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. Author manuscript; available in PMC: 2022 Sep 1.
Published in final edited form as: Curr Opin Gastroenterol. 2021 Sep 1;37(5):520–525. doi: 10.1097/MOG.0000000000000754

Distinguishing Diabetes Secondary to Pancreatic Diseases from Type 2 Diabetes Mellitus

Phil A Hart 1, Dana K Andersen 2, Maxim S Petrov 3, Mark O Goodarzi 4
PMCID: PMC8364493  NIHMSID: NIHMS1704973  PMID: 34265796

Abstract

Purpose of review:

Diabetes secondary to pancreatic diseases (i.e., acute pancreatitis, chronic pancreatitis, and pancreatic cancer) is increasingly studied, but remains challenging to distinguish from type 2 diabetes (T2DM). We review the clinical significance and potential biomarkers that may help differentiate these types of diabetes.

Recent findings:

Recent studies have identified several complications (including non-vascular) that occur more frequently in patients with diabetes secondary to acute and chronic pancreatitis than T2DM, and biomarkers to differentiate the two types of diabetes. There have been advances that may enable the enrichment of a population of adults with new onset diabetes to potentially screen for occult pancreatic cancer, but efforts are needed to identify and validate promising diagnostic biomarkers.

Summary:

High-quality studies are needed to more precisely understand the risk factors and natural course of diabetes secondary to pancreatic diseases. Mechanistic and interventional studies are awaited to provide insights that will distinguish diabetes secondary to pancreatic diseases and refine the management of hyperglycemia in this patient population.

Keywords: pancreatogenic diabetes, type 3c diabetes mellitus, diabetes of the exocrine pancreas, acute pancreatitis, chronic pancreatitis, pancreatic cancer

INTRODUCTION

The majority of patients with diabetes are considered to have type 2 diabetes (T2DM); however, there is increasing recognition of a diverse group of etiologies for diabetes with adult onset[1]. Among these additional diabetes subtypes is an important group, variably referred to as pancreatogenic diabetes, type 3c diabetes, and/or diabetes of the exocrine pancreas, that develops secondary to an exocrine pancreatic disease. Diabetes secondary to acute pancreatitis, chronic pancreatitis, or pancreatic ductal adenocarcinoma (PDAC) is collectively referred to herein as diabetes secondary to pancreatic disease.

It has previously been estimated that approximately 2–9% of all patients with diabetes have an underlying pancreatic disease, and that up to 90% are originally diagnosed with T2DM[2, 3]. Although chronic pancreatitis was initially reported in single center studies to represent the most common etiology, population-based studies found that acute pancreatitis is the most common etiology[2, 4]. During follow-up, approximately 23% and 30% of patients with acute pancreatitis and chronic pancreatitis will develop diabetes within 3–5 years, respectively[5–7]. In patients with pancreatic cancer, up to two-thirds will have diabetes at the time of cancer diagnosis, including approximately 25% with new onset diabetes (NOD) that is believed to be caused by the tumor via a paraneoplastic mechanism[8]. The aim of the present article is to delineate the clinical significance of accurate and timely identification of diabetes secondary to pancreatic diseases, as well as to review emerging data on its differentiation from T2DM.

WHAT IS THE CLINICAL SIGNIFICANCE OF DIFFERENTIATING DIABETES SECONDARY TO PANCREATIC DISEASES FROM T2DM?

Differentiation will provide a potential window of opportunity for early detection of PDAC

The early detection of PDAC is a priority to improve survival as evidenced by the relatively favorable five-year survival rate (75%) for patients with localized disease who undergo surgery for tumors <10 mm in size (or 30–60% for tumors <20 mm in size) [9, 10]. The onset of diabetes in adults may provide a potential window of opportunity for early detection. The association of diabetes and PDAC has been known for decades and, until recently, this association was assumed to be due to the increased risk of PDAC secondary to T2DM, which is associated with a two-fold increased risk above that of a matched non-diabetic population. In the early 1990s, anecdotal reports of cases of diabetes that resolved after resection of the cancer suggested that in some patients the PDAC caused the diabetes. At the same time, studies of PDAC-associated diabetes revealed that about half of the diabetes occurred within 24–36 months of the PDAC diagnosis and was therefore referred to as new-onset diabetes (NOD). Further studies showed that the rise in blood glucose associated with NOD occurred before the cancer was radiologically detectable, which indicated that the diabetes was not due to destruction of the pancreas by the tumor. In 2008, Pannala and colleagues reported that in over half of NOD patients with PDAC, the diabetes paradoxically resolved after resection of the tumor, despite removal of half of the pancreas[11]. Since <1% of adults with NOD are found to have PDAC, the discrimination of diabetes caused by PDAC from T2DM is challenging, but several studies have been reported or are ongoing to accomplish this, as further discussed below[12–16].

