Diabetes Can Affect the Pancreas in Ways That Go Beyond Insulin
The pancreas is a complex digestive and endocrine gland that performs both exocrine and endocrine functions. It is the only organ in the human body that produces all the enzymes (proteases, amylase, and lipase) needed to break down the major components of food—proteins, fats, and carbohydrates. The endocrine part of the pancreas secretes the hormones insulin and glucagon, which regulate glucose metabolism. The exocrine (enzymatic) and endocrine functions of the pancreas are closely related. Therefore, when the pancreas is affected, digestive and metabolic disorders often occur, with some symptoms predominating while others remain unnoticed and untreated and continue to progress. Recent studies show that, at the time diabetes is diagnosed, most patients already have clinically apparent signs of exocrine dysfunction—digestive disorders. However, these are often overlooked, and patients’ complaints of abdominal discomfort or poor digestion are unjustifiably attributed to symptoms of the underlying disease (diabetes) or intolerance to medication. Pancreatic enzyme replacement therapy significantly improves these patients’ well-being and quality of life. We discuss digestive disorders associated with diabetes and the importance and possibilities of their treatment with Dr. Aida Žvirblienė, a gastroenterologist and dietitian at the Gastroenterology Clinic of the Lithuanian University of Health Sciences Medical Academy.
What are the most common causes of exocrine pancreatic insufficiency?
Exocrine pancreatic insufficiency is most commonly caused by the following factors:
a) reduction of pancreatic tissue (chronic pancreatitis, cystic fibrosis, pancreatic resection, pancreatic tumors, diabetes mellitus [DM]);
b) reduction of pancreatic secretion in healthy pancreatic tissue (pancreatic duct obstruction, impaired endogenous pancreatic stimulation, e.g., after pancreatic denervation, lymph node removal, truncal vagotomy during gastric resection, pancreatic tumors, diabetes mellitus [DM]);
c) reduction of pancreatic secretion in healthy pancreatic tissue (pancreatic duct obstruction, impaired endogenous pancreatic stimulation, e.g., after pancreatic denervation, lymph node removal, truncal vagotomy during gastric cancer surgery, celiac disease, Crohn’s disease, inactivation of pancreatic enzymes in the intestine in the presence of H. pylori infection, gastritis);
d) asynchrony between food passage and pancreatic secretion (after gastric, intestinal, or pancreatic resection, short bowel syndrome, diseases causing cholestasis, Sjögren’s syndrome, inflammatory bowel diseases, celiac disease, DM).
Protein digestion disorders in pancreatic pathology are rare because proteins are also digested in the stomach and by peptidases in the brush border of the intestinal epithelium. Pancreatic amylase is a relatively stable enzyme and is highly resistant to proteolysis. In the absence of pancreatic amylase, 80% of carbohydrates can be broken down by salivary amylase and oligosaccharidases of the intestinal epithelial brush border. Pancreatic lipase is the least resistant enzyme; therefore, impaired fat digestion is the main cause of patient complaints and weight loss in exocrine pancreatic insufficiency. In clinical practice, insufficient attention is paid to the assessment and treatment of exocrine pancreatic insufficiency.
How often does pancreatic enzyme deficiency occur in diabetes?
According to the literature, direct tests of pancreatic exocrine function diagnose exocrine pancreatic insufficiency in 73–80% of patients with type 1 or type 2 DM, whereas indirect tests diagnose it in 45–55% of patients with type 1 or type 2 DM. According to prospective study data, 50% of people with type 2 DM already had complications at the time of diagnosis, suggesting that these patients may have had undiagnosed disease for approximately 10 years before diabetes was confirmed. Once diabetes is diagnosed, pancreatic exocrine insufficiency can almost always be suspected.
In which type of diabetes is pancreatic enzyme deficiency more common, and in which does it manifest earlier or more prominently?
Pancreatic exocrine insufficiency is slightly more common in patients with type 1 DM. Regardless of the type of DM, the pathophysiology of pancreatic exocrine insufficiency is practically the same: an impaired pancreatic exocrine response to nutrients, decreased bicarbonate secretion, and alterations in gastrointestinal motility are observed.
How does pancreatic enzyme deficiency clinically manifest in patients with diabetes?
Pancreatic exocrine insufficiency caused by diabetes has no distinctive features and presents with common symptoms: steatorrhea, deficiency of vitamins, especially fat-soluble vitamins (A, D, E, K), deficiency of trace elements (Mg, Ca), signs of impaired digestion and nutrient absorption—varying degrees of malnutrition, peptic ulcers due to decreased bicarbonate secretion, etc. Pancreatic exocrine insufficiency also increases the risk of cardiovascular diseases due to decreased levels of lipoproteins C, A, and apolipoprotein A-I.
Can diabetes mask the symptoms of pancreatic enzyme deficiency and complicate its diagnosis?
