As part of the Diabetes UK Professional Conference at London Excel in March 2018, Mylan organised a symposium entitled Pancreatic exocrine insufficiency (PEI) in diabetes – the overlooked condition. Is IBS the right diagnosis? Debbie Hicks (Nurse Consultant, Barnet, Enfield and Haringey Mental Health Trust) opened the symposium, which also included presentations by Dr Mayank Patel (Consultant in Diabetes, University Hospital Southampton NHS Foundation Trust) and Professor Mike Cummings (Consultant in Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth).
You can view a full video of the symposium here:
The management of PEI is increasingly recognised as an important part of diabetes care. People with diabetes may have mild but persistent gastrointestinal symptoms that are due to PEI but go unrecognised and untreated. In part this is because people with diabetes do not discuss their symptoms with health professionals, but there is also a lack of awareness about the relationship between pancreatic endocrine dysfunction and impaired exocrine function. The traditional model of pancreatic function considers these two components to be distinct, but they are in fact interdependent and closely linked with the incretin gut hormone response. The presentations at this meeting reviewed the pathophysiology of pancreatic dysfunction, explored the relationship between endocrine and exocrine function, and summarised evidence of the impact of PEI on glycaemic control and its treatment with pancreatic enzyme replacement therapy (PERT).
Ms Hicks described a person with diabetes that everyone would recognise from their clinics but whose suboptimal diabetes control could be due to PEI. Joanne, who is 62 years old, was diagnosed with type 2 diabetes 11 years ago and she treats this with a basal bolus insulin regimen plus metformin 1g twice daily. She works as a sales rep and is a smoker and social drinker. Her body mass index is 32kg/m2. Her glycaemic control is suboptimal (HbA1c 75mmol/mol [9%]) and she experiences unexplained episodes of hypoglycaemia two to four times a week. She constantly feels tired. She has had bowel symptoms for about a year, with flatulence, bloating and diarrhoea.
Many factors could contribute to Joanne’s poor glycaemic control and hypoglycaemic episodes. It is not uncommon for episodes of hypoglycaemia to occur when blood glucose levels are high. For example, one study in older people with diabetes with a mean HbA1c of 76mmol/mol (9.3%) found that 65% had evidence of hypoglycaemia, 46% experienced blood glucose levels <2.8mmol/L, 69% had nocturnal hypoglycaemia and 95% of hypoglycaemic episodes were undetected by routine blood glucose monitoring.1
Low adherence is common, with 30–50% of medicines for long-term conditions not taken as recommended.2 Injection technique, timing and location could be inappropriate. One large multinational survey (n=13 289) found that 30% of patients had lipohypertrophy; this was associated with unexplained hypoglycaemia, with HbA1c 0.55% higher and mean insulin dose 10.1 units/day higher than in people without lipohypertrophy.3 Joanne may also be making mistakes estimating her carbohydrate consumption and calculating her insulin requirement. There is growing awareness that malabsorption may cause poor glycaemic control and gastrointestinal symptoms; clinicians should therefore consider the potential role of pancreatic exocrine dysfunction in people with diabetes like Joanne.
1,2,3c – what is pancreatic diabetes?
Dr Mayank Patel (Consultant in Diabetes, University Hospital Southampton NHS Foundation Trust) described how diabetes may be associated with exocrine dysfunction, though it is usually considered to be an endocrine disorder. Diabetes causes inflammatory changes in the pancreas, pancreatic atrophy and reduced pancreas size and weight, each of which reduces the capacity of the pancreas to meet demand for pancreatic enzyme secretion. PEI and other forms of abnormal exocrine function may occur in about half of people with type 1 diabetes and almost a third of those with type 2 diabetes.4 The category of type 3 diabetes covers a group of unusual causes of uncontrolled diabetes and hyperglycaemia; type 3c diabetes is specifically due to pancreatogenic diabetes. In one analysis of hospital records for 1868 patients diagnosed with diabetes mellitus, type 3c diabetes accounted for 9% of cases.5
PEI is the state in which the quantities of enzymes secreted into the duodenum in response to a meal are insufficient to maintain normal digestive processes. Causes include: reduced enzyme production due to loss of functioning pancreatic tissue (eg chronic pancreatitis, cystic fibrosis, pancreatic tumours and/or resection); decreased enzyme secretion but normal pancreatic function (obstruction of the pancreatic duct – for example due to a tumour, coeliac disease, Crohn’s disease); or impaired coordination of gastrointestinal motor and secretory functions secondary to surgical procedures such as gastrectomy.