Differentiation will identify patients at potentially increased risk for diabetic complications

The ‘legacy effect’ of early derangements in glucose metabolism on diabetes complications and death is well described[17]. Therefore, the observation that diabetes secondary to pancreatic disease is associated with worse glycemic control than T2DM suggests that accurate differentiation between the two types of diabetes carries extra importance. For example, a population-based study of 31,789 adults with incident diabetes (of whom 559 had diabetes secondary to pancreatic diseases) showed that mean HbA1c levels were significantly higher in people with diabetes secondary to pancreatic diseases than in subjects with T2DM at diagnosis (8.3% vs. 7.9%, p=0.002), 1-year follow-up (7.1% vs. 6.8%, p<0.001), and 5-year follow-up (7.6% vs. 7.2%, p<0.001)[2]. As a result, the risks of poor glycemic control (defined as HbA1c >7%) associated with diabetes secondary to pancreatic diseases were 30% and 70% higher at 1-year and 5-year follow-ups, respectively. The above analyses were adjusted for age, sex, ethnicity, body mass index, alcohol consumption, smoking status, and index of multiple deprivation (a measure of socioeconomic status).

Additionally, several retrospective studies in the 1970s suggested that diabetes secondary to pancreatic diseases is characterized by a more unstable (i.e., ‘brittle’) pattern of glycemic control[18, 19]. A modern study using continuous glucose monitoring found that 90% of people with diabetes secondary to pancreatic disease experienced an episode of hypoglycemia (of whom 29% had symptoms)[20]. The study also reported that the period between 3 a.m. and 6 a.m. was the most common time for hypoglycemia in this setting. In a separate publication, these investigators also used continuous glucose monitoring to compare glycemic variability in diabetes secondary to chronic pancreatitis versus T2DM and found that most indices of glycemic variability were significantly higher in the former group (and also directly correlated with HbA1c levels). Rigorous long-term studies of diabetic complications in patients with pancreatic diseases are lacking, but a small case-control study suggests patients with diabetes secondary to chronic pancreatitis have an increased risk for long-term microvascular complications compared to controls with T2DM matched for diabetes duration, supporting the need for a larger study[21].

Differentiation can guide treatment decisions regarding diabetes

Differentiating diabetes secondary to pancreatic diseases from T2DM can be helpful to guide clinical decision making; however, in the absence of evidence-based guidelines, treatment for these patients is highly variable[22]. While there have been no randomized clinical trials evaluating antidiabetic agents specifically in diabetes secondary to pancreatic diseases, metformin has been favored as initial treatment, particularly in patients with chronic pancreatitis, given its favorable safety profile and potential anti-neoplastic effects[23]. Although preclinical studies support the benefit of metformin for preventing the development of PDAC as well as its use as adjuvant therapy in those who have PDAC, these beneficial effects have not been consistently demonstrated in humans[24, 25]. At the same time, a nationwide prescription database study found that metformin use in patients with diabetes after onset of acute or chronic pancreatitis was associated with reduced overall mortality[26].

In a mixed series of subjects with diabetes due to various pancreatic disorders, the majority (30 of 38) required insulin within 12 months of diagnosis[22]. Similarly, in the study by Woodmansey et al., there was more rapid progression to insulin use in a population-based study of adults with newly diagnosed diabetes following pancreatic disease compared to adults with newly diagnosed T2DM[2]. At one and five years, 1.4% and 4% of those with T2DM required insulin whereas 16% and 30% of those with diabetes secondary to pancreatic diseases required insulin. The need for insulin was markedly higher in those with diabetes after chronic pancreatic disease (46% at five years) versus diabetes after acute pancreatitis (21% at five years). The early transition to insulin therapy should be carefully considered in those with diabetes after acute pancreatitis, given the recent suggestion that liberal use of insulin may accelerate progression of acute pancreatitis to recurrent acute pancreatitis or chronic pancreatitis[27]. Caution is also reasonable for patients with underlying acute pancreatitis since dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with increased risk for acute pancreatitis, with mixed evidence[28–30].

