Diagnosis and Treatment of Diabetes Mellitus in Pediatric Patients with Pancreatitis Followed in a Multidisciplinary Clinic

Abstract

Introduction:

Pancreatogenic diabetes can occur in children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) due to chronic inflammation and islet cell loss.

Objectives:

We evaluated the incidence, progression, and management of pancreatogenic diabetes in youth followed-up in our multidisciplinary clinic.

Results:

Among 141 patients with ARP or CP, 27 (19%) had diabetes with a predominance of female (70%), Hispanic/Latino (52%), and youth with obesity (55%). Diabetes was diagnosed at an average of 12.9 ± 4.3 years. Point-of-care hemoglobin A1c (HbA1c) was used to track glycemic control. Diabetes was diagnosed prior to presentation (44%), at the first visit (15%), during follow-up (15%), or after total pancreatectomy with islet autotransplantation (26%). Less than half of patients (44%, 12/27) met the American Diabetes Association target HbA1c of <7.0% with an average recent HbA1c of 8.9% ± 3.2%.

Conclusion:

Despite diverse diabetes treatments, most patients did not meet glycemic targets. This study highlights the burden of pancreatogenic diabetes in pediatric pancreatitis and underscores the need for standardized management protocols.

Introduction

Pancreatitis results from multifactorial inflammation to the pancreas and is rare in youth.^1,2 Multiple episodes are classified as acute recurrent (ARP), which can progress to chronic pancreatitis (CP).³ Ongoing inflammation causes irreparable damage to the pancreatic parenchyma and leads to severe pain, diminished quality of life, malnutrition, frequent hospitalizations, and exocrine and endocrine pancreatic insufficiency.^1,4,5 Chronic inflammation and fibrosis causes islet cell loss, insufficient insulin secretion, and the development of pancreatogenic diabetes.^1,2 The prevalence of diabetes among youth with ARP and CP is 4%–9%, which is 16–36 times higher than the prevalence of type 1 or type 2 diabetes in the general pediatric population.^1,2,6–8 Treatment standards for pediatric patients with pancreatitis and diabetes are lacking.^1,9

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Pancreas Committee advises yearly screening for diabetes in children with pancreatitis using a fasting glucose and hemoglobin A1c (HbA1c).¹⁰ The committee recommends further evaluation with a 2-h oral glucose tolerance test for patients with a prediabetes range HbA1c (5.7%–6.4%) or fasting glucose (100–125 mg/dL), which can be time consuming for patients.¹⁰ The primary treatment for diabetes in youth with pancreatitis is exogenous insulin but for those with elevated body mass index (BMI) treatment includes lifestyle modifications and oral antidiabetes agents such as metformin.¹⁰ The American Diabetes Association (ADA) supports the use of point of care (POC) HbA1c for diabetes screening, diagnosis, and monitoring in youth and adults with type 1 or type 2 diabetes.¹¹ However, there are no guidelines on its use as a routine diabetes screening method in youth with pancreatitis.

Due to the extensive potential sequalae of ARP or CP, patients receive care from multiple subspecialists, including gastroenterology, endocrinology, pain anesthesia, and nutrition, requiring multiple follow up visits.² Our center has a pediatric pancreatitis multidisciplinary clinic (PMDC) caring for 141 youth with pancreatitis. As part of our in-clinic protocols, POC HbA1c is routinely obtained during clinic check-in. We sought to characterize glycemic outcomes in pediatric patients with pancreatogenic diabetes followed at our PMDC. We describe both the utility of POC HbA1c testing in a multidisciplinary clinic setting and its potential impact on treatment decisions and glycemic control for youth with pancreatitis and diabetes.