In the long term, PEI may cause malnutrition, deficiency of fat-soluble vitamins and reduced bone mineral density leading to osteopenia, osteoporosis and increased fracture risk. It is therefore important to correct PEI as early as possible in a person with diabetes. Referring to the risk of PEI in people with type 2 diabetes, Dr Patel pointed out that it is possible to be overweight and still be malnourished.
Living with diabetes is challenging and clinicians owe it to people with diabetes to make every effort to find out why their diabetes is not as well controlled as it should be – particularly when, as with PEI, the cause is treatable. PEI should be considered when glycaemic control is poor and the person with diabetes reports symptoms such as abdominal pain and bloating (particularly among people with type 2 diabetes), flatulence, diarrhoea, weight loss and steatorrhoea. Dr Patel described these symptoms as ‘nebulous’, noting that the list of possible explanations is long, but PEI is now recognised as a complication of diabetes (and other disorders) that causes non-specific symptoms and interferes with glycaemic control.
PEI is associated with type 1 and type 2 diabetes, and misclassification of patients with type 3c diabetes is common. Further assessment often clarifies the diagnosis. Unplanned weight loss and steatorrhoea, in particular, are red flag symptoms mandating further investigations. PEI symptoms can be mistaken for the effects of diabetic neuropathy (which may cause both gastroparesis and diarrhoea) or disorders of the bowel (Crohn’s disease, coeliac disease, ulcerative colitis, small intestinal bacterial overgrowth and gastroenteritis). Gastrointestinal symptoms are common with metformin but can be minimised by initial dose titration and dose reduction. GLP-1 agonists are another common cause of gastrointestinal symptoms but they are usually transient; acarbose is also associated with gastrointestinal intolerance but is little used in the UK.
Pancreatic exocrine and endocrine functions are mutually dependent (Figure 1). The proper functioning of exocrine cells depends on insulin synthesis by endocrine cells whereas exocrine dysfunction causes impaired nutrient absorption and contributes to the hypo- and hyperglycaemia that characterises type 3c diabetes. Several mechanisms may cause PEI in people with diabetes:4,6 pancreatic atrophy secondary to loss of the anabolic effects of insulin; changes in the secretion or action of islet-derived hormones other than insulin; autoimmune damage extending beyond the islet cells to the exocrine pancreas; an underlying pancreatic disease; exocrine dysfunction due to diabetic neuropathy; or pancreatic fibrosis and atrophy secondary to diabetic angiopathy.
The risk factors for PEI include a history of pancreatic disease or surgery, high alcohol consumption (the main driver of chronic pancreatitis) and recurrent unexplained hypoglycaemia. In people with diabetes, when the possibilities of non-adherence with medication and difficulties with injection technique have been excluded, PEI should be suspected in those who have recurrent unexplained hypoglycaemia, decreasing insulin requirements or erratic blood glucose control. Individuals with a long duration of type 1 diabetes are also at greater risk and this is an important issue at a time when longevity is increasing among people with diabetes.
People with a long duration of chronic pancreatitis also seem to be at higher risk of developing type 3c diabetes. Chronic pancreatitis is associated with the destruction of parenchyma, islet cells and impaired incretin secretion secondary to nutrient maldigestion and malabsorption, leading to diminished insulin secretion from the surviving beta cells. Pancreatitis may be subclinical and it is therefore worthwhile taking a history when individuals report recent indigestion or heartburn – careful questioning is sometimes necessary to identify problems that people would not otherwise volunteer.
The objectives of treatment of PEI are to restore nutritional status, to relieve the symptoms of maldigestion and malabsorption by replacing the missing enzymes, and to reduce the risk of long-term complications. PERT, in which replacement enzymes are taken with meals and snacks, aims to mimic the exocrine response of a healthy pancreas. The enzymes are formulated as enteric-coated preparations that do not disintegrate until they reach the high pH of the duodenum.
The potential metabolic effects of PERT in diabetes
Professor Mike Cummings (Consultant in Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth) described the traditional view of the functions of the pancreas, in which 15% of the glands are responsible for the production of endocrine hormones and 85% are responsible for the production of digestive enzymes; these are considered to be distinct and to have very little overlap. He went on to summarise the growing body of evidence showing that this traditional view is not the case.