Yes, it can. Pancreatic exocrine insufficiency occurring in patients with DM is often confused with diabetic neuropathy, which has a different pathogenesis from pancreatic exocrine insufficiency. It is currently debated whether pancreatic exocrine dysfunction may be a cause or a consequence of diabetic neuropathy. The prevalence of diabetic neuropathy at the time of DM diagnosis ranges from 4% to 7.5%. Symptoms of diabetic visceral neuropathy and pancreatic exocrine dysfunction may be similar and include gastroparesis, diabetic diarrhea or constipation, and fecal incontinence.
How can a doctor recognize pancreatic exocrine insufficiency in a patient with DM?
A well-documented medical history, assessment of exocrine pancreatic function, and imaging methods demonstrating structural changes in the pancreas can help identify or at least raise suspicion of pancreatic exocrine insufficiency.
Could effective DM treatment and good glycemic control prevent the development of pancreatic enzyme deficiency, or at least delay or alleviate it? Is prevention of enzyme deficiency possible in DM?
In the treatment of DM, the primary goal is to regulate pancreatic endocrine function, so antidiabetic treatment does not ensure adequate digestion of nutrients. I believe that prevention of pancreatic exocrine insufficiency would be beneficial, especially since scientists are still debating which pancreatic function is affected first—exocrine or endocrine. This question is relevant because approximately 85% of pancreatic tissue is exocrine.
How is pancreatic exocrine insufficiency treated? When is a properly selected diet sufficient, and when should pancreatic enzyme replacement therapy be considered?
According to the European guidelines for enteral and parenteral nutrition therapy, it is no longer recommended to significantly reduce fat intake when treating pancreatic exocrine insufficiency: fats should account for 20–30% of the patient’s total daily intake. Pancreatic enzyme replacement therapy is prescribed alongside dietary management. The diet is selected according to the specific clinical situation: mashed food, reduced calorie intake in cases of obesity, reduced fiber content, and replacement of some fats with medium-chain fats. Fat-soluble vitamin replacement therapy is also recommended.
Is it rational to prescribe pancreatic enzymes to patients with CD who do not yet have symptoms of digestive disorders, i.e., for the prevention of insufficiency?
According to current scientific recommendations, it is rational to prescribe pancreatic enzymes after pancreatic exocrine insufficiency has been diagnosed. Prophylactic use of pancreatic enzymes is not recommended because there are no scientifically based recommendations supporting it.
How should pancreatic enzyme preparations be administered to a patient with CD and digestive disorders? Can additional enzyme supplementation improve metabolic control in CD?
Pancreatic enzyme preparations should be taken with main meals and snacks. The dosage is based on lipase units, for example, 25,000–75,000 lipase units with main meals and 10,000–25,000 lipase units with snacks. Enzyme preparations are most effective and act most physiologically when taken neither before eating nor after finishing the meal, but at the beginning of the meal—after swallowing the first bites, with the first third of the meal.
There are various pancreatic enzyme preparations on the market. How should the most suitable one be selected? What requirements are imposed on modern pancreatin preparations?
Pancreatic enzyme preparations should be non-toxic, well tolerated, and resistant to pH changes in the digestive tract within the range of 3–7. Pancreatin preparations with an enteric coating are better protected from the effects of digestive juices. Pancreatic enzymes without an enteric coating can be prescribed to patients with achlorhydria due to atrophic gastritis or after gastric resection.
Preparations consisting of fine pancreatin particles are the most active because they mix best with chyme in the digestive tract. Pancreatin is currently available in the form of tablets, granules, and capsules filled with microspheres or small tablets. An important requirement is that the preparation contain an adequate amount of enzymes.
One example of a pancreatin preparation that meets modern requirements is Pangrol. The uniqueness of this medicine lies in its specific technological structure and higher amounts of proteases and amylase (Pangrol 25000) compared with other enzyme preparations. One of the most advanced technologies that significantly improves the pharmacokinetic and pharmacodynamic (clinical) properties of any drug is coating the active substance with special coatings. These coatings are now predominantly made of polymers.
Among the most promising materials used in the pharmaceutical industry are methacrylic acid copolymers: they are pharmacologically inactive, physiologically neutral, and excreted from the body unchanged. Eurand Minitabs® methacrylic acid polymer technology is used in the production of Pangrol. One tablet (small tablet) of the medicine, coated with a sufficiently thick polymer layer that protects it from the acidic environment of the stomach, contains 500 USP lipase units. Due to the advantages of the coating and its acid resistance, the capsule can, if necessary, be opened and the required dose of small tablets selected. Even when removed from the capsule, the coating “preserves” enzyme activity as the tablets pass through the stomach until they reach the pancreatic duct region.
The article is reprinted from the journal Lietuvos gydytojo žurnalas.
LT/Pan/2014/01