Materials and Methods

Study design and subjects

We retrospectively collected clinical and demographic data in pediatric patients followed in our PMDC from January 2018 to January 2023 who had both pancreatitis and diabetes. Patients were divided into four cohorts, those who: (i) were previously diagnosed with diabetes prior to first PMCD visit, (ii) were diagnosed with diabetes at their first PMDC visit, (iii) were followed over time and developed diabetes, or (iv) underwent total pancreatectomy with islet autotransplantation (TPIAT). We characterized demographics, most recent diabetes management, and progression of HbA1c during treatment. Weight was characterized by pediatric BMI percentiles: lean (BMI < 85^th percentile), overweight (BMI ≥85^th to <95^th percentile), and youth with obesity (≥95^th percentile).¹²

Diagnosis of diabetes and PMDC structure

POC HbA1c testing was collected using DCA Vantage (Siemens Medical Solutions, Malvern PA). Patients are screened with a POC HbA1c during the clinic every 3–12 months based on clinical history. The HbA1c criteria for diabetes diagnosis were utilized according to the ADA standards of care clinical guidelines (HbA1c ≥ 6.5%).¹¹

Statistical analysis

Cohorts were characterized using an exploratory data analysis approach. Summary statistics for demographic, clinical, and diabetes management variables among each cohort were presented as frequency count with percentages for categorical variables and mean ± standard deviation for continuous variables using PRISM (GraphPad Software, Inc., La Jolla, CA).

IRB statement

The Colorado Multiple Institutional Review Board approved this study.

Results

Of 141 patients followed for ARP or CP, we identified 27 (19.1%) patients with pancreatogenic diabetes (Table 1). Patients were 70% (19/27) female, 52% (14/27) identified as Hispanic/Latino, and 55% (12/22) were youth with obesity with a BMI of 27.3 ± 8.3. Patients were diagnosed with pancreatitis at 12.0 ± 3.7 years and diagnosed with diabetes at 12.9 ± 4.3 years. Patients had a history of acute pancreatitis (8%, 2/27), ARP (44%, 12/27) or CP (48%, 13/27). At the most recent PMDC visit, the mean HbA1c was 8.9% ± 3.2% for all patients with diabetes and pancreatitis.

Table 1.

Patient Demographic Characteristics

	All patients (n = 27)	Diabetes diagnosed prior to first PMDC visit (n = 12)	Diabetes diagnosed at first PMDC visit (n = 4)	Followed up and developed diabetes (n = 4)	TPIAT (n = 7)
Sex female n (%)	19 (70%)	6 (50%)	4 (100%)	3 (75%)	6 (86%)
Race n (%)
African American	3 (11%)	2 (17%)	1 (25%)	0	0
Other	8 (29%)	3 (25%)	2 (50%)	3 (75%)	0
White	16 (60%)	7 (58%)	1 (25%)	1 (25%)	7 (100%)
Ethnicity n (%)
Hispanic/Latino	14 (52%)	5 (42%)	3 (75%)	4 (100%)	2 (29%)
Non-Hispanic White	11 (41%)	5 (42%)	1 (25%)	0	5 (71%)
Non-Hispanic African American	2 (7%)	2 (16%)	0	0	0
Age (years) at pancreatitis diagnosis^*	12.0 ± 3.7	13.9 ± 2.8	13.3 ± 2.4	12.0 ± 2.7	8.0 ± 3.5
Age (years) at diabetes diagnosis^*	12.9 ± 4.3	11.8 ± 5.1	14.5 ± 1.0	14.0 ± 2.2	13.6 ± 4.7
BMI at diabetes diagnosis (kg/m²)^*	27.3 ± 8.3	24.9 ± 6.8	35.1 ± 5.3	33.8 ± 5.0	20.9 ± 6.2
HbA1c at first PMDC visit (%)^*	7.8 ± 2.7	9.6 ± 2.9	7.9 ± 1.6	5.6 ± 0.4	5.9 ± 1.5
HbA1c at most recent PMDC visit (%)^*	8.9 ± 3.2	10.7 ± 3.3	8.1 ± 1.7	9.2 ± 3.3	6.0 ± 1.0
Islet autoantibody positivity n positive/n tested (%)	12/23 (52%)	3/9 (33%)	2/4 (50%)	1/4 (25%)	6/6 (0%)
Pancreatitis type n (%)
Acute	2 (7%)	2 (16%)	0	0	0
Acute recurrent	12 (45%)	5 (42%)	4 (100%)	2 (50%)	1 (14%)
Chronic	13 (48%)	5 (42%)	0	2 (50%)	6 (86%)

mean ± SD.