Lastly, there may be a benefit in glycemic control related to the use of pancreatic enzyme replacement therapy (PERT) in patients with diabetes following pancreatic diseases. Prior studies in patients with diabetes secondary to chronic pancreatitis have demonstrated impairments in the incretin-insulin axis are partially reversed with pancreatic enzymes, leading to the recommendation to consider PERT in this patient population[23]. Whether or not this benefit is also observed in diabetes secondary to acute pancreatitis or PDAC and in patients without exocrine pancreatic insufficiency are areas of ongoing investigation.

Identification of undiagnosed acute or chronic pancreatitis would merit heightened surveillance for other complications

Another benefit of accurate differentiation between these two types of diabetes is that identification of a history of pancreatitis in patients with diabetes would also merit heightened surveillance for non-vascular complications, which are otherwise uncommon in T2DM. Recent population-based studies have shown that diabetes secondary to acute or chronic pancreatitis is associated with increased risks of infections, chronic pulmonary disease, renal disease, gout, and mental disorders[31–33]. Additionally, there is excess cause-specific risk for cancer (particularly due to pancreatic and colon cancer) in diabetes secondary to acute or chronic pancreatitis versus T2DM[34]. Such a vast array and high frequency of non-vascular complications may explain, in part, the poor outcomes in patients with diabetes secondary to acute or chronic pancreatitis, who have a 13% higher risk of all-cause mortality compared with T2DM[31]. Therefore, earlier identification of diabetes secondary to acute or chronic pancreatitis may provide opportunities to improve the screening for these complications.

BIOMARKERS OF DIABETES SECONDARY TO PANCREATIC DISEASES

Differentiating Diabetes Secondary to Acute Pancreatitis from T2DM

The most promising biomarker of diabetes secondary to acute pancreatitis at this time is oxyntomodulin; a gut hormone related to GLP-1, which, unlike the incretin hormone, is involved in the regulation of exocrine pancreatic secretion[35]. Oxyntomodulin in individuals with a history of diseases of the exocrine pancreas was first investigated by the COSMOS (Clinical and epidemiOlogical inveStigations in Metabolism, nutritiOn, and pancreatic diseaseS) group. A series of studies demonstrated that fasting and postprandial circulating levels of oxyntomodulin were significantly reduced in subjects with prediabetes/diabetes secondary to acute pancreatitis compared to: 1. healthy controls, 2. acute pancreatitis controls without diabetes, and 3. acute pancreatitis controls with preexisting prediabetes/T2DM prior to acute pancreatitis onset[36–38]. Other biomarkers of diabetes secondary to acute pancreatitis have been previously reviewed [39].

Differentiating Diabetes Secondary to Chronic Pancreatitis from T2DM

The study of diagnostic biomarkers of diabetes secondary to chronic pancreatitis is challenging due to the absence of a gold standard to understand whether the diabetes in a patient with chronic pancreatitis is directly related to the exocrine pancreatic disease, T2DM, or a combination of factors. For example, two large multi-center cohort studies with >1,000 chronic pancreatitis participants identified obesity and family history of diabetes as risk factors for diabetes; however, whether or not this reflects the presence of T2DM in chronic pancreatitis patients remains uncertain[40, 41]. The onset of diabetes preceding chronic pancreatitis-related symptoms or a clinical diagnosis is favored to represent T2DM. In a case-control study, younger age and lower BMI were observed in subjects with diabetes secondary to chronic pancreatitis compared to T2DM[21]. Commonalities with T2DM have also been observed in genetic risk scores (based on single nucleotide polymorphisms associated with T2DM), which were not explained by sensitivity analyses to assess for confounding from different features of chronic pancreatitis[42]. Previous studies regarding the ability of fasting levels of pancreatic polypeptide (PP) to differentiate these diabetes subtypes have not been validated in recent studies[43]. In contrast, a blunted PP response to mixed meal stimulation has been proposed as a physiological means of differentiating these diabetes subtypes, but validation studies are needed[23].

