NIH programs aim to shed light on, optimize care for pancreatic diabetes
Click Here to Manage Email Alerts
Pancreatic diabetes may be as prevalent as type 1 diabetes, but knowledge of the disease is lacking. Several research programs are working to change that.
The confusion with pancreatic diabetes begins with the name. With no official term established, some researchers and organizations refer to it as diabetes of the exocrine pancreas, pancreatogenic diabetes or type 3c diabetes. In its Standards of Care, the American Diabetes Association refers to the condition as pancreatic diabetes or diabetes in the context of disease of the exocrine pancreas.
“People have started adopting terms like post-pancreatitis diabetes or diabetes related to chronic pancreatitis or acute pancreatitis,” Melena Bellin, MD, professor in the departments of pediatric endocrinology and surgery and co-director of the total pancreatectomy and islet autotransplant program at the University of Minnesota Medical School, told Healio | Endocrine Today. “One of the needs in the field is to establish what that nomenclature is, just because that makes it much easier for patients and providers to communicate, for everyone to understand what we’re talking about and to promote things in research and clinical care.”
One of the challenges with naming pancreatic diabetes is the heterogeneity of the disease. Unlike type 1 and type 2 diabetes, pancreatic diabetes involves dysfunction of both the endocrine and exocrine parts of the pancreas. However, Frederico G.S. Toledo, MD, an endocrinologist, professor of medicine and director of clinical research operations in the division of endocrinology and metabolism at University of Pittsburgh Medical Center and an investigator on the Type 1 Diabetes in Acute Pancreatitis Consortium and the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer, said pancreatic diabetes is a broad term for a disease with many different subtypes.
Another challenge is that the prevalence of pancreatic diabetes is unknown in the U.S. European studies show the condition is much less prevalent than type 2 diabetes but may occur as often as type 1 diabetes. However, many health care providers in the U.S. do not recognize or know about the condition, according to Richard E. Pratley, MD, a Healio | Endocrine Today Co-editor and the Samuel E. Crockett chair in diabetes research and medical director of AdventHealth Diabetes Institute.
“It’s not often diagnosed,” Pratley told Healio | Endocrine Today. “When we look in the medical records, it’s typically misdiagnosed as type 2 diabetes. There are ICD classifications for diabetes secondary for pancreatic disorders, but those are typically used for cystic fibrosis or when people have had a pancreatectomy. I don’t think people are making that link, at least in the diabetes or primary care space.”
The lack of a more specific code for pancreatic diabetes not only contributes to a lack of recognition of the disease, but also creates potential barriers for people who are diagnosed with the condition.
“These patients typically require insulin, so they are candidates for insulin pumps and for continuous glucose monitors,” Dana K. Andersen, MD, program director for the clinical studies program in the division of digestive diseases and nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases, told Healio | Endocrine Today. “It can be a challenge to access those technologies, due to costs, insurance issues and other barriers.”
Pancreatic diabetes has captured the attention of the NIH and researchers across the country. Multiple NIH-funded consortiums are currently investigating the condition in hopes of gathering more data to eventually craft detailed recommendations for providers.
Pancreatic diabetes pathophysiology
Andersen said the mechanisms behind pancreatic diabetes are more complex than with type 1 or type 2 diabetes.
“In both type 1 and type 2 diabetes, the disease process is focused on the islets, it involves dysfunction of the release of insulin. Either there’s not enough [insulin] or none that’s produced in type 1 diabetes, or there’s an overabundance of insulin due to insulin resistance in type 2 diabetes,” Andersen said. “In pancreatic diabetes, the important feature is it involves disease of both the exocrine part of the pancreas and the endocrine part of the pancreas, and the dysfunction of both of those compartments need to be treated.”
People with chronic or acute pancreatitis have an increased risk for developing diabetes. A study published in United European Gastroenterology Journal in 2022 found that 5.1% of a group of 481 adults with chronic pancreatitis developed post-pancreatitis diabetes at 5 years of follow-up. The incidence increased to 38.9% at 20 years. Another study published in the American Journal of Gastroenterology in 2015 reported that adults with acute pancreatitis were 2.54 times more likely to develop diabetes more than 3 months later compared with controls.