The largest cohort followed (12/27, 44%) were patients with pancreatitis and diabetes that was diagnosed prior to PMDC presentation, of which 5/12 (42%) had a prior reported diagnosis of type 1 diabetes. HbA1c at their first PMDC visit was 9.6% ± 2.9%. Islet autoantibody testing was available for 9/12 of these patients. Two patients with reported known type 1 diabetes and 4 with pancreatitis associated diabetes were negative for islet autoantibodies. One patient with type 1 diabetes was single autoantibody positive and one patient was multiple autoantibody positive. One patient with pancreatitis associated diabetes was found to have islet autoantibodies to insulin (mIAA) after already starting insulin therapy.

Four patients (4/27, 15%) were diagnosed with diabetes at their first PMDC visit, with an average HbA1c of 7.9% ± 1.6%. Islet autoantibody testing was conducted in all patients in this cohort, and two patients were found to have positive mIAA, of which one patient had antibodies collected several years after diabetes diagnosis and >1 year after insulin was added to their oral diabetes regimen during a hospitalization.

Four patients (15%, 4/27) were followed up over 1.4 ± 0.6 years at the PMDC, and developed diabetes. HbA1c at initial PMDC presentation was 5.6% ± 0.4%. Islet autoantibody testing was conducted in all patients in this cohort, and zinc transporter 8 antibody was detected in 1 patient who was diagnosed with type 1 diabetes.

Seven patients underwent TPIAT prior to follow up at or PMDC (26%, 7/27). Patients in this cohort were predominantly non-Hispanic White (71%, 5/7), diagnosed with pancreatitis in childhood (8.0 ± 3.5 years), and had a BMI of 20.9 ± 6.2 at time of diabetes diagnosis. Islet autoantibody testing was available for 6/7 of patients in this cohort, all of whom were autoantibody negative.

Figure (1–4) demonstrates longitudinal HbA1c data. Among all patients, 44%(12/27) met the ADA recommended target HbA1c of <7.0%. Few patients (25%, 3/12) diagnosed with diabetes prior to PMDC presentation, Figure 1, had a target HbA1c <7.0% and the most recent HbA1c at follow-up in this cohort was 10.7% ± 3.3%. Five patients initially had progressive improvement on presentation to PMDC but then followed by marked worsening of glycemic control. In patients diagnosed with diabetes at their first PMDC visit, Figure 2, 25% (1/4) met the target HbA1c, and their most recent HbA1c was 8.1% ± 1.7%. Half (2/4, 50%) of the patients who developed diabetes while being followed at our clinic, Figure 3, met the goal HbA1c and their most recent HbA1c was 9.2% ± 3.3%. In contrast, target HbA1c was achieved by most patients (86%, 6/7) who underwent TPIAT, Figure 4, and their most recent HbA1c was 6.0% ± 1.0%.

FIG. 1.

Progression of HbA1c over time in patients with pancreatitis diagnosed with diabetes prior to initial presentation to PMDC (n = 12). PMDC, pancreatitis multidisciplinary clinic.

FIG. 2.

Progression of HbA1c over time in patients with pancreatitis who were diagnosed with diabetes at their first PMDC visit via point-of-care HbA1c (n = 4).

FIG. 3.

Progression of HbA1c over time in patients with pancreatitis who did not have diabetes at time of initial PMDC diagnosis. These patients were followed at the PMDC and developed diabetes (n = 4).

FIG. 4.

Progression of HbA1c over time in patients with pancreatitis who underwent total pancreatectomy with islet auto-transplantation (TPIAT) (n = 7).