Differentiating Diabetes Secondary to PDAC from T2DM

A key challenge in early detection of pancreatic cancer amongst adults with NOD is the relatively high incidence of T2DM and the low incidence of PDAC. The combination of these factors is that even a highly specific test will generate a large number of false positives. To overcome this problem, the use of a series of filters (or sieves) using increasingly invasive (and costly) testing has been advocated[8]. There are differences in the demographic and anthropometric characteristics of patients with diabetes secondary to pancreatic cancer compared to T2DM, such as older age and lower body mass index in the former type of diabetes[44]. Statistical models have recently been developed and validated using clinically available variables (e.g., age at diabetes onset, weight change, change in fasting glucose, etc.) to enrich a potential screening population[45–48]. A diagnostic biomarker(s) is needed to further augment these clinical models, but validation requires careful study design. For example, an immune signature (GM-CSF, IL-31, RANTES, resistin, FasL, and ICAM1) was shown to separate subjects with PDAC and diabetes from controls with diabetes with high accuracy (area under the receiver operating characteristics curve (AUC) 0.96), but the groups included those with both new onset and long-standing diabetes and the sample size was statistically small[49]. PP has been proposed as a diagnostic marker of various types of diabetes secondary to pancreatic diseases. Although fasting PP levels are similar, the response following mixed meal stimulation was blunted in a small study of patients with NOD secondary to PDAC compared to T2DM[43, 50]. More recently, a proteomic analysis of patients with diabetes in the setting of early stage PDAC and T2DM identified a panel of 11 proteins, which, when combined with serum CA19–9, resulted in an AUC of 0.85[51]. Lastly, two serum proteins (galectin-3 and S100AP) were identified as potential mediators of insulin resistance in diabetes secondary to PDAC, although their diagnostic performance was similar to weight loss in differentiating the groups[52]. Prospective validation in independent data sets is required to identify whether these models and candidate biomarkers should be promoted to routine clinical use.

FUTURE DIRECTIONS

Multiple efforts are ongoing internationally to address the numerous knowledge gaps in this field, including the work of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) featured in this issue of the Journal[53, 54]. This consortium is conducting three studies that were designed to provide key insights on this topic. The DETECT study is a cross-sectional study of subjects with diabetes secondary to chronic pancreatitis, PDAC, and T2DM[15]. Participants are being studied with mixed meal tolerance testing to characterize differences between measures of PP, insulin-related traits, glucagon, and incretin hormone responses between these diabetes subtypes. Control subjects without diabetes will permit comparisons to understand whether observed changes are related to the underlying pancreatic disease or the diabetic state. Second, the NOD study is a longitudinal study of adults with NOD who will be followed for at least 3 years with a primary goal of providing a precise estimate of risk for PDAC[16]. Lastly, the PROCEED study is a prospective cohort study of patients across the pancreatitis spectrum, which will provide clarification regarding the incidence rate and risk factors for development of diabetes in patients with chronic pancreatitis[55]. Each study has a biorepository that will allow retrospective derivation and verification of a wide variety of diagnostic biomarkers for diabetes in these different scenarios. These studies represent a sample of the research that is ongoing worldwide and provide hope that progress is on the near horizon.

CONCLUSIONS

There is growing awareness of the clinical significance of differentiating diabetes secondary to acute pancreatitis, chronic pancreatitis, and PDAC from the more common T2DM. Progress has been made to refine our understanding of the risk factors and natural course, but additional high quality studies are needed to better understand the pathophysiology and to identify clinically useful biomarkers to differentiate diabetes secondary to pancreatic diseases from T2DM. These investigations will help to refine the approach to diagnosis and classification and provide insights that are needed to identify opportunities for prevention, early recognition, and potentially improved treatment options.

KEY POINTS.

  1. Differentiating diabetes secondary to pancreatic diseases from T2DM is clinically significant for multiple reasons, including the following:

  2. Differentiation will provide a potential window of opportunity for early detection of PDAC.

  3. Differentiation will identify patients at potentially increased risk for diabetic complications.

  4. Differentiation can guide treatment decisions regarding diabetes.

  5. Identification of undiagnosed acute or chronic pancreatitis would merit heightened surveillance for other complications.

Grant Support:

Research reported in this publication was supported by the National Cancer Institute (NCI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award number U01DK108327 (PH), U01DK127388 (PH), U01DK108314 (MG), U01DK127403 (MG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abbreviations:

CPDPC

Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer

NOD

new onset diabetes

PDAC

pancreatic ductal adenocarcinoma

PERT

pancreatic enzyme replacement therapy

PP

pancreatic polypeptide

Footnotes

Conflicts of interest/disclosures: No conflicts of interest exist.

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