“The information that diabetes following pancreatitis is different is based largely on observational studies that suggest that these individuals progress to require insulin more commonly,” Pratley said. “Everyone’s thought turns to it being because of damage to the islets, but in fact, it [also] happens with relatively mild cases of pancreatitis where you should have adequate beta-cell mass to maintain normal glucose tolerance. There may be other mechanisms at play.”
While there are some common factors that all types of pancreatic diabetes share, Toledo said, the disease can differ based on an individual’s history. In addition to acute and chronic pancreatitis, pancreatic diabetes can also develop in a person with cystic fibrosis or pancreatic cancer. Since each patient has a different cause, Toledo said, treatment plans should differ from person to person, taking into account the underlying disease.
“These patients may have special needs because of what’s happening in the exocrine pancreas,” Toledo said. “If a patient has diabetes secondary to chronic pancreatitis, the physician needs to be mindful that this person may also have exocrine insufficiency. That’s one example how it affects treatment.”
Difficulties with diagnosis
Data are lacking on pancreatic diabetes prevalence in the U.S., but there have been studies conducted in Europe. One study published in Diabetes Metabolism Research and Reviews in 2012 analyzed data from 1,868 adults with diabetes who were admitted to a hospital in Germany over a 2-year period. Among the study group, researchers classified 9.2% as having pancreatic diabetes, with most of those people having chronic pancreatitis.
“Some of these European studies show the incidence [of pancreatic diabetes] approaches type 1 diabetes,” Toledo said. “In the U.S., it’s a black box, we don’t know. It could very well be different because we have a different population, different health care, etc.”
One reason the prevalence of pancreatic diabetes is unknown is because it is often misdiagnosed. According to the 2012 study, only 51.2% of people with pancreatic diabetes were initially diagnosed correctly, and many of those who were misdiagnosed were originally thought to have type 2 diabetes.
Bellin said misdiagnosis is common since most providers will automatically think of a person with high glucose as having either type 1 or type 2 diabetes.
“A lack of awareness that there is this distinct form of diabetes is part of the issue,” Bellin said. “There are different degrees of clinical severity of pancreatitis. For someone who has clinically severe chronic pancreatitis and is being seen frequently for chronic pancreatitis, it may be more intuitive to recognize [pancreatic diabetes]. Some people have chronic pancreatitis and their pain symptoms have gone away, so they’re minimally symptomatic and providers may not put these two things together.”
The lack of a specific ICD code for pancreatic diabetes is another reason the prevalence of the disease is unknown, according to Toledo.
“If someone develops acute or chronic pancreatitis that damages the pancreas and now has diabetes, some physicians will use a code of type 1 diabetes, some will use a code of type 2 diabetes,” Toledo said. “Technically, the person doesn’t have any of these. The person has diabetes secondary to disease of the exocrine pancreas. But unless the physician is aware of these things, the correct code may not be used.”
Misdiagnosis of pancreatic diabetes could lead to several adverse outcomes, Andersen said. Adults with pancreatic diabetes have an increased risk for metabolic bone disease as exocrine pancreas dysfunction could lead to vitamin D deficiency. Those with pancreatic diabetes may also need pancreatic enzyme therapy to help replace the enzymes the pancreas is unable to produce. Additionally, people with pancreatic diabetes due to chronic pancreatitis have a high risk for developing pancreatic cancer and should be screened at least annually for cancer development.
“If the provider assumes incorrectly that the patient has type 2 diabetes, they usually don’t think of pancreatic cancer as being a risk for that particular patient,” Andersen said.
Bellin said people who have a history of pancreatitis should be screened for diabetes annually with a fasting blood glucose test and HbA1c measurement. However, determining whether the type of diabetes is pancreatic or type 2 can be difficult, as there is currently no biomarker that has been verified in a large study to assist providers in identifying pancreatic diabetes.
