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Diarrhoea in Diabetes - is it metformin?

Dr Chee L Khoo

Diarrhoea is a common side effect of metformin in patients with diabetes. The exact mechanism is poorly understood. Starting at a lower dose and slowly titrating up may reduce the incidence of this side effect. Changing over to the extended release version may sometimes help. Some patients just can’t tolerate even the smallest dose of metformin extended version or nConstipationot.

What about patients with diabetes and suffers from frequent diarrhoea but not on metformin? In the absence of any other known causes, we often blame it on autonomic dysfunction. Are we missing other causes? What about pancreatic exocrine insufficiency?

Pancreatic exocrine insufficiency (PEI) is not an uncommon cause of diarrhoea especially if the diarrhoea is of the difficult-to-flush type but this is not always well described by the patient. In addition to diarrhoea, PEI is also associated with general abdominal discomfort, flatulence, weight loss and nutritional deficiencies including fat soluble vitamins and magnesium.

PEI can result from diseases of the pancreas - acute or chronic pancreatitis, surgical resection of the pancreas (e.g. Whipple’s procedure). Gastric or intestinal surgery can also interfere with pancreatic enzyme function and secretion. There is a higher incidence of PEI in patients with Crohn’s and Coeliac disease.  As patients with cystic fibrosis (CF) live longer with modern management, many older CF patients will suffer from PEI. Patients with pancreatic insufficiency are also at risk of secondary diabetes, so-called Type 3c Diabetes.

Patients with T1D and T2D are also at risk of PEI even without damage to the pancreas. In a study by Larger et al (2012), 11% to 30% of patients with T1DM and in 3% to 20% of patients with T2DM. were found to have PEI. Endocrine cells are thought to provide trophic factors necessary for the healthy functioning of the exocrine cells and the death of the endocrine cells in T1D or T2D may affect the health of the exocrine cells resulting in PEI. Patients with diabetes (T1D and T2D) are at higher risk of pancreatic acinar cell abnormalities including pancreatic cancer.

Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic enzyme activity in the intestinal lumen to a level that is below the threshold required to maintain normal digestion. Pancreatic exocrine secretion can be significantly reduced without PEI being present. In a landmark

paper four decades ago, DiMagno et al[1] demonstrated that steatorrhea does not occur until pancreatic lipase output is reduced to 5%-10% of normal output. The ability to digest fat is the determining factor that causes the most important symptoms and clinical complications because lipase, the major lipolytic enzyme of the pancreatic juice, is the pancreatic digestive enzyme with the poorest stability in the GI tract.

The gold standard for the diagnosis of PEI is three-day fecal fat quantification and determination of the coefficient of fat absorption but the test is cumbersome and unpleasant for both patient and lab staff. The patient is required to keep a strict diet, with 100 g of fat per day for five days, and to collect the complete volume of faeces for three days. Laboratory personnel need to handle large volumes of faeces!

Faecal Elastase 1

Pancreatic elastase 1 is an enzyme of the pancreatic juice that is highly stable during passage through the GI tract. The concentration of elastase 1 can be measured in faeces using a simple enzyme-linked immunosorbent assay on a spot faecal sample. Low FE-1 levels correlate well with  endoscopic retrograde pancreatogram and cholangio-pancreatographic MRI. However, studies evaluating the role of FE-1 testing in the detection of PEI in chronic pancreatitis are scarce.

13C-mixed triglycerides breath test

This test measures pancreatic degradation of triglycerides. The patient ingests a small amount of 13C-marked triglycerides together with butter on a piece of toasted bread, after an overnight fast. In the presence of normal lipase activity, 13C-triglycerides is degraded in the intestinal lumen and 13C-marked fatty acids is absorbed. The fatty acids is metabolised in the liver and exhaled 13CO2  is then measured.

Direct pancreatic function tests

Pancreatic juice can also be recovered endoscopically after stimulation but naturally, this is invasive.


Patients with definite PEI do not need diagnostic tests while those with possible PEI may undergo diagnostic tests but there are problems with availability of the tests. A trial of pancreatic anzyme replacement therapy (PERT) is sometimes the way to go.

Historically, a low-fat diet has been recommended in PEI to reduce steatorrhea. This recommendation has been abandoned in modern dietary counselling in PEI due to the risk of aggravating PEI-related weight loss and deficiencies of lipid-soluble vitamins.


Pancreatic enzyme replacement therapy (PERT) are extracts from the porcine pancreas  administered as enteric-coated mini-microspheres. There is evidence that patients with PEI with or without symptoms suffer from nutritional deficiencies. The Australian Pancreatic Club states that the goal of PERT is treatment of mal-digestion rather than treatment of symptoms. It recommends 25-40,000 lipase units (i.e. 2-4 capsules of CREON) per main meal and half of that dose for snacks or minor meals.

There is no consensus on how to measure success of treatment. Most international guidelines recommend assessment of symptoms, weight and serum tests of malnutrition.


Asbjørn Mohr Drewes. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol 2013 November 14; 19(42): 7258-7266.

Ranka N. Kangrga. Pancreatic Elastase Levels in Feces As A Marker of Exocrine Pancreatic Function in Patients With Diabetes Mellitus. Laboratory Medicine 47:2:140-148

Summary and recommendations from the Australasian guidelines for the management of pancreatic exocrine insufficiency. Pancreatology 16 (2016) 164e180


The views expressed are views of the authors and do not necessarily represent the views of the board of SSW GP Link