Pancreatogenic Diabetes Mellitus

Pancreatogenic diabetes mellitus (type 3c) is diabetes caused by structural or functional disease of the exocrine pancreas, with loss of insulin, glucagon and pancreatic polypeptide secretion. It is frequently misclassified as type 2 diabetes.

Causes include chronic pancreatitis (most common), pancreatic cancer, pancreatic resection, recurrent acute pancreatitis, cystic fibrosis, haemochromatosis and fibrocalculous pancreatic disease.

It accounts for a minority of all diabetes but is under recognised. Risk rises with disease duration, pancreatic calcification and extent of resection, and is near certain after total pancreatectomy.

Pathophysiology.

Islet loss from fibrosis, inflammation or resection reduces insulin and glucagon. Loss of the incretin effect and of pancreatic polypeptide increases hepatic insulin resistance.

Impaired glucagon response and variable intake from malabsorption make glycaemia labile, with frequent hypoglycaemia. Ketoacidosis is uncommon, and microvascular complications occur at rates similar to other diabetes.

• Diabetes in a patient with chronic abdominal pain, steatorrhoea, weight loss or known pancreatic disease or resection.
• Fat soluble vitamin deficiency (A, D, E, K), metabolic bone disease and unpredictable hypoglycaemia.

Red flags.

• New onset diabetes after age 50 with unexplained weight loss, back or epigastric pain or jaundice: investigate for pancreatic cancer.
• Recurrent severe hypoglycaemia on modest insulin doses.

• Diabetes by usual glucose or HbA1c criteria.
• Exocrine insufficiency: faecal elastase-1 under 200 micrograms/g (under 100 micrograms/g is severe). Watery stool gives falsely low values.
• Pancreatic disease on imaging: CT, MRI with cholangiopancreatography or endoscopic ultrasound.
• Absent islet autoantibodies. A low pancreatic polypeptide supports the diagnosis.
• Serum ferritin and transferrin saturation if haemochromatosis is possible, and sweat chloride or CFTR genotype in younger patients.

Differential diagnosis.

• Type 2 diabetes with incidental pancreatic findings.
• Type 1 diabetes or latent autoimmune diabetes of adults (antibodies present).
• Pancreatic cancer presenting as new diabetes.
• Cystic fibrosis related diabetes and haemochromatosis arthropathy with diabetes.

• Pancreatic enzyme replacement with meals: start 25,000 to 50,000 lipase units with each main meal and half that with snacks, titrated to stool and weight, maximum 10,000 lipase units/kg/day. Take at the start of the meal.
• Metformin first if eGFR is 30 or more (maximum 1000 mg daily at eGFR 30 to 44; stop under 30). Avoid in heavy alcohol use, ongoing weight loss or intolerance.
• Insulin when metformin is not enough, or from the outset if HbA1c is over 75 mmol/mol or symptoms are present. After total pancreatectomy use basal bolus insulin starting at the low end of usual doses, about 0.2 to 0.5 units/kg daily, because sensitivity is high and hypoglycaemia is frequent.
• Avoid sulphonylureas (hypoglycaemia) and sodium-glucose cotransporter 2 inhibitors (ketoacidosis with low insulin). Incretin based drugs are used with caution in active pancreatitis and when weight loss is unwanted.
• Replace fat soluble vitamins, treat pain, stop alcohol and smoking, and assess bone density.
• Hypoglycaemia: 15 to 20 g oral glucose, repeat at 15 minutes; glucagon 1 mg intramuscularly may be less effective because glycogen stores are low.

Special groups. After pancreatic resection or in alcohol related disease, hypoglycaemia risk is highest; agree higher glucose targets and teach carers glucagon use.

Monitoring. HbA1c every 3 months, weight, faecal fat or elastase response, vitamins A, D, E and K annually, bone density every 2 years, and usual diabetes complication screening annually.

Referral and escalation. Gastroenterology or pancreatic unit for enzyme titration and cancer surveillance. Urgent imaging for red flags.