Andersen said one way for providers to determine pancreatic diabetes is by identifying pancreatic enzyme deficiency through a stool sample. Another difference between type 2 diabetes and pancreatic diabetes is with insulin levels. Andersen said type 2 diabetes is usually associated with high levels of insulin, whereas people tend to have low insulin with pancreatic diabetes.
Treating pancreatic diabetes
The first step for treating pancreatic diabetes is lifestyle modification, according to Andersen. People diagnosed with the condition should stop smoking or drinking and may need to lose weight. These modifications should be started prior to drug therapy.
Medication for treating pancreatic diabetes is similar to treating type 2 diabetes in some ways, but not others. Bellin said people with pancreatic diabetes tend to have a defect in insulin secretion, making insulin a primary therapy.
“Patients who have diabetes related to acute or chronic pancreatitis are more likely to need insulin therapy and more likely to need it earlier in the course of their disease than type 2 diabetes,” Bellin said. “That just reflects the pathology of insulin deficiency.”
Andersen said people with pancreatic diabetes may have an increased sensitivity to insulin while also experiencing insulin resistance at the liver, making it difficult for providers to keep a person’s glucose in normal range. Additionally, pancreatic diabetes can cause low glucagon secretion. These combined factors could lead to hypoglycemia with some medications.
“You have to be very cautious and avoid drugs that stimulate insulin release, such as the sulfonylureas and incretin-based drugs like GLP-1 receptor agonists,” Andersen said. “Those drugs are problematic because they are associated with an increased risk for pancreatitis, and they cause increased levels of insulin.”
One medication that can be prescribed for people with pancreatic diabetes is metformin. Andersen said metformin should be prescribed initially at low doses and then gradually increased over time. If metformin is not well tolerated, patients can receive a pioglitazone, a class of medications that increases insulin sensitivity at the liver.
“[Metformin] may be helpful if someone has obesity and is insulin resistant,” Bellin said. “There’s a theoretical benefit that metformin may have some protection against cancer risk. Knowing that these individuals are at risk for pancreatic cancer, that appeals to some providers.”
Endocrinologists and gastroenterologists must work in tandem when caring for a person with pancreatic diabetes, Andersen said. Gastroenterologists should screen people with diagnosed pancreatic exocrine disease for diabetes regularly. Endocrinologists need to understand the treatment differences with pancreatic diabetes compared with type 2 diabetes and that some medications should not be used by people with the condition.
“There has to be a dialogue, there has to be a combined approach with treating these patients,” Andersen said.
NIH consortiums key to pancreatic diabetes research
Researchers are hoping to fill the many gaps in pancreatic diabetes research through a pair of consortiums established by the National Institute of Diabetes and Digestive and Kidney Disease, and the National Cancer Institute, both part of the NIH. One group, the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC), is conducting research on diabetes stemming from acute pancreatitis. According to an article published in Pancreas in 2022, the consortium includes four scientific working groups that are focused on diabetes, pancreatitis, immunology, and imaging and artificial intelligence.
The consortium is currently enrolling participants in the DREAM study, which will examine how often people with acute pancreatitis develop diabetes. In the study, adults aged 18 to 75 years diagnosed with acute pancreatitis up to 90 days before enrollment will participate in follow-up visits over a 3- to 5-year period.
“We’re aiming to enroll about 1,000 patients with acute pancreatitis in 13 clinical centers around the country and perform glucose tolerance tests, other metabolic tests, like frequently sampled intravenous glucose tolerance tests and mixed-meal tests, and to do pancreatic imaging with both CT and MRI,” said Pratley, who is a researcher involved in T1DAPC. “The whole goal of this is to understand the incidence, so we get a good idea on the risk of progression, and then [examine] whether or not people have more of an insulin secretory or an insulin resistant phenotype, or whether or not there are subtypes in this population.”
The second group is the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC). In an article published in Current Opinion in Gastroenterology in 2021, the authors discussed conducting multiple prospective cohort studies analyzing several pancreatic conditions. One of the working groups within the consortium is conducting studies on the interaction of diabetes and pancreatic disease.