PERT and glycaemic control
PERT has been shown to improve glycaemic control (Figure 2).7 Forty people with diabetes with tropical calculous pancreatitis (a form of chronic pancreatitis and diabetes) received treatment with PERT while continuing their glucose-lowering medication with no change in lifestyle. After six months, mean HbA1c was reduced by 11mmol/mol (1%), largely due to a reduction in postprandial glucose (Figure 2). This is an important improvement in glycaemic control by current therapeutic standards. Clinical trials of glucose-lowering therapies show that metformin, sulfonylureas and glitazone offer a reduction in HbA1c of 1.0–1.5% and dipeptidyl peptidase 4 (DPP-4) inhibitors can achieve a reduction of 0.5% to 1.0%.8 The UK prospective diabetes study (UKPDS) has shown that reducing HbA1c by 11mmol/mol is associated with substantial long-term benefits including a 37% reduction in the risk of microvascular complications, a 43% lower risk of amputation or peripheral vascular disease, a 21% lower risk of diabetes-related death and a 14% reduction in the risk of heart attack (Figure 3).9
In people with chronic pancreatitis, steatorrhoea (faecal fat >25g/day) and glucose intolerance, adding pancreatin to a test meal reversed the impairment of gastric inhibitory peptide secretion, improved the incretin effect of dietary fat and increased the insulin response, and reduced postprandial glucose.10
PERT also reduces the frequency of hypoglycaemic episodes. In one trial, 80 people with insulin-treated diabetes and exocrine pancreatic insufficiency (confirmed by measurement of faecal elastase-1 concentration) were randomised to receive placebo or the formulation of pancreatin (a mixture of digestive enzymes produced by the exocrine cells of the pancreas) (40 000 units three times a day with main meals plus two to three snacks with 20 000 units) (Figure 4).11 At the beginning of the study, the people in the group randomised to treatment with PERT reported more episodes of mild to moderate hypoglycaemia than people assigned to placebo; after 16 weeks, the frequency of hypoglycaemia was similar in the two groups.
Professor Cummings described the impact of PERT in one person with poor glycaemic control (HbA1c 98mmol/mol [11.1%]) characterised by large variation in blood glucose levels during the day. This person also experienced bowel symptoms, raising the suspicion of PEI. This was confirmed by measurement of faecal elastase-1. Figure 5 shows that the ambulatory glucose profile was improved by PERT, with a reduction in blood glucose and HbA1c together with less variation in blood glucose during a 15-day period.
The endocrine–exocrine–incretin gut axis
The incretin response and the exocrine and endocrine functions of the pancreas are interdependent and glucose homeostasis is compromised if the function of any of the three components is impaired.12 Insulin deficiency due to diabetes promotes pancreatic fibrosis, acinar atrophy and adipogenesis. A lack of exocrine pancreatic enzymes secreted to the gut results in incomplete breakdown of fat, protein and carbohydrate and may lead to dysfunctional incretin synthesis and secretion. This has profound implications for glycaemic control because the incretin hormone GLP-1 has multiple effects on the pathways that regulate glucose metabolism: it stimulates insulin secretion, suppresses glucagon secretion, slows gastric emptying, increases beta cell mass, maintains B-cell function, improves insulin sensitivity and enhances glucose disposal. Pancreas morphology and exocrine function are frequently and severely altered in people with different types of diabetes, the weight of the pancreata is reduced in people with diabetes4 and the incretin effect is impaired in people with type 2 diabetes.12 Changes in glucagon and somatostatin secretion may also contribute to exocrine damage.4 Diabetic neuropathy may cause functional and morphological alterations in the pancreas.4
Vitamin D deficiency
PEI impairs the absorption of fat-soluble vitamins, notably vitamin D. In the long term, this may be expected to promote the loss of bone mineral density and increase the risk of osteoporosis. About 40% of people with type 2 diabetes have suboptimal vitamin D levels (defined as 25-hydroxyvitamin D levels of 25–75nmol/L) and almost 60% have vitamin D deficiency (<25nmol/L).13 Compared with controls, elderly men with type 2 diabetes (mean age 68–69) are four to five times more likely to have low bone mineral density (59% versus 24%; odds ratio 4.6, confidence interval 95% 2.51–8.21; p<0.001).14 In this study, men with diabetes were more likely to have osteoporosis (33% versus 1.6%, statistical significance not reported) and fractures (30% versus 14%, p<0.004).
