The relationship between the pancreas and diabetes was established when Minkowski performed a pancreatectomy in the dog in 1889. Early clinicians distinguished between 'pancreatic' diabetes, due to obvious pancreatic disease, and the much more common form of diabetes in which the pancreas appeared normal. Only about 1–2% of human diabetes is considered to be due to overt pancreatic disease, but this may be an underestimate. The pancreas has a considerable reserve of islet beta cells, and investigators need to excise 70–90% from healthy animals before they will develop diabetes. Extensive pancreatic damage is therefore needed to cause human diabetes. Such damage occurs in severe cases of acute pancreatitis, in chronic pancreatitis, in pancreatic fibrosis (due for example to iron overload), or following surgical excision of the pancreas. Pancreatic carcinoma predisposes to diabetes by secreting circulating factors promoting insulin resistance as well as by pancreatic destruction. Pancreatic diabetes results in loss of both insulin and pancreatic glucagon, diabetic ketoacidosis is rare, and patients are sensitive to the action of insulin.
Although some 19th century physicians had noted an association between diabetes and pancreatic disease, proof came when Oskar Minkowski removed the pancreas from a dog in 1889, although diabetes was an unexpected development! The role of the pancreatic islets emerged more slowly, in the absence of specific stains for islet cells and insulin, and early pathologists were baffled by the apparently normal appearance of the pancreas in most cases of diabetes.
The work of Frederick Allen showed that dogs did not develop diabetes until 80–90% of the pancreas had been removed, and that the development of diabetes could be avoided by use of a low-carbohydrate, low-energy diet. This was the origin of the starvation regimen for children with diabetes.
Any form of extensive pancreatic damage may result in diabetes. These range from surgical excision of the pancreas (usually for a pancreatic tumour) to acute and chronic pancreatitis, tropical chronic pancreatitis (previously referred to as fibro-calculous pancreatic disease), pancreatic fibrosis, carcinoma of the pancreas, and inherited disorders affecting the pancreas such as cystic fibrosis.
A recent survey of 1868 people with diabetes found that 172 (7.2%) had identifiable pancreatic disease, including 135 with chronic pancreatitis (78.5%), 12 with hereditary haemochromatosis, 14 with pancreatic cancer and 7 with cystic fibrosis. The underlying diagnosis had been missed in half of these patients, and it seems likely that exocrine pancreatic problems are underdiagnosed in the diabetic clinic.
Acute pancreatitis is a medical emergency resulting from inflammation of the pancreas. It presents with the cardinal features of acute upper abdominal pain radiating to the back, elevated levels of the pancreatic enzymes amylase and lipase, and characteristic features on imaging.
The mechanism involves premature activation of enzyme precursors produced by the acinar cells triggering an inflammatory cascade. The common associated causes are gall stones and alcohol abuse; the role of some other conventionally listed 'causes' as memorised by medical students is more controversial.
Acute pancreatitis is more common in people with diabetes than in non-diabetics. In some instances it may be a reflection of the underlying pancreatic disease that has caused the diabetes. This apart, acute pancreatitis does appear to be more common in people with type 2 diabetes, possibly as a consequence of the associated obesity. It has been reported as a potential complication of the GLP-1 based therapies.
Acute pancreatitis is self-limiting in about 80% of cases, and resolves with conservative management. More severe cases are associated with profuse fluid loss into the peritoneal cavity, shock, and development of renal and pulmonary problems. Haemorrhage and necrosis may produce extensive loss of pancreatic tissue, and secondary infection may develop as the result of invasion by gut bacteria. The mortality of acute pancreatitis is about 4–5%.
Acute pancreatitis may sometimes occur as a manifestation of a chronic inflammatory process, or even pancreatic cancer, and may predispose to chronic pancreatitis. The pancreatic islets are relatively spared during acute pancreatitis, even when there is extensive damage to exocrine tissue, but acute hyperglycaemia develops in >50% of cases and permanent diabetes in about 5%
Chronic pancreatitis is due to persistent inflammation of the pancreas resulting in progressive loss of exocrine function, with secondary damage to the pancreatic islets. Chronic disabling pain is a common clinical feature, as are weight loss and (less frequently) jaundice. About 50% of those affected develop diabetes.
The commonest cause is alcohol abuse, defined as consumption of >60 g of alcohol per day, and this accounts for about 75% of cases, although only about 5% of those with alcoholic problems develop pancreatitis. Other known causes include tropical pancreatitis, cystic fibrosis, and genetic syndromes such as hereditary pancreatitis, which account for about 5% of cases. The remaining 20% of cases develop for reasons that are unknown.
Diagnosis is best made by contrast-enhanced computerised tomography (CT). Medical treatment includes avoidance of predisposing factors such as alcohol, oral ingestion of pancreatic enzymes with food, control of diabetes and pain control. Pain may be intractable and result in narcotic addiction, and patients may require pancreatic resection to treat this complication.
Chronic pancreatitis predisposes to pancreatic carcinoma, which develops in about 40% of those with hereditary pancreatitis. The prognosis of chronic pancreatitis may be limited by other factors such as alcohol abuse, but is otherwise good.
Tropical chronic pancreatitis
Tropical chronic pancreatitis is a unique form of chronic pancreatitis seen only in developing countries, and can result in the condition of fibrocalculous pancreatic diabetes (FCPD). It has clinical, radiological and pathological features that distinguish it from alcoholic and other forms of chronic pancreatitis. It affects young adults, who present with abdominal pain due to pancreatic calculi. In contrast to alcoholic chronic pancreatitis, these stones are typically large and discrete. The condition progresses to progressive exocrine pancreatic failure resulting in malabsorption and diabetes. Alcohol abuse is not a feature.
The aetiology of the condition is unknown, although it commonly develops against a background of poverty and malnutrition. Genetic mutations in the SPINK gene have been reported, and micronutrient deficiency and/or toxins are possible predisposing factors. Typical microvascular complications of diabetes may develop, although macrovascular complications are rare, and the condition also carries a high risk of carcinoma of the pancreas. Diabetes develops up to a decade after the first symptoms of tropical chronic pancreatitis, typically in the 20–40-year age group. Patients may present with very high blood glucose levels, but diabetic ketoacidosis is rare. Most patients will require insulin for glucose control, and the long-term prognosis is good relative to other causes of chronic pancreatitis.
Carcinoma of the pancreas
Carcinoma of the pancreas is due to ductal adenocarcinoma in about 90% of cases. The condition is clinically silent until the tumour has reached an advanced stage, when it presents with weight loss, pain, and/or jaundice. Late presentation largely explains its poor prognosis, with about 5% survival at 5 years. The condition is about twice as common in those with obesity or type 2 diabetes as in those without. Conversely, diabetes is present in up to 50% of those with carcinoma of the pancreas, and the diagnosis of diabetes often precedes the diagnosis of cancer. Tumour-associated humoral factors conferring insulin resistance may be responsible. Progression to pancreatic cancer has been shown to involve a cascade of gene mutations, of which KRAS is the most important. These occur in parallel with the development of progressive premalignant histological changes known as pancreatic intraepithelial neoplasia (PanIN) lesions. Early PanIN lesions are relatively common in the general population, and reflect the prevalence of other risk factors for pancreatic cancer. Since humoral markers are unavailable, pancreatic biopsy is impractical, and imaging techniques are expensive and carry the risk of false positives, possibilities for screening are currently limited.
^ Ewald N et al. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabet Metab Res Rev 2012;28:338-42