A CPDPC study published in 2022 looked at a biomarker that may assist providers with identifying pancreatic diabetes. Pancreatic polypeptide is a hormone produced within the islets of the pancreas, according to Andersen. Using data from participants in the DIRECT study, researchers found people with diabetes attributed to either pancreatic ductal adenocarcinoma or chronic pancreatitis had lower concentrations of pancreatic polypeptide than adults with type 2 diabetes. The researchers said the findings should pave the way for more research into the utility of pancreatic polypeptide for diagnosing some forms of pancreatic diabetes.
“We want to continue to understand the mechanisms of this disease and how to distinguish this form of diabetes from other forms of diabetes,” said Bellin, who is a researcher in both consortiums and a co-author on the 2022 CPDPC study. “That’s the stage we’re at now. The place where we want to use that information is to be able to identify people who are at risk and to identify early treatment or prevention strategies.”
Recommendations for treating pancreatic diabetes from medical organizations have been limited due to a lack of strong evidence. Before 2023, the ADA Standards of Care included just a two-paragraph description of pancreatic diabetes in the Classification and Diagnosis of Diabetes section of the document. That changed with the 2024 ADA Standards of Care, however, as the ADA greatly expanded its section on pancreatic diabetes.
“We had to shed light on screening people for diabetes within 3 to 6 months of episodes of pancreatitis and how to follow up on that,” Nuha El Sayed, MD, MMSc, senior vice president for health care improvement for the ADA, told Healio | Endocrine Today during a press conference about the updates on the 2024 Standards of Care. “The other [recommendation] is to clarify cystic fibrosis-related diabetes and [discuss] care for people with cystic fibrosis-related diabetes. These were very important clinical [areas] that we needed to focus on.”
The updated standards include a recommendation that people with acute pancreatitis be screened for diabetes at 3 to 6 months and then annually thereafter. Annual diabetes screening is also recommended for people with chronic pancreatitis. The document also advises providers to avoid medications associated with an increased risk for pancreatitis for people with diabetes and pancreatitis, such as incretin-based medications, and to consider early initiation of insulin therapy. The other change was that the ADA moves its definition and recommendations on cystic fibrosis-related diabetes into the pancreatic diabetes section of the standards.
Pratley said although the update to the Standards of Care was a step in the right direction, most are focused on screening and more studies need to be conducted before more detailed recommendations can be made regarding treatment.
“We don’t have specific recommendations for [pancreatic diabetes] because we don’t have any evidence,” Pratley said. “There are no prospective studies that suggest people respond better to one treatment or another. That’s one of the barriers to making recommendations to treatment.”
- References:
- American Diabetes Association Professional Practice Committee. Diabetes Care. 2023;doi:10.2337/dc24-S002.
- Dugic A, et al. United European Gastroneterol J. 2022;doi:10.1002/ueg2.12344.
- Ewald N, et al. Diabetes Metab Res Rev. 2012;doi:10.1002/dmrr.2260.
- Hart PA, et al. Lancet Gastroenterol Hepatol. 2021;doi:10.1016/S2468-1253(21)00019-4.
- Hart PA, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac670.
- Pandol SJ et al. Curr Opin Gastroenterol. 2021;doi:10.1097/MOG.0000000000000765.
- Serrano J, et al. Pancreas. 2022;doi:10.1097/MPA.0000000000002073.
- Shen H, et al. Am J Gastroenterol. 2015;doi:10.1038/ajg.2015.356
- For more information:
- Dana K. Andersen, MD, can be reached at dana.andersen@nih.gov.
- Melena Bellin, MD, can be reached at bell0130@umn.edu.
- Nuha El Sayed, MD, MMSc, can be reached at nuha.elsayed@joslin.harvard.edu; X (Twitter): @nuhaaelsayed.
- Richard E. Pratley, MD, can be reached at richard.pratley.md@adventhealth.com; X (Twitter): @RpratleyMD.
- Frederico G. S. Toledo, MD, can be reached at toledofs@upmc.edu.
Collapse
Read more about
Click Here to Manage Email Alerts