Nutrition counseling was provided to all patients as part of their PMDC visits. Most patients were managed on insulin (96%, 26/27), with 65% (17/26) managed using multiple daily injections (MDI) and 35%(9/26) used automated insulin delivery (AID). The most recent total daily dose for all patients on insulin was 0.75 ± 0.53 units/kg/day.

Continuous glucose monitors were used by 52% (14/27) of all patients and 29% (5/17) of patients were on MDI. Most patients who underwent TPIAT were on AID (60%, 6/10). Among all patients, some were on other diabetes treatments including: one patient on insulin and metformin and another on insulin and pioglitazone. One patient was managed on semaglutide and pioglitazone and another only on metformin.

Discussion

This study highlights the high incidence of diabetes among youth with ARP and CP in a single-center cohort in the Rocky Mountain West, with a focus on how our clinic carries out diabetes management. It emphasizes our clinic’s challenges in achieving glycemic targets despite our screening process and management practices. It underlines the importance of pediatric endocrinology involvement in the care of these patients. POC HbA1c testing provides accessible, real-time data and enables changes in management. Our PMDC uses a variety of diabetes treatment modalities and therapy combinations, including nutritional counseling, insulin therapy, and oral and injectable diabetes medications. Despite close monitoring and use of numerous therapeutic strategies, most patients fail to reach target HbA1c.

Studies have yet to evaluate the clinical implications of routine outpatient HbA1c screening for youth or adults with pancreatitis. Our clinic routinely performs POC HbA1c testing at all PMDC visits, in comparison with NASPGHAN’s Pancreas Committee’s recommendation of annual HbA1c testing.¹⁰ While previous multicenter and single-center observational studies reported diabetes in up to 9% of youth with pancreatitis, we observed a markedly higher incidence of 14% (20/141) excluding and 19% (27/141) including those who underwent TPIAT.^1,2 The routine use of POC HbA1c testing may be contributing to faster diagnosis of diabetes, and thus leading to our higher prevalence of diabetes.

Patients who have undergone TPIAT share pathophysiologic characteristics such as islet cell dysfunction and loss, glucose dysregulation, impaired insulin secretion, and insulin dependence with other forms of pancreatogenic diabetes, thus we chose to include TPIAT patients in our overall study cohort. Although preservation of the remaining islet cells in TPIAT is meant to ameliorate the development of diabetes, it is not guaranteed. Often patients experience variable durations of protection against diabetes leading to insulin dependence secondary to insufficient islet cell function.^13,14

Hispanic/Latino ethnicity and obesity are known risk factors for insulin resistance in people with type 2 diabetes¹⁵ and both emerged as major risk factors for diabetes in our population. Similar associations have been reported in studies of adults with CP.⁶ Our center’s location in the Rocky Mountain West lends itself to a more diverse community. Our study population was predominantly Hispanic (52%), in contrast to 35% Hispanic in the multicenter, international INSPPIRE study, which reported a similar number of pediatric patients with diabetes and CP/ARP (n = 24) as our study (n = 27).⁶ In addition, an increased prevalence of obesity (55%) was noted in our cohort, in comparison with 26% in the INSPPIRE study.⁶ A recent report demonstrated that subcutaneous fat, along with age, severity of AP, CRP, and interleukin-6, can be used in a predictive model for the development of prediabetes or diabetes in youth after their initial episode of AP.¹⁶ Perhaps the greater presence of type 2 diabetes risk factors in our cohort, specifically Hispanic/Latino ethnicity and obesity, may be influencing our center’s higher prevalence of diabetes (19%, 27/141; 14%, 20/141 if excluding TPIAT patients), in comparison with 6% (24/397) in the INSPPIRE study, of which their population also had a lower prevalence of both these risk factors.⁶

Achieving target HbA1c levels remains challenging for youth with pancreatitis and diabetes, mirroring patterns observed in type 1 and type 2 diabetes.^17,18 For example, the T1D Exchange Quality Improvement Collaborative and the SEARCH for Diabetes in Youth study reported only 18% of youth with type 1 diabetes and 35% of youth with type 2 diabetes achieve an HbA1c <7.0%.^17,18 In contrast, our study found that 44% of youth with pancreatitis and diabetes reached this target and most of the patients doing so, had undergone TPIAT and most of whom were managed on AID. Obesity and Hispanic/Latino ethnicity, both contributors to insulin resistance, likely contribute to the challenges our patients face in achieving recommended targets.