PERT may increase vitamin D absorption. The placebo-controlled CANADA study in 80 men with diabetes and PEI (faecal elastase-1 <100mcg/g) showed that PERT raised vitamin D levels after 16 weeks’ treatment.11
In summary, the available evidence refutes the traditional interpretation that the exocrine and endocrine functions of the pancreas are distinct. Instead, they are interdependent and form an axis with incretin gut hormone secretion that comprises a complex regulatory mechanism for glycaemic control. People with diabetes are at increased risk of PEI and its metabolic complications. There is growing evidence that PERT improves glycaemic control and gastrointestinal symptoms and has the potential to lower long-term risks associated with malnourishment.
Is there a case for routinely screening patients with diabetes for PEI?
This question was asked in the Q&A session that took place after the presentations. Professor Cummings said that about 25% of people with diabetes have gastrointestinal symptoms and measurement of faecal elastase-1 shows that 40% of these have some degree of PEI, of whom one-third are severely affected. Given the cost of measurement of faecal elastase, he considered screening for bowel symptoms and PEI would be worthwhile. Dr Patel added that it is important to raise awareness about PEI among people with diabetes because they do not always volunteer information about gastrointestinal symptoms.
Ms Hicks commented that people with diabetes prescribed PERT often take too low a dose and do not take the capsules with meals and snacks as they have been advised to do. With the support of Mylan, she has prepared an information leaflet for people with diabetes and PEI that explains what PEI is and how to get the most from their treatment (Diabetes and Pancreatic Exocrine Insufficiency. TREND-UK. January 2018).
What referral pathways are available for patients with suspected PEI?
A specialist nurse described the difficulties she had experienced persuading some people with diabetes to accept referral to a gastroenterologist; what alternative is there? The speakers agreed that PEI is traditionally the province of the gastroenterologist, but emphasised that endocrinologists have a role in investigating the cause of bowel symptoms in people with diabetes. Most people with diabetes have mild, persistent and nagging symptoms and it is important to identify red flag signs such as weight loss that suggest the possibility of a sinister cause. Faecal elastase-1 screening should be considered in a person with diabetes when no other cause of their symptoms is likely and their glycaemic control is poor. PERT is feasible in primary care without the need for referral; the response to treatment is usually rapid, so a lack of early improvement should prompt a review of the diagnosis. Ms Hicks
re-emphasised the importance of ensuring people with diabetes take an adequate dose, noting that GPs may be reluctant to prescribe a sufficiently high dose of PERT without advice from a gastroenterologist.
- Munshi MN, Segal AR, Suhl E, et al. Frequent hypoglycemia among elderly patients with poor glycemic control. Arch Intern Med 2011;171:362–4.
- National Institute for Health and Care Excellence. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. NICE Clinical Guideline CG76. January 2009 (www.nice.org.uk/guidance/; accessed 21 May 2018).
- Frid AH, Hirsch LJ, Menchior AR, et al. Worldwide injection technique questionnaire study: injecting complications and the role of the professional. Mayo Clin Proc 2016;91:1224–30.
- Hardt PD, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a
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- Ewald N, Kaufmann C, Raspe A, et al. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 2012;28:338–42.
- Vacca JB, Henke WJ, Knight WA. The exocrine pancreas in diabetes mellitus. Ann Intern Med 1964;61:242–7.
- Mohan V, Poongothai S, Pitchumoni CS. Oral pancreatic enzyme therapy in the control of diabetes mellitus in tropical calculous pancreatitis. Int J Pancreatol 1998;24:19–22.
- Paschou SA, Leslie RD. Personalizing guidelines for diabetes management: twilight or dawn of the expert? BMC Med 2013;11:161.
- Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–12.
- Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia 1980;19:198–204.
- Ewald N, Bretzel RG, Fantus IG, et al. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev 2007;23:386–91.
- Hayden MR, Patel K, Habibi J, et al. Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes: pancreatic extracellular matrix ultrastructural abnormalities. J Cardiometab Syndr 2008;3:234–43.
- Al-Zaharani M. The prevalence of vitamin D deficiency in type 2 diabetic patients. J Health Sci 2013;1:18–22.
- Chen HL, Deng LL, Li JF. Prevalence of osteoporosis and its associated factors among older men with type 2 diabetes. Int J Endocrinol 2013;2013:285729.