to the pancreas from diseases like pancreatitis, pancreatic surgery, cystic fibrosis, or pancreatic cancer—resulting in loss of both insulin and glucagon secretion alongside exocrine pancreatic dysfunction. 1

Definition and Core Pathophysiology

Type 3c diabetes (also called pancreatogenic or pancreatic diabetes) develops when primary pancreatic disorders damage the pancreatic islets of Langerhans, destroying both endocrine and exocrine pancreatic tissue. 1, 2 This is fundamentally different from type 1 and type 2 diabetes because:

• Dual hormone deficiency occurs: Loss of both insulin AND glucagon secretion, unlike type 1 (insulin only) or type 2 (insulin resistance with eventual insulin deficiency). 1, 3
• Exocrine dysfunction is concurrent: Pancreatic enzyme insufficiency causes malabsorption, steatorrhea, and malnutrition—features absent in type 1 and type 2 diabetes. 1, 4
• Hepatic insulin resistance develops: This is caused by deficiencies of both insulin and pancreatic polypeptide, creating a unique metabolic pattern. 5

Common Causes

The diverse etiologies include: 1

• Chronic pancreatitis (accounts for 75% of cases) 5
• Acute pancreatitis (even a single episode can trigger postpancreatitis diabetes) 1
• Pancreatic surgery or trauma (pancreatectomy) 1
• Pancreatic cancer (pancreatic ductal adenocarcinoma) 6
• Cystic fibrosis (affects 20% of adolescents and 40-50% of adults with CF) 1
• Hemochromatosis 1
• Hereditary pancreatitis (e.g., PRSS1 gene mutations) 7

Clinical Characteristics That Distinguish Type 3c

"Brittle" glucose control is the hallmark: Patients experience erratic swings between severe hypoglycemia and hyperglycemia due to impaired glucagon secretion, which normally protects against low blood sugar. 8, 3 This creates:

• Higher-than-expected insulin requirements despite lower overall insulin production 1
• Increased risk of severe hypoglycemic events that can be life-threatening 9, 2
• Significant glucose variability making management challenging 7

Additional distinguishing features include: 1

• Concurrent pancreatic exocrine insufficiency (low fecal elastase)
• Pathological pancreatic imaging findings (on endoscopic ultrasound, MRI, or CT)
• Absence of type 1 diabetes autoantibodies
• Lower levels of pancreatic polypeptide 3

Diagnostic Approach

Screen with oral glucose tolerance test (OGTT), NOT A1C, as A1C has low sensitivity for type 3c diabetes. 9, 8 However, an A1C ≥6.5% is consistent with diagnosis if present. 1

Timing of screening is critical: 1, 8

• Screen within 3-6 months following ANY episode of acute pancreatitis
• Screen annually thereafter in all patients with chronic pancreatitis
• Begin annual screening by age 10 in cystic fibrosis patients

Confirm pancreatic exocrine insufficiency by measuring fecal elastase in all patients with pancreatitis. 1, 8

Assess residual insulin production using C-peptide levels to differentiate from type 1 diabetes (which has absolute insulin deficiency versus variable deficiency in type 3c). 9

Critical Pitfall: Frequent Misdiagnosis

Type 3c diabetes is commonly misdiagnosed as type 2 diabetes, leading to inappropriate treatment. 1, 2 This matters because:

• Type 3c accounts for 5-10% of all diabetes cases in Western populations 5, 2
• Type 2 and type 3c can co-exist, complicating diagnosis 8
• Treatment strategies differ significantly between the two conditions 9

Management Principles

For mild type 3c diabetes: Oral agents including metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors can be appropriate, BUT avoid incretin-based therapies (GLP-1 agonists, DPP-4 inhibitors) if there is concern for recurrent pancreatitis. 9, 8

For severe type 3c diabetes: Insulin therapy is required, with management becoming similar to type 1 diabetes but with critical differences due to impaired glucagon secretion and higher hypoglycemia risk. 9 Consider early insulin initiation. 1, 8

Pancreatic enzyme replacement therapy (PERT) is mandatory: All type 3c patients with low fecal elastase require PERT, typically Creon 25,000 IU with meals and 10,000 IU with snacks, to improve nutritional outcomes and stabilize glycemia. 9, 8

Individualized medical nutrition therapy is paramount due to malabsorption, poor dietary intake from chronic pain, and risk of malnutrition and muscle wasting. 9, 4

Complications and Prognosis

• Microvascular complication risk appears similar to other forms of diabetes 1
• Higher mortality risk related to hypoglycemic events compared to type 1 or type 2 diabetes 2
• Increased risk of pancreatic carcinoma, particularly in chronic pancreatitis patients (75% of type 3c cases) 5
• Metabolic bone disease affects approximately two-thirds of chronic pancreatitis patients due to malabsorption of fat-soluble vitamins and calcium 8

Essential Specialist Management

All persons with type 3c diabetes should be managed by an endocrinology team due to the complexity of managing variable pancreatic damage and residual beta cell function. 9 The combination of endocrine dysfunction, exocrine insufficiency, malnutrition risk, and brittle glucose control requires specialized expertise beyond typical diabetes management.