Insulin therapy remains the cornerstone of diabetes management in youth with pancreatitis as irreversible islet cell loss leads to insulin insufficiency and thus need for replacement.^1,2 Earlier studies have highlighted the use of nutritional counseling and oral diabetes medications, such as metformin and sulfonylureas, primarily in youth with elevated BMI or other markers of insulin resistance.¹⁰ Importantly, our clinic incorporates nutrition counseling as a standard component of care for all patients, regardless of BMI. Our patient population had many risk factors for insulin resistance and in one patient, we incorporated semaglutide, a glucagon-like-peptide-1 receptor agonist (GLP-1RA), as part of their treatment strategy. Although this study did not investigate adverse effects, GLP-1RA are known to carry a potential risk of exacerbating pancreatitis.¹⁹ Studies have yet to assess safety and efficacy of GLP-1RA in youth with pancreatitis and diabetes but these have been shown to lower HbA1c levels in youth with type 2 diabetes.^19,20 More work is needed to address multi-modality therapeutic strategies to optimize management of diabetes in this population.^1,2

Limitations include small cohort size, single center study, short follow-up, and retrospective design that relied on chart review. While POC HbA1c testing is practical, its accuracy varies across devices compared with serum testing and should be considered when making clinical decisions.^21–23

Future efforts should prioritize the development of standardized diabetes screening protocols for patients with a history of pancreatitis. Research should focus on evaluating patients over longer follow-up periods and explore the clinical implications of poor glycemic control and insulin resistance in youth with ARP or CP, which could inform targeted interventions and therapeutic strategies. Assessing the safety and efficacy of GLP-1RA in youth with pancreatitis and diabetes is important given its success in patients with type 2 diabetes. In addition, investigating the feasibility of incorporating mixed meal tolerance testing could provide valuable insight into beta cell reserve in this population. Establishing standardized treatment protocols to optimize glycemic outcomes in youth with pancreatitis and diabetes remains a critical area for future study.

Conclusions

Diabetes is a prevalent complication among youth with ARP and CP and is associated with risk factors for insulin resistance. Routine POC HbA1c testing in a multidisciplinary clinic setting facilitates timely diagnosis and management support. Despite ongoing monitoring and use of various treatment strategies, achieving glycemic targets remains challenging. This study emphasizes the propensity for diabetes in youth with ARP and CP and highlights the need for close monitoring and individualized diabetes therapeutic strategies. Further research is needed to understand long-term diabetes-related outcomes, develop standardized screening protocols, and targeted interventions for pancreatogenic diabetes management.

Footnotes

Acknowledgments

The authors acknowledge the patients and their families.

Authors’ Contributions

E.V.: Formal analysis (lead), investigation (lead), visualization (lead), writing—original draft (lead), funding acquisition (supporting). J.A.M.: Resources (equal), writing—review and editing (equal). G.P.F.: Resources (equal), writing—review and editing (equal). T.M.T.: Conceptualization (lead), funding acquisition (lead), methodology (lead), project administration (lead), supervision (lead), resources (equal), writing—review and editing (equal), visualization (supporting).

Author Disclosure Statement

G.P.F. conducts research sponsored by Medtronic, Dexcom, Abbott, Tandem, Insulet, Beta Bionics, Lilly, and Sequel and has been a speaker/consultant/ad board member for Medtronic, Dexcom, Abbott, Tandem, Insulet, Beta Bionics, Lilly, and Sequel. The remaining authors have no personal or financial conflicts of interest to disclose.

Funding Information

E.V. is funded by the NIDDK T32 institutional training grant (5T32DK06387). T.M.T. is funded by K23 DK136931 and the Culshaw Family Junior Investigator Award. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Abbreviations Used

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